Contents

CLASSIFICATION OF ANTICANCER DRUGS.............................................................................................................2

Classification of anticancer drugs.......................................................................................................................................2
ANTI-TUMOUR TREATMENT.......................................................................................................................................2
INTRODUCTION..............................................................................................................................................................2
DRUGS DIRECTED AGAINST TUMOUR DNA............................................................................................................3
DNA-RELATED PROTEINS............................................................................................................................................6
DRUGS DIRECTED AGAINST TUMOUR RNA............................................................................................................7
SPECIFIC GENES.............................................................................................................................................................7
DRUGS DIRECTED AGAINST PROTEINS IN THE TUMOUR CELL.........................................................................8
RECEPTORS IN THE TUMOUR MEMBRANE..............................................................................................................8
INTRACELLULAR PATHWAYS IN TUMOUR CELLS..............................................................................................10
TUBULIN........................................................................................................................................................................ 11
DRUGS ACTING ON THE ENDOTHELIUM AND EXTRACELLULAR MATRIX..........................................................................12
ENDOTHELIUM.............................................................................................................................................................13
EXTRACELLULAR MATRIX........................................................................................................................................13
HOST CELL INHIBITORS AND OTHER DRUGS.......................................................................................................14
CONCLUSIONS..............................................................................................................................................................14
REFERENCES.................................................................................................................................................................15

1
 CLASSIFICATION OF ANTICANCER DRUGS
Classification of anticancer drugs:- A new system based on therapeutic targets

ANTI-TUMOUR TREATMENT
Classification of anticancer drugs—a new system based on therapeutic targets

The arrival of a great number of new antineoplastic agents has made it necessary to reclassify
all of them. Anticancer drugs may act at different levels: cancer cells, endothelium,
extracellular matrix, the immune system or host cells. The tumour cell can be targeted at the
DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour
DNA, whereas monoclonal antibodies and small molecules are directed against proteins. The
endothelium and extracellular matrix may be affected also by specific antibodies and small
molecules.

INTRODUCTION
Most patients with advanced solid tumours still die of their disease. For this reason, new
effective drugs are needed and, in fact, new agents appear every few months. The last years
have witnessed the ap-pearance of a great number of anticancer drugs, many of which cannot
be included in a simple classification. Classically, anticancer drugs were grouped as
chemotherapy, hormonal therapy and immunotherapy. Chemotherapy included a number a
families defined by both their chemical structure and mechanism of action: alkylating agents,
antibi-otics, antimetabolites, topoisomerase I and II inhib-itors, mitosis inhibitors, platinum
compounds and others (Table 1). However, the group ‘‘others’’ has expanded so much that
this classification is no longer useful.

A drug classification serves two main objectives: the achievement of a comprehensive view
of the available drugs and the design of combination therapy. A global view is important to
remember the drugs and their mechanism of action and also for teaching purposes. On the
other hand, multidrug regimens usually include drugs belonging to differ-ent groups to
increase efficacy and decrease toxicity, at least whenever classical chemotherapy is con-
cerned.

2
We hereby propose a new drug classification based on the kind of target. Drugs may be
directed at tumour cells or other elements involved in carcino-genesis, i.e., the endothelium
and extracellular ma-trix, and the immune system. Potential host cells such as the bone may
also be targeted. Table 2 shows all these groups. The target may be located at the DNA, RNA
or protein level. In general, chemother-apy acts at the DNA level in tumour cells, whereas
monoclonal antibodies and small molecules interact with proteins, either in the tumour cells
or in other elements. Antisense oligonucleotides are the main drugs directed against mRNA.

It is beyond our scope to describe the mechanism of action of every drug in detail. In some
cases, the precise mechanism is still uncertain. Besides, some of the compounds we shall
mention may not go beyond phase III trials. We would like to offer a useful tool to classify
both available and forthcoming
TABLE 1 Classical classification of anticancer drugs

Chemotherapy Alkylators
Antibiotics
Antimetabolites
Topoisomerases inhibitors
Mitosis inhibitors
Other
Hormonal therapy Steroids
Anti-estrogens
Anti-androgens
LH–RH analogs
Anti-aromatase agents
Immunotherapy Interferon
Interleukin 2
Vaccines

anticancer drugs, even when a global classification might have some exceptions or could be
very sche-matic in some instances. We have restricted the in-clusion of new compounds to
those under clinical development.

