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The Alkaloids Chemistry and Biology Vol 60 1st Edition
Geoffrey A. Cordell (Ed.) Digital Instant Download
Author(s): Geoffrey A. Cordell (Ed.)
ISBN(s): 9780124695603, 0124695604
Edition: 1st
File Details: PDF, 4.76 MB
Year: 2003
Language: english
 CONTENTS

CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Clinical Studies of Camptothecin and Derivatives

OTTO SOEPENBERG, ALEX SPARREBOOM, AND JAAP VERWEIJ
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
III. Mutagenicity and Resistance Mechanisms . . . . . . . . . . . . . . . . . 7
IV. Irinotecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
V. Topotecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
VI. Considerations of Route of Administration . . . . . . . . . . . . . . . . 27
VII. Investigational Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . 29
VIII. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Tremorgenic and Nontremorgenic 2,3-Fused

Indole Diterpenoids
HEATHER SINGS AND SHEO SINGH
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
II. Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
III. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
IV. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
V. Structure and Tremorgenicity . . . . . . . . . . . . . . . . . . . . . . . . 155
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

The Daphniphyllum Alkaloids

JUN’ICHI KOBAYASHI AND HIROSHI MORITA
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
II. Structures of Representative Alkaloids . . . . . . . . . . . . . . . . . . . 170
III. Biosynthesis and Biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 184
IV. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
V. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

v
vi CONTENTS

The Manzamine Alkaloids

JIN-FENG HU, MARK T. HAMANN, RUSSELL HILL,
AND MICHELLE KELLY

I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
II. Isolation and Structure Elucidation from Marine Sponges . . . . . . . . 214
III. Biogenesis and Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . 223
IV. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
V. Pharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
VI. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

Sesquiterpene Pyridine Alkaloids

LUCIANO M. LIÃO
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
II. Evoninate Sesquiterpene Pyridine Alkaloids and Derivatives . . . . . . . 289
III. Wilfordate Sesquiterpene Pyridine Alkaloids and Derivatives . . . . . . 307
IV. Edulinate Sesquiterpene Pyridine Alkaloids . . . . . . . . . . . . . . . . 315
V. Cassinate Sesquiterpene Pyridine Alkaloids . . . . . . . . . . . . . . . . 317
VI. Lower Molecular Weight Sesquiterpene Pyridine Alkaloids. . . . . . . . 317
VII. Non-Celastraceous Sesquiterpene Pyridine Alkaloids . . . . . . . . . . . 318
VIII. Biosynthesis and Biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 322
IX. Biological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
X. Taxonomic Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . 334
XI. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Chemical and Biological Aspects of Melanin

D.P. CHAKRABORTY AND SHYAMALI ROY
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
II. Biogenesis of Melanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
III. Natural Melanins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
IV. Investigations of Melanins by Physical Methods. . . . . . . . . . . . . . 373
V. Synthetic Melanins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
VI. Physicochemical Properties and Biological Functions of Melanins . . . . 379
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
 CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

D.P. CHAKRABORTY (345), Institute of Natural Products, Calcutta 700 036, India

MARK T. HAMANN (207), Department of Pharmacognosy and National Center for

the Development of Natural Products (NCNPR), School Pharmacy, The
University of Mississippi, University, Mississippi, USA

RUSSELL HILL (207), The Center of Marine Biotechnology (COMB), University of

Maryland Biotechnology Institute, Columbus Center, Baltimore, MD, USA

JIN-FENG HU (207), Department of Pharmacognosy and National Center for the

Development of Natural Products (NCNPR), School Pharmacy, The University of
Mississippi, University, Mississippi, USA

MICHELLE KELLY (207), National Center for Aquatic Biodiversity and Biosecurity,
National Institute of Water and Atmospheric Research (NIWA) Ltd., Newmarket,
Auckland, New Zealand

JUN’ICHI KOBAYASHI (165), Graduate School of Pharmaceutical Sciences,

Hokkaido University, Sapporo 060, Japan

LUCIANO M. LIÃO (287), Instituto de Quimica, Universidade Federal de Goiás,

Goiânia, GO, 74001-970, Brazil

HIROSHI MORITA (165), Graduate School of Pharmaceutical Sciences, Hokkaido

University, Sapporo 060, Japan

SHYAMALI ROY (345), Institute of Natural Products, Calcutta 700 036, India

SHEO SINGH (51), Merck Research Laboratories, Rahway, NJ 07065, USA

HEATHER SINGS (51), Merck Research Laboratories, Rahway, NJ 07065, USA

OTTO SOEPENBERG (1), Department of Medical Oncology, Erasmus MC – Daniel

den Hoed Cancer Center, Rotterdam, The Netherlands

vii
viii CONTRIBUTORS

ALEX SPARREBOOM (1), Department of Medical Oncology, Erasmus MC – Daniel

den Hoed Cancer Center, Rotterdam, The Netherlands

JAAP VERWEIJ (1), Department of Medical Oncology, Erasmus MC – Daniel den

Hoed Cancer Center, Rotterdam, The Netherlands
 PREFACE

This volume marks the 60th in this series, which began publication in 1950
under the editorship of the late Professor R.H.F. Manske. Through the
successive editorships of Professor Russell Rodrigo and Dr. Arnold Brossi, the
series evolved in scope in an effort to try to keep up with the burgeoning field of
‘‘alkaloids.’’ As Editor, I have tried to continue this evolutionary process,
blending together diverse chapters on the discovery, biological evaluation, and
clinical applications of alkaloids. In this volume, the six chapters reflect areas
of alkaloid research which are new to the series and others which require
updating because of the recent progress.

In Chapter 1, Soepenberg, Sparreboom, and Verweij present a detailed

discussion of the clinical aspects of camptothecin, one of the most important
alkaloids to be studied in the past 40 years. In Chapter 2, Sings and Singh
describe the various 2,3-fused indole diterpenoid derivatives and their powerful
biological effects. A much needed update on the Daphniphyllum alkaloids is
offered by Kobayashi and Morita in Chapter 3.

A significant group of marine alkaloids, the manzamines, which have

attracted a lot of interest in the past few years, is reviewed by Hamann and
colleagues in Chapter 4, and Lião summarizes in Chapter 5 the advances that
have been made in the sesquiterpene alkaloids, a group not reviewed previously
in the series. Finally, following the untimely death of Professor D.P.
Chakraborty, Dr. Shyamali Roy agreed to complete the work of updating the
field of melanin chemistry and biology.

Geoffrey A. Cordell
University of Illinois at Chicago

ix
 —CHAPTER 1—

CLINICAL STUDIES OF CAMPTOTHECIN

AND DERIVATIVES

OTTO SOEPENBERG, ALEX SPARREBOOM, AND JAAP VERWEIJ

Department of Medical Oncology, Erasmus MC – Daniel den Hoed Cancer

Center, Rotterdam, The Netherlands

I. Introduction
II. Mechanisms of Action
III. Mutagenicity and Resistance Mechanisms
IV. Irinotecan
V. Topotecan
VI. Considerations of Route of Administration
VII. Investigational Derivatives
VIII. Conclusions
References

I. Introduction

About a half century ago, thousands of natural products were chemically

screened in a program initiated by the National Cancer Institute to search for
steroidal sapogenins which would be cortisone precursors. This program led to the
discovery of the plant alkaloids, the camptothecins (CPTs) – isolated from the stem
wood of the Chinese tree Xi Shu or Camptotheca acuminata (Decaisne, Nyssaceae)
(1–5). Initial in vitro and in vivo studies using the chloroform extract of the aqueous
ethanolic residue of C. acuminata suggested widespread antitumor activity (2,3).
Camptothecins are related to the monoterpenoid indole alkaloids, and the parent
alkaloid was shown to be a high-melting substance [molecular weight (MW)
348.111] comprising a unique and highly unsaturated pentacyclic-ring structure
(1,3). The structures of CPT and selected analogs are shown in Fig. 1.

The six-membered quinoline B-ring and the five-membered C-ring are

formed by a ring expansion and contraction sequence of reactions. The E-ring
presents a -hydroxylactone system which can undergo a pH-dependent reversible

THE ALKALOIDS, Vol. 60 Copyright ß 2003 Elsevier (USA)

ISSN: 0099-9598 1 All rights reserved
DOI: 10.1016/S0099-9598(03)60001-5
2 SOEPENBERG ET AL.