DRUGS DIRECTED AGAINST TUMOUR DNA

3
The drugs may act on DNA either by breaking the helix itself, interfering with DNA-related
proteins, or modifying the expression of specific genes. Most classical anticancer agents have
one of these mech-anism of action, and new drugs are being incorpo-rated every year (Tables
3a and 3b).

DNA HELIX

Alkylating agents were the first compounds identi-fied to be useful in cancer. They form a
variety of interstrand cross-links called adducts, that alter DNA structure or function. The
most common site of alkylation is the N-7 position of guanine, but it varies depending on the
family of drugs. Alkylators belong to one of several families: nitrogen mustards, nitrosoureas,
triazenes, platinum compounds and antibiotics (Table 3a) (1).
TABLE 2 Proposed new classification

Target

Tumour DNA Non-specific

DNA break: chemotherapy
DNA-related proteins: chemotherapy
Specific
Hormonal therapy, retinoids
Interferon a
Gene therapy
RNA Antisense oligonucleotides
Proteins Membrane receptors
Extracellular domain: MoAb
Intracellular domain: small molecules
Cytoplasm
Intracellular pathways: small molecules
Tubulin: chemotherapy

Endothelium (*) DNA Combretastatin

Proteins Monoclonal antibodies
Small molecules

Extracellular matrix MMPs MMPs inhibitors

Other elements Monoclonal antibodies and small
molecules

Immune system Lymphocytes and Interferons

4
 macrophages Interleukin2
Vaccines

Host cells Bone cells Bisphosphonates, osteoprotogerin

In this group, antisense therapy might also be developed in the future.

MoAb, monoclonal antibodies and MMPs, metalloproteinases.
TABLE 3a Drugs directed against tumour DNA: chemotherapy

DNA break
Nitrogen mustards Cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine Cross links
Nitrosoureas BCNU Cross links
Triazenes Dacarbazine, temozolomide Cross links
Antibiotics Bleomycin, mitomycin Cross links
Platinum compounds Cisplatin, carboplatin, oxaliplatin Cross links

DNA-related proteins
Antibiotics Anthracyclines: doxorubicin, epirubicin, idarubicin, mitoxantrone Free radicals & £ Topo II
Podophillotoxins Etoposide £ Topo II
Topo I inhibitors Topotecan, irinotecan, rubitecan £ Topo I
Antimetabolites Antifolates: methotrexate, trimetrexate £ DHFR & other enzymes
Fluoropyrimidines (5FU, ftorafur, capecitabine) and raltitrexed £ TS
Pemetrexed £ DHFR, TS, FTRG
Cytarabine, fludarabine £ DNA polymerase & RR
Gemcitabine £ RR
Adenosine analogs: deoxycoformycin, cladribine £ Adenosine-deaminase
Other Ecteinascidin £ Transcription factors

Topo, topoisomerase; DHFR, dihydrofolic reductase; TS, thymidilate synthase; FTRG,

formyltransferase ribonucleotide glycinamide; RR, ribonucleotide reductase; £, inhibition.

TABLE 3b Drugs directed against tumour DNA: modifiers of specific genes

Steroids Prednisolone, dexamethasone Union to specific receptors, transcriptional

interaction with specific genes
Antihormones Ant estrogens: tamoxifen, fulvestrant
Antiandrogens: flutamide,
bicalutamide
Antiaromatase: anastrozole, letrozole,
exemestane
LH-RH agonists: goserelin,
tryptorelin, buserelin
Retinoids ATRA, fenretidine, bexarotene
Interferon a

5
Gene therapy

There are some new experimental agents among the alkylators, such as bendamustine or tira-
pazamine. Bendamustine, a nitrogen mustard compound, has activity in lymphomas (2–4).
Tira-pazamine is activated in hypoxic cells and en-hances the cytotoxicity of radiation,
cisplatin and the taxanes (5,6). It has been used for the treatment of non-small cell lung
cancer and head and neck tumours. Some antibiotics also belong to the group of al-kylators:
bleomycin and mitomycin C. The anthra-cyclines have a different mechanism of action and
are included in the next group.

DNA-RELATED PROTEINS

Topoisomerase I and II inhibitors, antimetabolites and ecteinascidin could be grouped

together as drugs directed at protein–DNA complexes, because they do not bind directly to
DNA (1).
The anthracyclines (doxorubicin and their analogs epirubicin and idarubicin) inhibit
topoisomerase II and form free radicals. Mitoxantrone, although synthetic, can be regarded as
an anthracycline. The main epipodophillotoxin, etoposide, also inhibits topoisomerase II.
Topoisomerase I transiently breaks a single strand of DNA during DNA replication, thereby
reducing torsional strain. Inhibitors of this enzyme derive from camptothecin. This family has
grown rapidly in recent years. In addition to topotecan and irino-tecan, new experimental
agents could join the family in the near future, for instance rubitecan (7,8), lur-totecan (9,10)
or exatecan (11,12).
On the other hand, antimetabolites interfere with enzymes that contribute to DNA synthesis.
In this group we have antifolates, fluoropyrimidines, ral-titrexed, cytarabine, gemcitabine,
and adenosine analogs (fludarabine, pentostatin, cladribine). Pemetrexed has recently been
incorporated to the clinic. This drug shows activity in non-small cell lung cancer, breast
cancer, mesothelioma and head and neck tumours (13–15). Table 3a indicates the target
enzyme for each antimetabolite.
A marine derivative, ecteinascidin or ET-743, has a unique mechanism of action. Formerly
thought to be an alkylator, recent investigations have shown that it blocks transcriptional

6
factors—such as TC-NER or Sp1—and seems to affect RNA polymerase II-mediated gene
transcription (16). Ecteinascidin has been used in patients with refractory sarcomas (17).
Specific genes does not mean that this activity is re-stricted to tumour cells.Gene therapy also
targets specific genes, but in this case the mechanism of action differs substan-tially from that
of the hormones. Genes are intro-duced in vectors to either repair or block specific DNA
sequences.

DRUGS DIRECTED AGAINST TUMOUR RNA

A number of anticancer drugs such as the fluoro-pyrimidines and platinum compounds

interfere with RNA synthesis. However, they mainly act by binding to DNA. The major
representatives in this group are antisense oligonucleotides. These mole-cules are directed
against specific mRNAs. The mRNAs of bcl-2, myb, p53, mdm2, Her-2 and
methyltransferase-1 have been targeted with these oligonucleotides (19–25). The synthesis of
antisense oligonucleotides is complex and improved methods to deliver the compound in the
target are needed (25–27). These problems are delaying the develop-ment of antisense
therapy. Another drug in this group is angiozyme, which blocks the mRNA of the vascular
endothelial growth factor (28,29).

SPECIFIC GENES

The classical representatives in this group are hor-monal agents. Steroids, antihormones and
retinoids share a common mechanism of action because they modify the expression of
specific genes (Table 3b). Steroid hormones, such as glucocorticoids, bind to receptor
proteins in the cytoplasm or nucleus to form a hormone–receptor complex. This complex has
the capacity to activate regulatory sequences in DNA. Antioestrogens and antiandrogens
block re-ceptors of oestrogens and androgens, respectively. These receptors are ligand-
regulated transcription factors located in the nucleus. The antiaromatase agents anastrozole,
letrozole and exemestane act in the cytoplasm, mainly in tumour cells but also in peripheral
tissues.

7
LH–RH analogs bind to a specific membrane re-ceptor linked to a G protein in the
hypothalamus. However, the ultimate effect takes place in the tu-mour cell, and for this
reason the analogs should be grouped together with the other hormones (Table 2).
The antitumour activity of interferon a appears to be due to a combination of direct
antiproliferative as well as indirect immune-mediated effects. It has also antiangiogenic
effects mediated through interferon gamma (18). Thus, this drug may appear in several
groups in our classification. Activity over some.

DRUGS DIRECTED AGAINST PROTEINS IN THE TUMOUR CELL

In the last decade, a great number of compounds have joined this group, mainly monoclonal
anti-bodies and small molecules. They are all very spe-cific and their effect is cytostatic
rather than cytotoxic. They can bind to membrane receptors or cytoplasmic proteins.

RECEPTORS IN THE TUMOUR MEMBRANE

Two groups may be distinguished: monoclonal an-tibodies and small molecules. The former
block the extracellular domain of the receptor, whereas the latter cross the membrane and
inhibit the intracel-lular domain, usually a tyrosin-kinase (Table 4). The term ‘‘small
molecule’’ may be misleading, because classical chemotherapy compounds are also small in
size, but it allows the distinction with monoclonal antibodies.
The first antitumour antibodies were directed against lymphoid antigens, such as CD20 and
CD52. Some of them combine the antibody with an isotope to increase efficacy (30–34).
These highly active.