Figure 1. Lactone–carboxylate interconversion and chemical structures of six- and

seven-membered E-ring camptothecin analogs.

hydrolysis. Camptothecin forms the sodium salt of a hydroxy acid after adding
alkali and is relactonized on acidification. Both the E-ring and the D-ring, which
has a conjugated pyridone moiety, are essential structural features for the
antitumor activity of CPT (3).
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 3

Triggered by the preclinical antitumor activity, early Phase I clinical trials

were performed in the early 1970s using CPT as a water-soluble sodium salt
formulation, because of its ease of use as an intravenous (i.v.) formulation (6).
Although in the first Phase I study five, short-lasting partial remissions were
reported in 18 patients with primarily gastrointestinal cancers, these results could
not be confirmed in subsequent Phase I and II studies in the USA (7–9). In contrast,
a large program in the People’s Republic of China involving up to 1000 patients
treated with the sodium salt formulation of CPT reported favorable results, but for
a variety of reasons these had to be interpreted with caution (3). However,
unpredictable severe adverse events, i.e., life-threatening diarrhea, considerable
hemorrhagic cystitis, and myelosuppression, likely related to the poor aqueous
solubility of the parent compound, led to the suspension of the further development
of this antineoplastic agent during the next two decades. The recognition that the
nuclear enzyme DNA topoisomerase I was the prime target in the mechanism of
action of the CPTs, and the possibility to develop numerous semisynthetic CPT
analogs with improved aqueous solubility, and, in consequence, a more predictable
toxicity profile, resulted in renewed interest in these cytotoxic agents.

Currently, two CPT derivatives, irinotecan and topotecan, are registered for
use in oncologic practice. Irinotecan is registered for use in metastatic colorectal
cancer. Topotecan is approved for the treatment of patients with cisplatin-
refractory ovarian cancer and for small-cell lung cancer (SCLC) after the failure of
first-line chemotherapy. During the last 10 years, knowledge of the pharmaco-
kinetic and pharmacodynamic properties of the semisynthetic CPT analogs has
significantly increased. The next challenge in their development will be to maximize
efficacy and to minimize side effects in the treatment by biomodulation of
the pharmacokinetic and pharmacodynamic properties. For instance, the
pharmacological profile of irinotecan is extremely complex and the various
processes involved in drug elimination, either through metabolic breakdown or
excretion, likely impact substantially on interindividual variability in drug
handling. Strategies to individualize irinotecan administration schedules based on
patient profiles in enzyme and protein expression or by co-administration of
specific agents modulating side effects are under investigation (10). Once the results
of pharmacogenetics can be more crystallized, this may ultimately lead to more
selective or ‘‘tailor-made’’ dose scheduling for patients to adjust the ‘‘fine-tuning’’
administration of these agents.

In this review, we will focus on the clinically important aspects of the CPT
alkaloids with an emphasis on their mechanisms of action and resistance, their
pharmacokinetic and pharmacodynamic behavior, and their routes of administra-
tion.

II. Mechanisms of Action

The cytotoxic CPTs belong to the class of topoisomerase I inhibitors. DNA

topoisomerases are essential enzymes found in all nucleated cells. These enzymes
4 SOEPENBERG ET AL.

are involved in the regulation of DNA topology and are necessary for the
preservation of the integrity of the genetic material during DNA metabolism,
e.g., RNA transcription, DNA replication, recombination, chromatin remodeling,
chromatin condensation, and repair during cell division (11,12). Based on
their different reaction mechanism and cellular function, there are two types of
DNA topoisomerases (type I and type II). Their characteristics are summarized
in Table I.

Human topoisomerase I is a monomeric
91-kDa polypeptide of 765

amino acids encoded by an active-copy gene located on chromosome 20q12–13.2
and two pseudogenes on chromosomes 1q23–24 and 22q11.2–13.1 (13–15). The
coding sequence of the gene is split into 21 exons spread over at least 85 kilobase
pairs of human genomic DNA (16). The human topoisomerase I gene promoter is
influenced by positively and negatively acting transcription factors, which are
described in more detail elsewhere (16,17).

This protein is comprised of four major domains: a highly charged NH2-

terminal domain (MW 24 kDa), a conserved core domain (MW 56 kDa), a

TABLE I.
Differentiation of Human DNA Topoisomerases Type I and II.

Type I topoisomerase
– Monomeric protein, molecular weight
91 kDa
– Single-copy gene located on chromosome 20q12–13.2
– Transiently breaks one strand of duplex DNA and forms a 30 -phosphotyrosine
covalent intermediate
– Single-step changes in the linking number of circular DNAs
– Its expression is continuous during the cell cycle and in quiescent cells
– Mainly involved in relaxation of supercoiled DNA during RNA transcription
– ATP independent
Type II topoisomerase
– Homodimeric protein, molecular weight 170 kDa (isoenzyme II ) and 180 kDa
(isoenzyme II )
– Single-copy gene located on chromosome 17q21–22 (isoenzyme II ) and
chromosome 3p24 (isoenzyme II )
– Breaks both strands of duplex DNA and forms a pair of 50 -phosphotyrosine
covalent intermediates
– Generates a gate through which another region of DNA can be passed
– Double-step changes in the linking number of circular DNAs
– Its expression increases during S-phase of the cell cycle (especially isoenzyme II )
and almost absent in quiescent cells (primarily expression of isoenzyme II )
– Involved in DNA replication, recombination, RNA transcription, and repair
– ATP dependent
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 5

positively charged linker domain (MW 7 kDa), and a highly conserved COOH-
terminal domain (MW 6 kDa) containing the active-site thyrosine, i.e., the
nucleophilic Tyr723 amino acid residue (15,18). Human topoisomerase promotes the
relaxation of both positively and negatively torsionally strained (supercoiled)
duplex DNA with equal efficiency so that transcription and replication can proceed
(15). Hereby, a transesterification reaction takes place by which topoisomerase
I cleaves one strand of the double-helix structure of DNA using the C4-oxygen
atom of the active-site tyrosine (Tyr723) residue and constitutes a transient, covalent
phosphotyrosyl intermediate with the 30 end of the nicked DNA strand, the
so-called cleavable complex. This way it changes the linking number in single steps
(15,19). Later, the energy of this covalent attachment is recycled for the reverse
transesterification reaction that reseals the DNA strands (religation) and liberates
the enzyme. Consequently, for these intertwining processes neither energy cofactors
nor metal cations are required by human topoisomerase I (20).

Recent studies have revealed more detailed insights in the three-dimensional

structure of human topoisomerase I and its interactive function with the DNA
molecule (21,22). In Table II, the principal structural characteristics of human
topoisomerase I are summarized.

The mechanism of DNA relaxation after formation of the covalent complex

and before religation is still not completely elucidated (21). So far, two mechanisms
are supposed, viz. the strand-passage model and the free-rotation model. Both
models represent the two extremes of a continuum in the conceptual framework
for how topoisomerase I might effect changes in linking number (21,22). In the
strand-passage (or enzyme-bridging) model, it is hypothesized that the intact DNA
strand is passed through an enzyme-bridged gate, which is made by the covalent
linkage of the 30 end and by noncovalent binding to the 50 end of the broken strand.
On the other hand, in the free-rotation model, relaxation of torsonially strained
duplex DNA is possible due to releasing of the 50 end of the broken strand from the
active site and as a result is allowed to rotate freely about the complementary
unbroken strand (15,22). X-Ray crystallographic studies with complexes of human
topoisomerase I and DNA lead to the proposal that the relaxation of supercoiled
DNA elapsed by a controlled rotation mechanism (21,22).

In the controlled rotation model, the DNA structure is allowed to rotate

completely free at 30 intervals downstream of the cleavage site round the intact
DNA strand modulated by the interaction of the nose-cone helices of subdomains I
and II in a positively charged cavity formed by the cap of the enzyme and the linker
domain (15). In vitro studies with reconstituted human topoisomerase I have
revealed the more precise function of the linker region. During the normal
relaxation of supercoiled DNA it acts to slow the religation (18). From these
studies, it is also hypothesized that the inhibition of DNA relaxation caused by
CPT – by stabilizing the cleavable complex – depends on a direct effect of the
cytotoxic agent on DNA rotation which is mediated by electrostatic interactions
between the linker domain and DNA (18).
6 SOEPENBERG ET AL.

TABLE II.
Structural Characteristics of Human DNA Topoisomerase Type I.

Two domains with essential functions for catalytic activity and relaxation function
I. Core domain (MW 56 kDa)
– Amino acid residues 215–635 (Ile215–Arg635)
– Subdomain I
– Amino acid residues 215–232 and 320–433
– Two helices and nine strands
– Subdomain II
– Amino acid residues 233–319
– Five helices and two strands
– Subdomain III
– Amino acid residues 434–635
– Ten helices and five strands
– Contains all active-site residues except the Tyr723
– Extends from the top half of the molecule downward through two long
helices that functions like a hinge that opens and closes the enzyme around
the DNA
j Subdomains I and II are folded tightly together and form the ‘‘cap’’ (top-lobe)
region of the enzyme
j Subdomains I and II have two long ‘‘nose-cone’’ helices ( 5 and 6) that make
an
90 angle with each other and come together in a ‘‘V’’-figure at a point 25 Å
away from the body of the molecule, and enclose a triangular-shaped empty
space between them
j Subdomain III forms the bottom lobe of the enzyme
j Subdomains I and III interact via two short ‘‘lips’’ opposite from the long-hinge
helices
II. COOH-terminal domain (MW 6 kDa)
Amino acid residues 713–765 (Gln713–Phe765)
Contains the active-site (catalytic) thyrosine Tyr723
Two domains without essential functions for catalytic activity and
relaxation function
III. NH2-terminal domain (MW 24 kDa)
– Amino acid residues 1–214 (Met1–Gly214)
– Highly charged, very few hydrophobic amino acids, is largely disordered, and
contains several nuclear-targeting signals
– Involved in nucleolar localization through interactions with nucleolin
IV. Linker domain (MW 7 kDa)
– Amino acid residues 636–712 (Pro636–Lys712)
– Coiled-coil structure that is positively charged
– Reaches 50 Å away from the body of the enzyme
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 7

When the attachment of CPT is modeled in the three-dimensional structure

of human topoisomerase I, it is believed that the DNA duplex is extended in such
a way that carbon positions 7 and 9 of the CPT structure are facing out into
open space. These carbon positions are very accessible to chemical modifications.
Consequently, this gives the opportunity to expand the potency of modified
CPT analogs by auspicious interactions of these derivatives with distant proteins or
DNA atoms at the binding site (22).