8
 TABLE 4 Drugs directed against the membrane receptors of the tumour cell

Extracellular domain
Monoclonal antibodies
Rituximab Anti CD20
Ibritumomab-I*, Anti CD20
tositumomab-I*
Alemtuzumab Anti CD52
Trastuzumab Anti Her-2
Cetuximab Anti EGFR (Her-1)
Intracelular domain
Small molecules
£ Tyrosin-kinase
ZD-1839 (gefitinib) EGFR
£ Tyrosin-kinase
OSI-774 (erlotinib) EGFR
£ Tyrosin-kinase EGFR
PKI-166 and
Her-2
£ Tyrosin-kinase of all
CI-1033 Her

Compounds have expanded the possibilities of treatment in patients with refractory

lymphomas and are now being evaluated in first- line therapy. New antibodies are under
investigation at this mo-ment: the anti-CD33 gemtuzumab and the anti-CD22 epratuzumab,
for instance (35,36).
The main antibodies for carcinomas are trast-uzumab (37,38) and cetuximab (39,40).
Trastuzumab is available for the treatment of Her-2 positive breast tumours, either alone or in
combination with che-motherapy, and new possible indications are being studied. On the
other hand, an anti-MUC antibody could be used in the future as a vaccine in patients with
carcinomas (41).
Small molecules bind to receptors of the epider-mal growth factor family. Some of them are
specific for EGFR (Her-1), such as gefitinib (ZD-1839) (42–43) or OSI- 774 (44). Gefitinib is
the only member of the group that has been tested in phase III trials so far. It obtains
responses as single agent in non-small cell lung cancer and head and neck tumours. PKI-166
inhibits both Her-1 and Her-2 (45). CI-1033 is an ir-reversible inhibitor of all the epidermal
growth fac-tor receptors (46).

9
INTRACELLULAR PATHWAYS IN TUMOUR CELLS

A number of metabolic pathways carry proliferation signals to the nucleus. Although we shall
comment on them separately, all of them are interrelated. These pathways are activated by
growth factors and a few of them have been targeted with specific drugs. Figure 1 shows a
scheme of the pathways that are being used in cancer therapeutics. The better known drug in
this group is imatinib, which inhibits the tyrosine kinase of bcr/abl and c-kit (47,48).

Figure 1 Metabolic pathways currently used by small molecules inside the cancer cell.

It is one of the most active drugs in chronic myeloid leukaemia and in gastrointestinal stromal
tumours. Other drugs are aimed at the ras or the phosphati-dyl-inositol pathways, as well as
the proteasome and the cyclin-dependent kinases. With few exceptions, these agents are now
in the first steps of clinical development. Table 5A includes some of them.
Ras is activated by farnesyl transferase. Once ac-tivated, the ras protein activates raf and
MEK. Farnesyl-transferase inhibitors act as false metabo-lites of this enzyme, for instance,
lonafarnib

TABLE 5 Drugs acting in the cytoplasm of the tumour cell

(A) Inhibitors of intracellular pathways in tumour cells

Imatinib £ Tyrosin-kinase of bcr/abl and c-kit

Ras
SCH-6636 (lonafarnib), R115,777 Ras mimetic
BMS-214662 £ Farnesyl transferase

10
 CI-1040 £ MEK
Phosphatidyl-inositol and PKC
CI-779 £ mTOR
Bryostatin, PKC-412 £ Protein-kinase C
Proteasome/chaperones
PS-341 £ Proteasome
17-AAG (ansamycin) Increases degradation of
HSP90
Cyclin-dependent kinases
Flavopiridol, CYC-202 £ CDKs
UCN-01 £ CDK-2

(B) Inhibitors of tubulin

Vinca alkaloids: vincristine, £ Microtubule
vinblastine, vindesine, vinorelbine polymerization
Taxanes: paclitaxel, docetaxel, Microtubule stabilization
BMS-275183
Epothilones: BMS-257000,
BMS-310705, EPO-906