Stabilization of the cleavable complex by CPTs is not sufficient in itself for

the induction of cell death because the complex can reverse spontaneously in a
short time. The lethal effects of these drugs are caused by the interaction between a
moving replication fork (or transcription process) and the drug-stabilized cleavable
complex, resulting in irreversible arrest of DNA replication and the formation of
a double-strand break located at the fork. This so-called fork-collision model
leads to the arrest of the cell cycle in the S/G2-phase, and finally to apoptosis (23).
As cells in the S-phase division are up to 1000-fold more sensitive to topoisomerase
I inhibitors than cells in G1- or G2/M-phases after exposure, the cytotoxicity of
these agents is considered S-phase specific (24–27).

The time of persistence of the drug-stabilized cleavable complex depends

on the production and/or repair of replication or transcription lesions. In
general, transcription lesions require longer persistence, i.e., greater stability of the
cleavable complex, than do replication lesions (28). Unfortunately, the fraction of
replicating cells in tumor tissues is underrepresented. This means that cell kill
results predominantly from the transcription lesion mechanism. For this reason,
the potency of different CPT analogs to stabilize the cleavable complex is of
paramount importance for efficacious therapeutic use (28). Of relevance for all
topoisomerase I inhibitors are the data from in vitro experiments which revealed
that the cytotoxicity increases with the duration of exposure. Short-time exposures
to high concentrations are less effective than long-term exposures to low
concentrations (29,30).

III. Mutagenicity and Resistance Mechanisms

Owing to their mechanism of action, topoisomerase I inhibitors are a

double-edged sword, because besides their cytotoxic properties, these agents are
potential mutagens, although their mutagenicity and oncogenicity still remain to be
elucidated (31–33). This is stressed by the fact that mutations may lead to drug
resistance, limiting further treatment, or to the development of secondary
malignancies. If mutations arise in germ cells, this could eventually be transmitted
to subsequent generations. Furthermore, the tendency to administer topoisomerase
I inhibitors in protracted schedules or prolonged exposure regimens could
hypothetically lead to an increased risk of mutagenicity (34,35).

The stabilization of the cleavable complexes by topoisomerase I inhibi-

tors disrupts the DNA integrity and interferes with the normal processes of
8 SOEPENBERG ET AL.

DNA topology, including replication, transcription, DNA repair, chromosome

condensation, and chromosome separation (31). The formation of these drug-
induced cleavable complexes is essential, but is not sufficient in itself to cause
cytotoxicity. This implies that cells need to undergo DNA synthesis to yield
maximum toxicity (31,36–38). Experimental studies showed that in the presence of
topoisomerase II inhibitors chromosomal aberrations arise during replication
which seems a more important cause of cytotoxicity (31,36,39). Furthermore, it was
postulated that recombination processes must be initiated to bypass the replication
block created by topoisomerase II inhibitor-stabilized complexes, and that some
of these events cause aberrant, illegitimate, or nonhomologous recombination,
which may lead to cytotoxicity and/or mutations. Nonhomologous recombination
that causes deletions of an essential gene, partially or completely, resulted in the
loss of gene products and finally to cell death. In contrast, aberrant recombination
or rearrangement causing deletion of a suppressor gene, or activation of a
proto-oncogene, stimulated cell growth with the potential to induce secondary
cancers (31).

Similar data exist for topoisomerase II inhibitors (31), one use of which has
been related to the occurrence of acute myeloid leukemia (40–51). These secondary
leukemias are characterized by a short induction period and present as
myelomonocytic or monocytic leukemia, rather than myelodysplasia (52). The
rearrangements are usually distinguished by balanced chromosomal translocations
involving either the MLL (ALL-1, HRX) gene at 11q23 or the AML1 gene
21q22 (53,54).

In principle, topoisomerase I inhibitors can produce similar molecular

alterations as those caused by topoisomerase II inhibitors. Consequently, they may
have similar clinical consequences (31). Direct comparative in vitro studies have
shown that, on a molar basis, the topoisomerase I inhibitors were more mutagenic
than the topoisomerase II-inhibitor etoposide (31). Topotecan was found to be less
mutagenic than the parent compound CPT.

So far, the clinical use of topoisomerase I inhibitors has not been linked to
secondary malignancies. However, the relative survival time of patients treated with
irinotecan or topotecan as compared with those treated with epipodophyllotoxins
(e.g., testicular cancer or hematological malignancies) possibly results in a less
clinically apparent mutagenic risk of topoisomerase I inhibitors.

As with decreased levels of topoisomerase I, various point mutations of

topoisomerase I in different CPT-resistant cell lines have been associated with CPT
resistance (55–63). The different point mutations in human topoisomerase I in
several CPT-resistant cell lines are summarized in Table III. These point mutations
cause alterations to the topoisomerase I enzyme, resulting in decreased
topoisomerase I catalytic activity or impaired binding of CPT to topoisomerase I
(55,64). In some models, single amino acid changes resulted in partial resistance,
while double mutation induced a synergistic resistance (55).
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 9

TABLE III.
Different Point Mutations of Human Topoisomerase I.

CPT-resistant cell line Point mutation Reference

CPTR-2000 cell line Gly717 to Val, and Thr729 to Ile (55)

CPT-K5 cell line Asp533 to Gly*, and Asp583 to Gly (58)
Asp583 to Gly
PC-7/CPT cell line Thr729 to Ala (59)
By in vitro mutagenesis Gly363 to Cys (60)
Chinese hamster DC3F/C-10 Gly505 to Ser (62)
U-937/CR cell line Phe361 to Ser (63)

*Only Asp533 to Gly is responsible for resistance.

In a small clinical study involving eight non-small cell lung cancer (NSCLC)
patients treated with irinotecan, two-point mutations were identified that were
located near a site in topoisomerase I that was previously identified as a position
of a mutation in the CPT-resistant human lung cancer cell line PC7/CPT (64).
Although this is the first prospective clinical study which demonstrates that point
mutations in topoisomerase I occur after chemotherapy with irinotecan, further
clinical studies will be needed to verify if the occurrence of topoisomerase I gene
mutations relates to the occurrence of clinical resistance to topoisomerase I
inhibitors (64).

IV. Irinotecan

A. CLINICAL PHARMACOLOGY

Irinotecan (CPT-11; 7-ethyl-10-{4-[1-piperidino]-1-piperidino}-carbonyl-

oxycamptothecin) is a semisynthetic, water-soluble prodrug that requires hydrolysis
or de-esterification by carboxylesterases to form its active-metabolite SN-38
(7-ethyl-10-hydroxycamptothecin), which is 100–1000-fold more cytotoxic in vitro
than the parent compound (65). Irinotecan contains a dibasic, bispiperidine
substituent, linked through a carbonyl group to the hydroxyl at C-10, crucial for
water solubility.

Irinotecan pharmacology is extremely complex and still the subject of

research (65). It is known to be dependent on various enzyme and protein systems
for metabolic transformation and active transport, all regulating intestinal
absorption and hepatobiliary secretion mechanisms. Both irinotecan and SN-38
exist in an active lactone form and an inactive carboxylate form, through
an equilibrium that depends on the pH and the presence of binding proteins (65).
SN-38 is detoxified in the liver by the polymorphic enzyme uridine-diphosphate
glucuronosyltransferase 1A1 (UGT1A1) to SN-38 glucuronide (SN-38G) (66). This
isoenzyme is also responsible for bilirubin glucuronidation (67). Because of this,
10 SOEPENBERG ET AL.

patients with hereditary UGT enzyme polymorphism – e.g., familial hyperbili-

rubinemia conditions (Crigler–Najjar syndrome types I and II or Gilbert’s
disease) – are at increased risk for irinotecan-induced diarrhea due to decreased
glucuronidation of SN-38 (68).