The phosphatidyl-inositol pathway starts with the serin threonine PI-3K, which is connected
with mTOR through PKB/Akt. MTOR controls apoptosis and is related to the balance
between cellular ca-tabolism and anabolism. Specific drugs in this pathway are rapamycin
derivatives such as CCI-779, which inhibits mTOR (53). PI-3K is also connected with
protein-kinase C, a family of enzymes that ac-tivate the transcription factor NF-jB. Protein-
kinase C is inhibited by bryostatin (54,55) and PKC-412 (56).
The proteasome—a group of enzymes that de-grade proteins—is inhibited by PS-341 (57,58).
On the other hand, the chaperones exert the opposite function, i.e., they protect proteins from
degrada-tion. Geldanamycin derivatives such as 17-AAG in-crease the degradation of one of
the main chaperones, heat shock protein 90 (59,60).
Finally, flavopiridol and CYC-202 (a roscovitine derivative) inhibit cyclin-dependent kinases
(61,62). The staurosporin compound UCN-01 inhibits CDK-2 selectively (63,64).

TUBULIN

11
Tubulin contributes to the maintenance of cell shape, intracellular transport and mitosis, so
drugs inter-fering with tubulin are grouped here in the present classification. The vinca
alkaloids bind to specific sites on tubulin and prevent polymerization of tu-bulin dimers,
thereby disrupting the formation of microtubules. The taxanes have a different binding site
and stabilize microtubules: this unusual stability inhibits the normal reorganization of the
microtu-bule network. Oral formulations of taxanes will improve convenience if they prove
to be as active as the parent drugs (65). The epothilones are a new group of tubulin-
stabilizing agents. Preclinical studies have shown promising activity of these compounds, but
the results of phase II and III clin-ical trials are not still available (66,67). Table 5B shows all
these drugs.

DRUGS ACTING ON THE ENDOTHELIUM AND EXTRACELLULAR MATRIX

Compounds directed against the endothelium in-hibit either endothelial growth factors or the
recep-tors of such factors. On the other hand, most drugs acting in the extracellular matrix
inhibit metallo-proteinases (MMPs). They all have antiangiogenic effects (Table 6).

TABLE 6 Drugs directed against the endothelium and the extracellular matrix

Endothelial growth factors

Thalidomide £ VEGF, bFGF, TGF-a
Carboxiamide-triazol (CAI) £ Synthesis of VEGF
Receptors of endothelial cells
Bevacizumab Anti VEGFR
SU-5416, SU-6668, endostatin £ Tyrosin-kinase of VEGFR
Extracellular matrix
Marimastat, AG-3340 £ Metalloproteinases
(prinomastat), AE-941
(Neovastat)
Vitaxin Anti integrin
ABT-510 Mimetic of thrombospondin

12
ENDOTHELIUM

The main endothelial growth factors—vascular en-dothelial growth factor (VEGF)and basic
fibroblast growth factor (bFGF)—are inhibited by thalido-mide (68,69). Another inhibitor
specific for VEGF is carboxyamido-triazole (70,71). Interferon a also re-duces VEGF
synthesis in tumour cells, but this effect seems to be mediated through interferon gamma
(18,72,73). Cyclo-oxygenase 2 may stimulate endo-thelial growth, hence one of the possible
mecha-nisms of action of COX-2 inhibitors (74,75).
With regard to VEGF receptors, the monoclonal antibody bevacizumab binds to all of these
receptors (70,76,77). SU-5416 is a small molecule binding to the tyrosine kinase of VEGFR-
1 and VEGFR-2 (70,78). It also binds to platelet derived growth factor receptor and c-kit.
Clinical trials with SU-5416 in haemato-logical malignancies and colorectal cancer have been
initiated. Another small molecule, SU-6668, binds to VEGFR, bFGFR and platelet derived
growth factor receptor (PDGFR) (79,80).
Finally, combretastatin inhibits the mitotic spin-dle in the endothelium and induces apoptosis
(81,82).

EXTRACELLULAR MATRIX

Activation of MMPs in tumours facilitates invasion and is an essential step in angiogenesis.

MMPs may also stimulate the release of VEGF, bFGF and insulin growth factor. A number
of MMP inhibitors are currently under clinical investigation (83). Most of them are synthetic
inhibitors of the enzyme activity, such as marimastat (84–86), prinomastat or BAY 12-9566
(83). Tetracycline derivatives such as neovastat also down regulate the production, inhibit the
acti-vation and increase the degradation of MMPs (87,88).
Apart from MMPs, other elements of the extra-cellular matrix could be targeted as a form of
anti-cancer therapy, for instance, integrin, endothelin and thrombospondin (Table 6) (89,90).

13
HOST CELL INHIBITORS AND OTHER DRUGS

Some drugs are directed to organs that may harbour tumour cells. At present, these only
relate to agents that inhibit bone cell function and the bone micro-environment, such as
bisphosphonates (91,92), os-teoprotogerin (93) and PTHRP antibodies. In the future, more
drugs could be developed to target other organs at risk of metastasis.
Finally, cytokines such as interferon and inter-leukin 2 enhance the antitumour activity of the
im-mune system and are already well known.

CONCLUSIONS

A great number of anticancer agents are under clinical investigation at this moment. Some of
them belong to classic groups of chemotherapy, but others are the first of new families of
drugs. For clinicians, it is important to have the main groups in mind and, for this reason, we
propose a classification that is based on the target. The target may be located in the tumour
cell or in other elements that interact with the tumour cells (endothelium, extracellular matrix,
immune system, host cells). We hope that this clas-sification will be able to incorporate new
drugs coming up in the next years.

14
REFERENCES

Hurley LH. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer
2002; 2(3): 188–200.

Bremer K. High rates of long-lasting remissions after 5-day bendamustine chemotherapy

cycles in pre-treated low-grade non-Hodgkin’s-lymphomas. J Cancer Res Clin Oncol 2002;
128(11): 603–609.

Aivado M, Schulte K, Henze L, Burger J, Finke J, Haas R. Bendamustine in the treatment of

chronic lymphocytic leukemia: results and future perspectives. Semin Oncol 2002; 29(4
Suppl 13): 19–22.

Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, et al. Bendamustine is

effective in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol 2002;
13(8): 1285–1289.

Gandara DR, Lara Jr PN, Goldberg Z, Le QT, Mack PC, Lau DH, et al. Tirapazamine:
prototype for a novel class of therapeutic agents targeting tumor hypoxia. Semin Oncol 2002;
29(1 Suppl 4): 102–109.

Peters KB, Brown JM. Tirapazamine: a hypoxia-activated

topoisomerase II poison. Cancer Res 2002; 62(18): 5248–5253.

Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ, Vardeman DM. Preclinical
evaluation of the anticancer activity and toxicity of 9-nitro-20(S)-camptothecin (Rubitecan).
Int J Oncol 2002; 20(1): 81–88.

Schoffski P, Herr A, Vermorken JB, Van den Brande J, Beijnen JH, Rosing H, et al. Clinical
phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with
metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral
camptothecin analogue. Eur J Cancer 2002; 38(6): 807–813.

Emerson DL, Bendele R, Brown E, Chiang S, Desjardins JP, Dihel LC, et al. Antitumor
efficacy, pharmacokinetics, and biodistribution of NX 211: a low-clearance liposomal
formulation of lurtotecan. Clin Cancer Res 2000; 6(7): 2903–2912.

Kehrer DF, Bos AM, Verweij J, Groen HJ, Loos WJ, Sparreboom A, et al. Phase I and
pharmacologic study of liposomal lurtotecan, NX 211: urinary excretion predicts hematologic
toxicity. J Clin Oncol 2002; 20(5): 1222–1231.

Giles FJ, Cortes JE, Thomas DA, Garcia-Manero G, Faderl S, Jeha S, et al. Phase I and
pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a
daily-times-five schedule in patients with advanced leukemia. Clin Cancer Res 2002; 8(7):
2134–2141.

15
Minami H, Fujii H, Igarashi T, Itoh K, Tamanoi K, Oguma T, et al. Phase I and
pharmacological study of a new camptothecin derivative, exatecan mesylate (DX-8951f),
infused over 30 min every three weeks. Clin Cancer Res 2001; 7(10): 3056–3064.

Calvert H, Bunn Jr PA. Future directions in the development of pemetrexed. Semin Oncol
2002; 29(2 Suppl 5): 54–61.

Novello S, le Chevalier T. ALIMTA (pemetrexed disodium, LY231514, MTA): clinical

experience in non-small cell lung cancer. Lung Cancer 2001; 34(Suppl 4): S107–S109.

Pivot X, Raymond E, Laguerre B, Degardin M, Cals L, Armand JP, et al. Pemetrexed

disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head
and neck. Br J Cancer 2001; 85(5): 649–655.