Irinotecan showed a linear pharmacokinetic behavior (69–73). Both the

lactone form and the carboxylate form of irinotecan and SN-38 are detectable in
plasma shortly after i.v. administration (74). The AUC of SN-38 is only
approximately 4% of the AUC of irinotecan, which means that only a small
fraction of the dose is converted to the active form. After administration of
irinotecan as a short-time i.v. infusion over 30–90 min, there is a three-exponential
decline of the plasma concentration of the drug (75). The biological half-life of the
lactone form of SN-38 is 11.5 h. This is much longer than for other CPTs, for
instance topotecan (70,74). The clearance of irinotecan lactone (53.5 l/h/m2) is
approximately two times larger than that of topotecan. At steady state, the mean
volume of distribution of the total drug is 142 l/m2, representing approximately
four times the total body weight (74). When irinotecan is administered as a
protracted i.v. infusion over 7–21 days, the plasma levels of irinotecan, SN-38, and
SN-38G are comparable on days 7, 14, or 21 during the infusion. The AUC ratio of
SN-38 to irinotecan was 16% and was constant over the tested dose range (76).
This metabolic ratio was higher compared with the ratios found after short-time
infusion, namely 3–9%. This partly explains the relatively low maximum-tolerated
doses (MTDs) achieved with the continuous infusion regimens, which are thus due
to the greater conversion of irinotecan to the cytotoxic-metabolite SN-38.

Recently, Xie et al. reported a population analysis in 70 cancer patients on

the clinical pharmacokinetics of irinotecan and four of its metabolites (77). These
authors found that the interconversion between the lactone and carboxylate forms
of irinotecan was relatively rapid, with an equilibration half-life of 14 min in the
central compartment and hydrolysis occurring at a rate five times faster than
lactonization. Also, the same interconversion took place in the peripheral
compartments. The irinotecan lactone form had extensive tissue distribution (Vss,
445 l) in comparison with the carboxylate form (Vss, 78 l, excluding peripherally
formed irinotecan carboxylate) (77). The clearance of the lactone form (74.3 l/h)
was higher than the carboxylate form (12.3 l/h). These models revealed that there
was a preference of SN-38 and NPC to be formed out of the lactone form of
irinotecan, whereas APC could be modeled best by presuming formation from
irinotecan carboxylate (77). The interconversion between SN-38 lactone and
carboxylate was slower than that of irinotecan. SN-38 lactone is more tightly
bound to serum albumin than the carboxylate form, and for this reason the
dynamic equilibrium is preferential toward the lactone form. Although the
clearances for SN-38 lactone and carboxylate were similar, the lactone form had
more extensive tissue distribution (77).

Diarrhea originates from intestinal epithelium cell damaged by SN-38.

This reversible reaction can be modulated by changing the intestinal flora using
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 11

Figure 2. Summary of irinotecan-elimination (CPT-11) routes, showing esterase- (hCE1

and hCE2) mediated conversion to the active-metabolite SN-38, its further conjugation
into the glucuronic-acid derivative SN-38G by UGT1A1, the reversible deconjugation
by bacterial beta-glucuronidase (Beta-Glu), CYP3A-mediated conversion to the
oxidized derivatives APC and NPC, P-glycoprotein- (ABCB1) mediated cellular efflux
of irinotecan, and MDR1- (ABCC1), cMOAT- (ABCC2), and BCRP- (ABCG2)
mediated transport of SN-38.

antibiotics, e.g., neomycin or other beta-glucuronidase inhibitors, such as

cyclosporin A, which inhibits the cMOAT-mediated biliary excretion of
SN-38 (78,79). Furthermore, cytochrome P-450 3A4 (CYP3A4) metabolizes
irinotecan into several oxidized derivatives, including APC (7-ethyl-10-[4-N-5-
aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin) and NPC (7-ethyl-
10-[4-N-(-1-piperidino)-1-amino]-carbonyloxycamptothecin) (71,80–83). The
various genes with a putative role in irinotecan disposition are shown in Fig. 2.
Both metabolites are also poor inhibitors of topoisomerase I and only the minor-
metabolite NPC can be further converted to SN-38 (74,83,84). Because CYP3A4
is involved in the biotransformation of many other drugs, there is a potential
risk of clinically relevant drug interactions. A Phase I study of irinotecan in
malignant glioma patients revealed that the clearance of irinotecan was significantly
faster in patients who required cotreatment with anticonvulsants and glucocorti-
coids – inducers of the CYP3A4 enzyme – as compared with patients who did not
12 SOEPENBERG ET AL.

receive such concomitant treatment (85). A recent investigation indicates that a

significant interaction occurs between irinotecan and the herbal product
St. John’s wort because of CYP3A4 induction, resulting in 42% decreased
circulating concentrations of SN-38 (86). In contrast, inhibition of CYP3A4
activity, for example by ketoconazole, leads to substantially increased exposure
(
two-fold) to SN-38 (87). It has also been shown that the sequence of treatment
with irinotecan and infusional 5-FU affects the tolerability of this combination,
with the SN-38 area under the concentration versus time curve (AUC) being
40% lower (P<0.05) when irinotecan preceded 5-FU. This suggests that well-
defined 5-FU/irinotecan regimens are needed because the administration sequence
or the interval between the agents might affect treatment tolerance and perhaps
also activity (88).

Elimination of irinotecan occurs primarily in the feces via hepatobiliary and

intestinal secretion and secondarily in the urine (89). Approximately, 50% of the
total administered dose of irinotecan is recovered in urine (28%) and feces (25%) as
unchanged parent compound or its inactive metabolites (81). The hepatobiliary
elimination route is dependent on the presence of drug-transporting proteins,
notably P-glycoprotein and canalicular multispecific organic anion transporter
(cMOAT), present on the bile canalicular membrane (10). Because of the close
connection of irinotecan with liver biotransformation and elimination, the drug
should not be administered in case of increased bilirubin concentrations or elevated
transaminases (68,90).

The cytotoxic activity of SN-38 is performed by producing intermediate

forms of drug-stabilized covalent DNA/topoisomerase I complexes, also referred
earlier as the cleavable complexes, as outlined previously. SN-38 exerts this
cytotoxic function by trapping cleavable complexes instead of inhibiting
topoisomerase I enzyme function. Antitumor activity of CPT analogs can be
predicted in vitro based upon gene-copy number, mRNA content, and protein
expression of topoisomerase I (90). The fact that in human tumor samples from
colon cancer, there was increased topoisomerase I expression and activity as
compared to normal mucosa, could partly explain the activity of irinotecan in this
disease (90–93).

B. DOSE-FINDING TRIALS

Phase I studies were performed first in Japan, later in the USA and Europe.
The recommended regimen of irinotecan in the USA is 125 mg/m2 administered
as a 90-min i.v. infusion once weekly for 4 or 6 weeks (70). In Europe, the approved
administration schedule of irinotecan is 350 mg/m2 given as an i.v. infusion
over 60–90 min once every 3 weeks (94), while a recent reevaluation indicated a
maximum-tolerable dose of 320 mg/m2, or 290 mg/m2 in patients with prior
abdominal/pelvic radiation therapy (95). Finally in Japan, the administration
schedule of irinotecan was developed as 100 mg/m2 every week or 150 mg/m2
every other week (96). Remarkably, the dose intensity (DI) of all applied dosage
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 13

regimens of irinotecan is approximately 100 mg/m2/week, which suggested a

schedule independency. This phenomenon can be explained by the long
half-life of SN-38, which is achieved after a single dosage of irinotecan.
Although the half-life of SN-38 does not fully support this approach, in an effort
to further explore the possible therapeutic advantage of prolonged exposure
to CPTs, protracted or repeated dosing regimens of irinotecan have been studied.
Irinotecan was administered as a short infusion repeated on 5 consecutive days,
as a 4-day i.v. continuous infusion weekly for 2 weeks every 3 weeks, and as a
14-day continuous i.v. infusion every 3 weeks (97). Since protracted i.v.
infusion is inconvenient for patients, an oral formulation of irinotecan is also
under study (71).

In the transatlantic Phase I clinical trials, the maximum DI of irinotecan

was achieved with short-time i.v. infusion once every 2 or 3 weeks (mean DI
125 mg/m2/week; range, 80–167 mg/m2/week), whereas the lowest DI was achieved
with continuous i.v. infusion (DI 27 and 47 mg/m2/week). In the
weekly  4 schedule and the daily i.v. infusion over 3 or 5 consecutive days, the
mean calculated DI was 83 mg/m2/week (range, 73–100 mg/m2/week). Thus,
the maximum DI achieved with prolonged exposure schedules of irinotecan is
2–3 times lower than that achieved with short-infusion administration. But, as
indicated previously, irinotecan is more effectively converted to SN-38
during protracted i.v. infusion. The SN-38 to irinotecan AUC ratios ranged from
16% to 24% (97). After oral administration of irinotecan, the absolute
bioavailability of the drug based on lactone measurements is relatively low (74).
However, the SN-38 to irinotecan AUC ratio, expressed on a molar basis, is
three times greater after oral administration than after i.v. infusion. Possibly, the
first-pass conversion of irinotecan to SN-38 in the intestine and liver could explain
this observation (74).