Scotto KW. ET-743: more than an innovative mechanism of

action. Anticancer Drugs 2002; 13(Suppl 1): S3–S6.

Delaloge S, Yovine A, Taamma A, Riofrio M, Brain E, Raymond E, et al. Ecteinascidin-743:

a marine-derived compound in advanced, pretreated sarcoma patients— preliminary evidence
of activity. J Clin Oncol 2001; 19(5): 1248–1255.

Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology,

clinical applications, and toxicities. Oncologist 2001; 6(1): 34–55.

Tolcher AW. Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy
in combination with docetaxel in hormone-refractory prostate cancer. Semin Oncol 2001;
28(4 Suppl 15): 67–70.

Del Bufalo D, Cucco C, Leonetti C, Citro G, D’Agnano I, Benassi M, et al. Effect of cisplatin
and c-myb antisense phosphorothioate oligodeoxynucleotides combination on a human colon
carcinoma cell line in vitro and in vivo. Br J Cancer 1996; 74(3): 387–393.

Strasberg Rieber M, Zangemeister-Wittke U, Rieber M. p53-Independent induction of

apoptosis in human melanoma cells by a bcl-2/bcl-xL bispecific antisense oligonucleotide.
Clin Cancer Res 2001; 7(5): 1446–1451.

Wang H, Nan L, Yu D, Lindsey JR, Agrawal S, Zhang R. Anti-tumor efficacy of a novel

antisense anti-MDM2 mixed-backbone oligonucleotide in human colon cancer models: p53-
dependent and p53-independent mechanisms. Mol Med 2002; 8(4): 185–199.

Rait AS, Pirollo KF, Rait V, Krygier JE, Xiang L, Chang EH. Inhibitory effects of the
combination of HER-2 antisense

oligonucleotide and chemotherapeutic agents used for the treatment of human breast cancer.
Cancer Gene Ther 2001; 8(10): 728–739.

16
Funato T, Kozawa K, Fujimaki S, Miura T, Kaku M. Increased sensitivity to cisplatin in
gastric cancer by antisense inhibition of the her-2/neu (c-erbB-2) gene. Chemotherapy 2001;
47(4): 297–303.

Goffin J, Eisenhauer E. DNA methyltransferase inhibitors-state of the art. Ann Oncol 2002;
13(11): 1699–1716.

Henry SP, Geary RS, Yu R, Levin AA. Drug properties of second-generation antisense
oligonucleotides: how do they measure up to their predecessors? Curr Opin Investig Drugs
2001; 2(10): 1444–1449.

Jansen B, Zangemeister-Wittke U. Antisense therapy for cancer—the time of truth. Lancet

Oncol 2002; 3(11): 672–683.

Sandberg JA, Parker VP, Blanchard KS, Sweedler D, Powell JA, Kachensky A, et al.
Pharmacokinetics and tolerability of an antiangiogenic ribozyme (ANGIOZYME) in healthy
volunteers. J Clin Pharmacol 2000; 40(12 Pt 2): 1462–1469.

Weng DE, Usman N. Angiozyme: a novel angiogenesis

inhibitor. Curr Oncol Rep 2001; 3(2): 141–146.

Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, et al.
Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and
efficacy of re-treatment. J Clin Oncol 2000; 18(17): 3135–3143.

Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, et al. Multicenter phase II
study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and
transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2000; 18(6): 1316–
1323.

Iodine-131 tositumomab (Bexxar) in relapsed/refractory non-Hodgkin’s lymphoma: Update

from the 2001 American Society of Hematology Meeting. Clin Lymphoma 2002; 2(4): 209–
211.

Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, et al.
Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had
received fludarabine. J Clin Oncol 2002; 20(18): 3891–3897.

Lundin J, Kimby E, Bjorkholm M, Broliden PA, Celsing F, Hjalmar V, et al. Phase II trial of
subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line
treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002;
100(3): 768–773.

Roboz GJ, Knovich MA, Bayer RL, Schuster MW, Seiter K, Powell BL, et al. Efficacy and
safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia.
Leukemia Lymphoma 2002; 43(10): 1951–1955.

17
Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL, et al. Antibody-
targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using
Mylotarg (gemtuzumab ozogamicin). Leukemia 2002; 16(9): 1627–1636.

Ligibel JA, Winer EP. Trastuzumab/chemotherapy combinations in metastatic breast cancer.

Semin Oncol 2002; 29(3 Suppl 11): 38–43.