The principal dose-limiting toxicity (DLT) for all schedules used

was delayed diarrhea, with or without neutropenia (70,94,96). The frequency of
severe diarrhea (grade 3 or 4) was reported as 35% in the Phase I studies.
The incidence of this toxicity can be reduced by more than 50% if an
intensive treatment with loperamide is used as described in the safety guidelines in
Table IV (98).

Neutropenia was dose related, generally of brief duration and noncumu-

lative, and occurred in 14–47% of patients treated once every 3 weeks and less
frequently using the weekly schedule (12–19%) (98–102). In approximately 3% of
patients, the neutropenia was associated with fever. In one Phase I study, where
irinotecan was given as a 96-h continuous infusion for 2 weeks every 3
weeks, thrombocytopenia was also dose limiting (103). Due to inhibition of
acetylcholinesterase activity by irinotecan within the first 24 h after dosing of the
drug, an acute cholinergic reaction can be observed. The symptomatology of this
syndrome, as well as the other nonhematological toxicities of irinotecan, is
summarized in Table V.
14 SOEPENBERG ET AL.

TABLE IV.
Safety Guidelines for the Use of Irinotecan.

d Proper patient selection according to known risk factors:

– For severe neutropenia: Performance status; serum bilirubin level
– For severe diarrhea: Performance status; prior abdominopelvic radiation therapy,
hyperleucocytosis
d Proper training of the treating medical oncologist and his staff, and extensive
information to the patient:
– Including patient’s information leaflet about management of toxicities
d Early use of high-dose loperamide as soon as the first loose stool occurs.
– Recommendation:
4 mg Loperamide for the first intake and then 2 mg every 2 h at least
12 h After the last loose stool for a maximum of 48 h
d Early use of oral broad-spectrum antibiotics (e.g., fluoroquinolone) in case of:
– Any grade 4a diarrhea
– Febrile diarrhea
– Diarrhea with concomitant grade 3a or 4 neutropenia
– Failure of a 48-h high-dose loperamide therapy
d Dose reduction in case of:
– Grade 4 neutropenia (even asymptomatic)
– Grade 3 neutropenia concomitant with fever and/or infection
– Severe diarrhea
d Contraindication for use in patients with:
– WHOb performance status >2
– Predictable poor compliance
– Baseline serum bilirubin >1.5  UNLc
d Treatment only with caution and close survey between cycles in patients with:
– WHO performance status ¼ 2
– Baseline serum bilirubin between 1 and 1.5  UNL
– Prior abdominopelvic radiation therapy
– Baseline hyperleucocytosis
a
Grade 3 and 4 according to NCI common toxicity criteria (version 2.0).
b
WHO, World Health Organization.
c
UNL, upper normal limit.

C. ANTITUMOR EFFICACY

Phase II studies consistently revealed response rates of 10–35% to single-

agent irinotecan in advanced or metastatic colorectal cancer (89,90,104,105),
independent of the applied schedules. There was no apparent difference between the
applied schedules with respect to the median remission duration and median
survival time, respectively 6–8 months and 8–13 months (90).
 CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES 15

TABLE V.
Main Toxicities of Irinotecan.

Hematological
a a
d Grade 3 and 4 neutropenia
– Dose and schedule dependent
– Lowest frequencies in protracted dose regimens
– Reversible, noncumulative, and of short duration
– Febrile neutropenia occurred in about 3% of patients
Nonhematological
d Acute cholinergic-like syndrome ( 9% of patients)
– Caused by rapid and reversible inhibition of acetylcholinesterase by lactone form
of irinotecan and can be induced by co-administration of oxaliplatin
– Symptoms may occur shortly or within several hours after drug administration,
and are short lasting, never life threatening
– Symptoms: diarrhea, gastrointestinal cramps, nausea, vomiting, anorexia,
asthenia, diaphoresis, chills, malaise, dizziness, visual-accommodation distur-
bances, salivation, lacrimation, and asymptomatic bradycardia
– Responsive to and preventable by subcutaneous administration of 0.25–1.0 mg
atropine
d Delayed-onset diarrhea
– Could be severe and unpredictable at all dose levels with increased intensity and
frequency at higher dose levels ( 34% of patients grade 3 or 4 after use of
loperamide) and occurred later than 24 h after drug administration with peak
incidence at day 5 or 6
d Nausea and vomiting ( 86% of patients, but  19% grade  3)
– Manageable with 5-HT3 antagonists
d Other common toxicities
– Fatigue ( 17%), mucositis ( 12%), skin toxicity ( 5%), asthenia, alopecia,
and elevated liver transaminases
d Less common toxicities
– Pulmotoxicity (pneumonitis), cardiotoxicity (bradycardia), microscopic hema-
turia, cystitis, dysarthria, and immune thrombocytopenia
a
Grade 3 and 4 according to NCI common toxicity criteria (version 2.0).

In a randomized Phase III study, comparing treatment with irinotecan

given as a 300–350 mg/m2 i.v. infusion every 3 weeks to best-supportive care
in patients refractory to previous treatment with 5-FU based chemotherapy, the
one-year survival rate was significantly greater for the irinotecan-treated group
than for the control group, 36% and 14% (P<0.01), respectively (99). Another
randomized Phase III study, comparing treatment with irinotecan to three different
continuous i.v.-infusion schedules of 5-FU in patients with previously treated
advanced colorectal cancer, revealed a survival advantage for the irinotecan-treated
group in comparison to the 5-FU-treated group (100). The one-year survival
rates were 45% and 32%, respectively (P<0.05).
Discovering Diverse Content Through
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up. He thinks now the Creator put into my heart to do that—doesn’t
give himself a bit of credit for it!”
He laughed reminiscently.
“I don’t suppose he has seen six hundred pounds to spend since he
bought that pony! He has had a hard row to hoe all his life, and
never did an ounce of harm to any living thing, yet at the first turn of
good luck, he fairly oozes thankfulness to the Almighty. He is a
churchman clear through. He believes in revealed religion—though
no religion ever is revealed—and yet he doesn’t mistake theology for
Christianity. He positively doesn’t know the meaning of the word
cant. Ah—there goes another type!”
Gordon was looking at a square, mottle-faced man passing slowly on
the opposite side of the street, carrying a bundle of leaflets from
which now and then he drew to give to a passer-by. He was high-
browed, with eyes that projected like an insect’s and were flattish in
their orbits. He wore a ministerial cloak over his street costume.
“There’s Cassidy,” he said to himself. “Dr. James Cassidy, on shore
leave, distributing his little doctrinal tracts. I remember him well. He
is in the navy medical service, but it’s the grief of his life he can’t be
a parson. He talked enough pedantry over the ship’s table of the
Pylades, while I was coming home from Greece, to last me till the
resurrection. He is as ardent a predestinarian as any Calvinistic dean
in gaiters, and knows all the hackneyed catch-phrases of eternal
punishment. He has an itch for propaganda, and distributes his
tracts, printed at his own expense, on the street-corner for the glory
of theology. He is the sort of Christian who always writes damned
with a dash. And yet, I wonder how much real true Christianity he
has—Christianity like Dallas’, I mean. I remember that scar on his
cheek; it stands for a thrashing he got once at Bombay from a
deserting ensign named Trevanion—a youth I met in Greece
afterward, and had cause to remember, by the way!”
His eyes had darkened suddenly. His brows frowned, his firm white
hand ran over his curls as though to brush away a disagreeable
recollection.
“Cassidy would travel half around the globe to find the deserter that
thrashed him and land him in quod. That man would deserve it richly
enough, but would Cassidy’s act be for the good of the king’s
service? No—for the satisfaction of James Cassidy. Is that
Christianity? Dallas never treasured an enmity in his life. Yet both of
them believe the same doctrine, worship the same God, read the
same Bible. Does man make his beliefs? Or do his beliefs make
him? If his beliefs make man, why are Dallas and Cassidy so
different? If man makes his beliefs, why should I not make my own? I
will be an Anythingarian, and leave dreams to Emanuel
Swedenborg!”
His gaze, that had followed the clerical figure till it passed out of
sight, returned meditatively to the slaty white buildings opposite.
“Some people call me an atheist—I never could understand why,
though I prefer Confucius to the Ten Commandments and Socrates
to St. Paul,—the two latter happen to agree in their opinion of
marriage,—and I don’t think eating bread or drinking wine from the
hand of an earthly vicar will make me an inheritor of Heaven. Dallas
would tell me not to reason, but to believe. You might as well tell a
man not to wake but to sleep. Neither Cicero nor the Messiah could
ever have altered the vote of a single lord of the bed-chamber! And
then to bully with torments and all that! The menace of hell makes as
many devils as the penal code makes villains. All cant—
Methodistical cant—yet Dallas believes it. And both he and Cassidy
belong to the same one of the seventy-two sects that are tearing
each other to pieces for the love of the Lord and hatred of each other
—the sects that call men atheists because the eternal why will creep
into what they write. If it pleases the Church—I except Dallas—to
damn me for asking questions, I shall be only one with some millions
of scoundrels who, after all, seem as likely to be damned as ever. As
for immortality, if people are to live, why die? And our carcases, are
they worth raising? I hope, if mine is, I shall have a better pair of legs
than I have moved on these three-and-twenty years, or I shall be
sadly behind in the squeeze into Paradise!”
There was a knock at the door. He rose and opened it. It was
Hobhouse. Gordon caught up his hat and they left the hotel together.
As they crossed Park Place a woman, draggled and gin-besotted,
strayed from some Thames-side stews, sat on the worn stone base
of the fountain, leaning uncertainly against its bronze rim. Her
swollen lids hid her eyes and one hand, palm up, was thrown out
across her lap. Gordon drew a shilling from his pocket, and passing
his arm in Hobhouse’s, laid it in the outstretched hand. At the touch
of the coin, the drab started up, looked at him stupidly an instant,
then with a ribald yell of laughter she flung the shilling into the water
and shambled across the square, mimicking, in a hideous sort of
buffoonery, the lameness of his gait.
Gordon’s face turned ashen. He walked on without a word, but his
companion could feel his hand tremble against his sleeve. When he
spoke, it was in a voice half-smothered, forbidding.
“The old jeer!” he said. “The very riffraff of the street fling it at me! Yet
I don’t know why they should spare that taunt; even my mother did
not. ‘Lame brat!’ she called me once when I was a child.” He
laughed, jarringly, harshly. “Why, only a few days before I sailed from
England, in one of her fits of passion, she flung it at me. ‘May you be
as ill-formed in mind as you are in body!’ Could they wish me worse
than she?”
“Gordon!” expostulated the other. “Don’t!—”
He had no time to finish. A grizzled man in the dress of an upper
servant was approaching them, his rubicund face bearing an
unmistakable look of haste and concern.
“Well, Fletcher?” inquired Gordon.
“I thought your lordship had gone out earlier. I have been inquiring
for you at the clubs. This message has just come from Newstead.”
His master took the letter and read it. A strange, slow, remorseful
look overspread the passion on his face.
“No ill news, I hope,” ventured Hobhouse.
Gordon made no reply. He crushed the letter into his pocket, turned
abruptly and strode up St. James Street.
“His lordship’s mother died yesterday, Mr. Hobhouse,” said the valet
in a low voice.
“Good God!” exclaimed the other. “What a contretemps.”

A knot of loungers were seated under the chandeliers in the bow-

window of White’s Club as Gordon passed on his way to the coach.
Beau Brummell, élégant, spendthrift, in white great-coat and blue
satin cravat exhaling an odor of eau de jasmin, lifted a languid glass
to his eye.
“I’ll go something handsome!” cried he; “I thought he was in Greece!”
“He’s the young whelp of a peer who made such a dust with that
Satire he wrote,” Lord Petersham informed his neighbor. “Hero of the
sack story I told you. Took the title from his great-uncle, the madman
who killed old Chaworth in that tavern duel. House of Lords tried him
for murder, you know. Used to train crickets and club them over the
head with straws; all of them left the house in a body the day he
died. Devilish queer story! Who’s the aged party with the
portmanteaus? Valet?”
“Yes,” asserted some one. “The old man was here a while ago trying
to find Gordon—with bad news. His lordship’s mother is dead.”
“Saw her once at Newstead Abbey,” yawned Brummell, wearily,
dusting his cuffs. “Corpulent termagant and gave George no end of a
row. He used to call her his ‘maternal war-whoop.’ My own parents—
poor good people!—died long ago,” he added reflectively; “—cut
their throats eating peas with a knife.”
 CHAPTER VI
WHAT THE DEAD MAY KNOW

Gordon was alone in the vehicle, for Fletcher rode outside. He set
his face to the fogged pane, catching the panorama of dark hedges,
gouged gravelly runnels and stretches of murky black, with
occasional instantaneous sense of detail—dripping bank, sodden
rhododendron and mildewed masonry—vivid in a dull, yellow,
soundless flare of July lightning. A gauze of unbroken grayness, a
straggling light—the lodge. A battlemented wall plunging out of the
darkness—and Gordon saw the Abbey, its tiers of ivied cloisters
uninhabited since Henry the Eighth battered the old pile to ruin, its
gaunt and unsightly forts built for some occupant’s whim, and the
wavering, fog-wreathed lake reflecting lighted windows. This was
Newstead in which the bearers of his title had lived and died, the
gloomy seat of an ancient house stained by murder and insanity, of
which he was the sole representative.
What was he thinking as he sat in the gloomy dining-room, with
Rushton, the footman he had trained to his own service, standing
behind his chair? Of his mother first of all. He had never, even as a
child, distinguished a sign of real tenderness in her moments of
tempestuous caresses. His maturer years had grown to regard her
with a half-scornful, half good-humored tolerance. He had shrugged
at her tempers, dubbing her “The Honorable Kitty” or his “Amiable
Alecto.” His letters to her had shown only a nice sense of filial duty:
many of them began with “Dear Madam”; more had been signed
simply with his name. Yet now he felt an aching hope that in her
seclusion she had not seen the unkindest of the stories of him. His
half-sister—now on her way from the north of England—absorbed
with her family cares, would have missed the brunt of the attacks; his
mother had been within their range. He recalled with a pang that she
had treasured with a degree of pride a single review of his earliest
book which had not joined in the sneering chorus.
He pushed back his chair, dismissed the footman, and alone passed
to the hall and ascended the stair. At the turn of the balustrade a
shaded lamp drowsed like a monster glow-worm. In his own room a
low fire burned, winking redly from the coronetted bed-posts, and a
lighted candle stood on the dressing-table. He looked around the
familiar apartment a moment uncertainly, then crossed to a carved
cabinet above a writing-desk and took therefrom a bottle of claret.
The cabinet had belonged to his father, dead many years before.
Gordon thought of him as he stood with the bottle in his hand, staring
fixedly at the dull, carved ebony of the swinging door.
His father! “Mad Jack Gordon” the world had called him when he ran
away with the Marchioness of Carmathen to break her heart!
Handsome he had been still when he married for her money the
heiress of Gight, Gordon’s mother. A stinging memory recalled the
only glimpse he had ever had of that father—a tall man in uniform on
an Aberdeen street, looking critically at a child with a lame leg.
Gordon winced painfully. He felt with a sharper agony the sensitive
pang of the cripple, the shame of misshapenness that all his life had
clung like an old-man-of-the-sea. It had not only stung his childhood;
it had stolen from him the romance of his youth—the one gleam that
six years ago had died.
Six years! For a moment time fell away like rotten shale from about a
crystal. The room, the wine-cabinet, faded into a dim background,
and on this, as if on a theater curtain, dissolving pictures painted
themselves flame-like.
He was back in his Harrow days now, at home for his last vacation.
“George,” his mother had remarked one day, looking up from a letter
she was reading, “I’ve some news for you. Take out your
handkerchief, for you will need it.”
“Nonsense! What is it?”
“Mary Chaworth is married.”
“Is that all?” he had replied coldly; but an expression, peculiar,
impossible to describe, had passed over his face. He had never
afterward seen her or spoken her name.
“Mary!” he murmured, and his hand set down the bottle on the table.
Love—such love as his verses told of—he had come to consider
purely subjective, a mirage, a simulacrum to which actual life
possessed no counterpart. Yet at that moment he was feeling the
wraith of an old thrill, his nostrils smelling a perfume like a dead
pansy’s ghost.
He withdrew his hand from the bottle and his fingers clenched. How
it hurt him—the sudden stab! For memory had played him a trick; it
had dragged a voice out of the past. It was her voice—her words that
she had uttered in a careless sentence meant for other ears, one
that through those years had tumbled and reëchoed in some under
sea-cavern of his mind—“Do you think I could ever care for that lame
boy?”
He smiled grimly. She had been right. Nature had set him apart,
made him a loup-garou, a solitary hob-goblin. He had been
unclubbable, sauvage, even at Cambridge. And yet he had had real
friendships there; one especially.
Gordon’s free hand fumbled for his fob and his fingers closed on a
little cornelian heart. It had been a keepsake from his college
classmate, Matthews, drowned in the muddy waters of the Cam.
He released the bottle hurriedly, strode to the window and flung it
open. A gust of rain struck his face and spluttered in the candle, and
the curtain flapped like the wing of some ungainly bird. Out in the
dark, beneath a clump of larches, glimmered whitely the monument
he had erected to “Boatswain,” his Newfoundland. The animal had
gone mad.
“Some curse hangs over me and mine!” he muttered. “I never could
keep alive even a dog that I liked or that liked me!”
A combined rattle and crash behind him made him turn. The wind
had blown shut the door of the cabinet with a smart bang, and a
yellow object, large and round, had toppled from its shelf, fallen and
rolled to his very feet.
He started back, his nerves for the instant shaken. It was a skull,
mottled like polished tortoise-shell, mounted in dull silver as a
drinking-cup. He had unearthed the relic years before with a heap of
stone coffins amid the rubbish of the Abbey’s ruined priory—grim
reminder of some old friar—and its mounting had been his own
fancy. He had forgotten its very existence.
Now, as it lay supine, yet intrusive, the symbol at one time of
lastingness and decay, it filled him with a painful fascination.
Picking it up, he set it upright on the desk, seized the bottle, knocked
off its top against the marble mantel and poured the fantastic goblet
full.
“Death and life!” he mused. “One feeds the other, each in its turn.
Life! yet it should not be too long; I have no conception of any
existence which duration would not render tiresome. How else fell
the angels? They were immortal, heavenly and happy. It is the
lastingness of life that is terrible; I see no horror in a dreamless
sleep.”
He put out his hand to the goblet, but withdrew it.
“No—wait!” he said, and seating himself at the desk, he seized a
pen. The lines he wrote, rapidly and with scarcely an alteration, were
to live for many a long year—index fingers pointing back to that dark
mood that consumed him then:

“Start not—nor deem my spirit fled:

In me behold the only skull,
From which, unlike a living head,
Whatever flows is never dull.

I lived, I loved, I quaffed, like thee:

I died: let earth my bones resign.
Fill up—thou canst not injure me;
The worm hath fouler lips than thine.
 Better to hold the sparkling grape,
Than nurse the earth-worm’s slimy brood;
And circle in the goblet’s shape
The drink of gods, than reptile’s food.

Quaff while thou canst: another race,

When thou and thine, like me, are sped,
May rescue thee from earth’s embrace,
And rhyme and revel with the dead.”

He repeated the last stanza aloud and raised the goblet in both
hands.
“Rhyming and revelling—what else counts? To drink the wine of
youth to the dregs and then—good night! Is there anything beyond?
Who knows? He who cannot tell! Who tells us there is? He who does
not know!”
Did the dead know?
He set the wine down, pushing it from him, sprang up, seized the
candle and entered the room on the other side of the corridor. The
bed-curtains were drawn close and a Bible lay open on the night-
stand. He wondered with a kind of impersonal pity if the book had
held comfort for her at the last.
He held the candle higher so its rays lighted the page: But the Lord
shall give thee there a trembling heart, and failing of eyes, and
sorrow of mind.... In the morning thou shall say, Would God it were
even! and at even thou shalt say, Would God it were morning!
It stared at him plainly in black letters, an age-old agony of
wretchedness. Had this been the keynote of her lonely, fitful,
vehement life? Had years of misery robbed her—as it had robbed
him, too? A distressed doubt, like a dire finger of apprehension,
touched him; he put out his hand and drew aside the curtains.
Looking, he shuddered. Death had lent her its mystery, its
ineffaceable dignity. He recognized it with a new and inexplicable
feeling, like rising from the grave. Back of the placid look, in
abeyance, in the stirlessness of the unringed hands—she had lost
her wedding-ring years ago—some quality, strange, unintimate, lay
confronting him. He remembered his words to Hobhouse in the
street—words that had not been cold on his lips when he read
Fletcher’s message. Ever since, they had lain rankling like a raw
burn in some crevice of his brain. “Lame brat!” And yet, beneath her
frantic rages, under the surface he had habitually disregarded, what
if in her own way she had really loved him!
A clutching pain took possession of him, a sense of physical
sickness and anguish. He dropped the curtain, and stumbled from
the room, down the long stair, calling for the footman.
“Rushton,” he shouted, “get the muffles! Let us have a bout like the
old times.” He threw off his coat, pushed the chairs aside and bared
his arms. “The gloves, Rushton, and be quick about it!”
The footman hesitated, a half-scared expression in his look.
“Never fear,” said Gordon, and laughed—a tightening laugh that
strained the cords of his throat. “Put them on! That’s right! What are
you staring at? Do you think she will hear you? Not she! Put up your
hands—so! Touched, by the Lord! Not up to your old style, Rushton!
You never used to spar so villainously. You will disgrace the fancy.
Ah-h!” And he knocked him sprawling.
Rushton scrambled to his feet as the housekeeper entered, dismay
upon her mask-like relic of a face. Gordon was very white and both
noticed that his eyes were full of tears.

Long after midnight, when the place was quiet, the housekeeper
heard an unaccustomed sound issuing from the chamber where the
dead woman lay. She took a light and entered. The candle had
burned out, and she saw Gordon sitting in the dark beside the bed.
He spoke in a broken voice:
“Oh, Mrs. Muhl,” he said, “she was my mother! After all, one can
have but one in this world, and I have only just found it out!”
 CHAPTER VII
THE YOUTH IN FLEET PRISON

Behind the closed shutters of the book-shop which bore the sign of
“The Juvenile Library,” in the musty room where George Gordon had
burned the errant copies of his ubiquitous Satire, old William Godwin
sat reading by a guttering candle, Livy’s Roman History in the
original. It was his favorite book, and in the early evenings, when not
writing his crabbed column for the Courier, or caustic diatribes for the
reviews, he was apt to be reading it. A sound in the living-room
above drew his eyes from the black-letter page.
“Jane!” he called morosely—“Jane Clermont!”
A lagging step came down the stair, and a girl entered, black-eyed,
creole in effect. Her cheeks held the flame of the wild-cherry leaf.
“Where is your sister?”
“I have no sister.”
The old man struck the table with his open hand. “Where is Mary, I
say?”
“At the door.”
“Go and see what she is doing.”
The girl stood still, regarding her stepfather with a look that under its
beauty had a sullen half-contempt.
“Why don’t you do as I tell you?”
“I’m not going to be a spy for you, even if you did marry my mother.
I’m tired of it.”
The anger on the old man’s face harshened. “If you were my own
flesh and blood,” he said sternly, “I would flog that French impudence
of yours to death. As long as you eat my bread, you will obey me.”
She looked at him with covert mockery on her full lips.
“I’m not a child any longer,” she said as she turned flauntingly away;
“I could earn my bread easier than by dusting tumble-down book-
shelves. Do you think I don’t know that?”
To William Godwin this defiant untutored girl had been a thorn in the
side—a perpetual slur and affront to the irksome discipline he laid
upon his own pliant Mary, the child of that first wife whose loss had
warped his manhood. Now he saw her as a live danger, a flagrant
menace whose wildness would infect his own daughter. It was this
red-lipped vixen who was teaching her the spirit of disobedience!
He raised his voice and called sharply: “Mary!”
There was no answer, and he shuffled down the shabby hall to the
street door. The old man glowered at the slender, beardless figure of
the youth who stood with her—the brown, long coat with curling
lamb’s-wool collar and cuffs, its pockets bulging with mysterious
books. In a senile rage, he ordered his daughter indoors.
Passers-by stopped to stare at the object of his rancor, standing
uncertainly in the semi-dusk, a brighter apparition, with luminous
eyes and extravagant locks. Words came thickly to the old man; he
launched into invective, splenetic and intemperate, at which the
listeners tittered.
As it chanced, a pedestrian heard the name he mouthed—a man
sharp-featured and ill dressed. With a low whistle he drew a soiled
slip of paper from his pocket and consulted it by a street lamp, his
grimy forefinger running down the list of names it contained.
“I thought so. I’ve a knack for names,” he muttered, and shouldered
through the bystanders.
“Not so fast, young master,” he said, laying his hand on the youth’s
arm; “t’other’s the way to the Fleet.”
The other drew back with a gesture of disgust. “The Fleet!” he
echoed.
“Aye,” said the bailiff, winking to the crowd; “the pretty jug for folk as
spend more than they find in pocket; with a nice grating to see your
friends so genteel like.”
Breaking from her father’s hand, the girl in the doorway ran out with
fear in her blue eyes.
“Oh, where are you taking him?” she cried.
The fellow smirked. “I’m just going to show his honor to a hotel I
know, till he has time to see his pal Dellevelly of Golden Square to
borrow a tidy eighteen pound ten, which a bookseller not so far off
will be precious glad to get.”
“Eighteen pounds!” gasped the youth, with a hysteric laugh.
“Debtors’ prison for only eighteen pounds! But I have the books still
—he can have them back.”
“After you’ve done with ’em, eh?” said the bailiff. “Oh, I know your
young gentlemen’s ways. Come along.”
“Father!” cried the girl, indignantly, as the bailiff dropped a heavy
grasp on the lamb’s-wool collar. “You’ll not let them take Shelley.
You’ll wait for the money, father.”
“Go into the house!” thundered the old man. “He’s a good-for-nothing
vagabond, I tell you!” He thrust her back, and the slammed door shut
between her and the youth standing in the bailiff’s clutch, half-
wonderingly and disdainfully, like a bright-eyed, restless fox amid
sour grapes.
“Go to your room!” commanded her father, and the girl slowly
obeyed, dashing away her tears, while the old bookseller went back
to the cluttered shop and his reading of Livy’s Roman History.

In the chamber the girl entered, Jane Clermont looked up half-

scornfully.
“I heard it all,” she burst; “you are a little fool to take it—scolding you
like a child, and before all those people!”
Mary opened a bureau drawer and took out a small rosewood box
containing her one dearest possession. As she stood with her
treasure in her hand, Jane jumped to her feet.
“I’ve borne it as long as I can myself,” she cried under her breath.
“I’m going to run away before I am a fortnight older.”
“Run away? Where?”
Jane had begun to dance noiselessly on tiptoe with swift bacchante
movements. “I’m going to be an actress,” she confided, as she stood
at a pirouette. “I’ve been to see Mr. Sheridan—the great Mr.
Sheridan—and he’s promised to get me a trial in a real part at Drury
Lane!” She paused, struck with the determination in the other’s face.
“What are you going to do?”
“I’m going to Shelley.”
“Good! I’ll go with you. But you have no money. How can you help
him?”
Mary held out the little box.
“Your mother’s brooch!” cried Jane. “Do you really care as much as
that for him?”—a little satirically.
Her companion was dressing for the street with rapid, uncertain
fingers. “It’s all I have,” she answered.
They sat in silence till they heard the outer door bolted and knew the
old man below had gone to his own room. Then they stole softly
down the creaking stair, undid the outer door cautiously and went out
into the evening bustle.
The pavements were crowded, and Mary clung to her companion’s
arm, but Jane walked nonchalantly, her dark eyes snapping with
adventure. Not a few turned to gaze at her piquant beauty. To one
whose way led in the same direction it brought a thought of a distant
land.
“In a Suliote shawl she might be a maid of Missolonghi!” mused
George Gordon, as he strode across Fleet market behind the two
girls. “Greece! I wonder when I shall see it again!”
A shade of melancholy was in his face as he walked on, but not
discontent. The resentment of his London home-coming and the
desolation of that first black night at Newstead he had overcome.
With the companionship of his sister and in the calm freshness of
frosty lake and rolling wind-washed moor he had recovered some of
the buoyant spirits so suddenly stunned by the impact of the
slanders that had met him. The London papers he had left
unopened, from a sensitive dread of seeing the recital of his
mother’s well-known eccentricities, which her death might furnish
excuse for recalling. His new book, whose stanzas stood like mental
mile-posts of his journey, had almost finished its progress through
the press. In its verses he hoped to stand for something more than
the petty cavilling of personal paragraphists. It was to his publisher’s
he was bound this night when that wistful thought of the shores he
best loved had shadowed his mood.
Crossing the open space on which faced the dark brick front and
barred windows of the Fleet Prison, he saw the two girlish forms
pause before its dismal entrance, where stood the shirt-sleeved
warden, pipe in mouth. What errand could have brought them there
unaccompanied at such an hour, he wondered.
Just then the clock of St. Dunstan’s-in-the-West began a ponderous
stroke, and the warden knocked the ashes from his pipe.
“Eight o’clock,” he announced gruffly. “Prison’s closed.”
A cry of dismay fell from Mary’s lips—a cry freighted with tears.
“Then we can’t get poor Bysshe!”
Gordon turned back and approached the dingy portal. “I have a
fancy to see the inside of the old rookery, warden,” he said. “Perhaps
these visitors may enter with me.” His hand was in his pocket and a
jingle caught the warden’s acute ear. The gruff demeanor of the
custodian merged precipitately into the obsequious. He pushed open
the gate with alacrity and preceded them into the foul area of the
prison.
Mary threw Gordon a quick glance of gratitude as she passed into
the warden’s office—to return without the little rosewood box. Across
the look had flitted a shudder at the shouts and oaths that tainted the
inclosure, and as she emerged he caught the gleam of relief with
which she saw him still in the court.
A moment later the bailiff, who had figured in the scene before
Godwin’s shop, was leading the way along a noisome gallery. It was
littered with refuse of vegetable and provision-men who cried their
wares all day up and down. At one side gaped a coffee-house, at the
other an ordinary, both reeking with stale odors and tobacco-smoke,
and a noisy club was meeting in the tap-room. Laughter and the click
of glasses floated in the air, a suffocating atmosphere of tawdry
boisterousness.
Jane Clermont stole more than one sidelong glance as Gordon’s
uneven step followed. At length the bailiff paused and unlocked a
barred door. Mary knocked, but there was no answer; she pushed
the door open and the girls entered.
From his station in the background, Gordon saw a dingy chamber,
possessing as furniture only a cot, a chair, and a narrow board
mantel, on which a candle was burning, stuck upright in its own
tallow. Standing before this breast-high impromptu table, a pamphlet
spread open, upon it, his shoulders stooped, his eyes devouring the
page, was the room’s solitary occupant. He had thrown off the long
coat with the lamb’s-wool trimming, his collar was open leaving his
throat unfettered, and his long locks hung negligently about his face.
“Bysshe!” cried Mary, ecstatically.
The figure by the mantel turned, flinging back his tumbled hair as if
to toss away his abstraction.
“Mary!” he echoed, and sprang forward. “What are you doing here?”
“We’ve come for you. The debt is cancelled. To think of your being
shut up here!” she said with a shiver, as a burst of noises rose from
the court below.
“Cancelled!” he repeated with a hesitating laugh. “Your father would
better have let me stay, Mary. I shall be just as bad again in a month.
I couldn’t resist buying a book if it meant the gallows!”
She did not undeceive him, but handed him his great-coat, and
gathered the volumes tossed on to the couch to stuff into its bulging
pockets.
Jane had been scrutinizing the room. “What’s that?” she inquired,
pointing to a plate of food which sat on the far end of the mantel, as
though it had been impatiently pushed aside.
The youth colored uneasily. “Why, I suppose that was my supper,” he
said shamefacedly; “I must have forgotten to eat it.”
Jane laughed, picked up the pamphlet for which the meal had been
forgotten, and read the title aloud. “‘Twelve Butchers for a Jury and a
Jeffreys for a Judge. An Appeal against the Pending Frame-
Breakers Bill to legalize the Murder of the Stocking-Weavers. By
Percy Bysshe Shelley!’”
“Frame-Breakers!” she finished disdainfully. “Stocking-Weavers!”
Shelley’s delicate face flushed as he folded the pamphlet.
“Are they not men?” he exclaimed. “And being men, have they no
natural rights? Is British law to shoot them down like wild beasts for
the defense of their livelihood? Oh, if I were only a peer, with a voice
in Parliament!” He spoke with fierce emphasis, but in tone soft,
vibrating and persuasive—a sustained, song-like quality in it.
“Percy Bysshe Shelley!” Gordon’s mind recited the name
wonderingly. He remembered a placard he had seen in a book-shop
window: “For writing the which he stands expelled from University
College, Oxford.” So this was the heir to a baronetcy, the author of
“Queen Mab,” the stripling iconoclast who had laughed at fulminating
attorney-generals, had fled to Lynmouth beach—where he had spent
his days making little wooden boxes, inclosed in resined bladders,
weighted with lead and equipped with tiny mast and sail, and had
sent them, filled with his contraband writings, out on the rollers of the
Atlantic in the hope that they might reach some free mind on the Irish
shore or on some ocean brig.
Gordon left his post and went slowly down the stair, past the
blackened office, wherein the warden sat admiringly fingering the
brooch that had wiped out a debt to old William Godwin the
bookseller, and into the street.
The words of the youth he had seen sounded in his brain: “If I were
only a peer, with a voice in Parliament!”
That voice was his. When had he used it for his fellow-man?
 CHAPTER VIII
A SAVAGE SPUR

John Murray, anax of publishers, sat that evening in his shop in Fleet
Street. He was in excellent humor, having dined both wisely and
well. His hair was sparse above a smooth-shaven, oval face, in
which lurked good-humor and the wit which brought to his drawing-
room the most brilliant men of literary London, as his genius as a
publisher had given him the patronage of the greatest peers of the
kingdom, and even of the prince regent. His black coat was of the
plainest broadcloth and his neck-cloth of the finest linen. Dallas sat
opposite, his scholarly face keen and animated. The frayed
waistcoat was no longer in evidence, and the worn hat had given
place to a new broad brim.
“Yes,” said the man of books, “we shall formally publish to-morrow. I
wrote his lordship, asking him to come up to town, to urge him to
eliminate several of the stanzas in case we reprint soon. They will
only make him more enemies. He has enough now,” he added
ruefully.
“You still think as well of it?”
The publisher pushed back his glasses with enthusiasm. “It is
splendid—unique.” He pulled out a desk-drawer and took therefrom
a printed volume, poising it proudly, as a father dandles his first-born,
and, turning its pages, with lifted forefinger and rolling voice read:

“Fair Greece! sad relic of departed worth!

Immortal, though no more; though fallen, great!
Who now shall lead thy scattered children forth,
And long accustomed bondage uncreate?
Not such thy sons who whilom did await,
The hopeless warriors of the willing doom,
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