McKeage K, Perry CM. Trastuzumab: a review of its use in the treatment of metastatic breast
cancer overexpressing HER2. Drugs 2002; 62(1): 209–243.

Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer
2001; 37(Suppl 4): S16–S22.

Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli MB, et al. Phase I
study of anti-epidermal growth factor receptor antibody cetuximab in combination with
radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 2001; 19(13):
3234–3243.

Reddish M, MacLean GD, Koganty RR, Kan-Mitchell J, Jones V, Mitchell MS, et al. Anti-
MUC1 class I restricted CTLs in
metastatic breast cancer patients immunized with a synthetic MUC1 peptide. Int J Cancer
1998; 76(6): 817–823.

Herbst RS, Kies MS. ZD1839 (Iressa) in non-small cell lung cancer. Oncologist 2002;
7(Suppl 4): 9–15.

Ranson M. ZD1839 (Iressa): for more than just non-small cell

lung cancer. Oncologist 2002; 7(Suppl 4): 16–24.

Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, et al. Phase I and
pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase
inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001; 19(13): 3267–
3279.

Baker CH, Kedar D, McCarty MF, Tsan R, Weber KL, Bucana CD, et al. Blockade of
epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial
cells for therapy of human carcinomas. Am J Pathol 2002; 161(3): 929–938.

Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW. Potential benefits of the
irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol
2002; 29(3 Suppl 11): 11–21.

Cohen MH, Moses ML, Pazdur R. Gleevec for the treatment of chronic myelogenous
leukemia: US. Food and Drug Administration regulatory mechanisms, accelerated approval,
and orphan drug status. Oncologist 2002; 7(5): 390–392.

18
Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of
malignant gastrointestinal stromal tumours. Lancet Oncol 2002; 3(11): 655–664.

Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the
farnesyl transferase inhibitor SCH66336. Blood 2002; 100(3): 1068–1071.

Karp JE, Kaufmann SH, Adjei AA, Lancet JE, Wright JJ, End DW. Current status of clinical
trials of farnesyltransferase inhibitors. Curr Opin Oncol 2001; 13(6): 470–476.

Hotte SJ, Hirte HW. BAY 43-9006: early clinical data in patients with advanced solid
malignancies. Curr Pharm Des 2002; 8(25): 2249–2253.

Dancey JE. Agents targeting ras signaling pathway. Curr Pharm Des 2002; 8(25): 2259–
2267.

Elit L. CCI-779 Wyeth. Curr Opin Investig Drugs 2002; 3(8): 1249–1253.

Brockstein B, Samuels B, Humerickhouse R, Arietta R, Fishkin P, Wade J, et al. Phase II

studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck
cancer. Invest New Drugs 2001; 19(3): 249–254.

Pfister DG, McCaffrey J, Zahalsky AJ, Schwartz GK, Lis E, Gerald W, et al. A phase II trial
of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head
and neck. Invest New Drugs 2002; 20(1): 123–127.

Virchis A, Ganeshaguru K, Hart S, Jones D, Fletcher L, Wright F, et al. A novel treatment

approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an
inhibitor of protein kinase C. Hematol J 2002; 3(3): 131–136.

Adams J. Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment
of cancer. Curr Opin Chem Biol 2002; 6(4): 493–500.

Orlowski R, Stinchcombe E, Mitchell B, Shea T, Baldwin A, Stahl S, et al. Phase I trial of the
proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin
Oncol 2002; 20(22): 4420–4427.

Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: its

molecular target and biochemical activity. Invest New Drugs 1999; 17(4): 361–373.

Nimmanapalli R, O’Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-

demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of
Bcr-Abl-positive human leukemic blasts. Cancer Res 2001; 61(5): 1799–1804.

CLASSIFICATION OF ANTICANCER DRUGS 523

19
Schwartz GK, O’Reilly E, Ilson D, Saltz L, Sharma S, Tong W, et al. Phase I study of the
cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with
advanced solid tumors. J Clin Oncol 2002; 20(8): 2157–2170.

McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM, et al. In vitro and in
vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine).
Int J Cancer 2002; 102(5): 463–468.

Koh J, Kubota T, Migita T, Abe S, Hashimoto M, Hosoda Y, et al. UCN-01 (7-

hydroxystaurosporine) inhibits the growth of human breast cancer xenografts through
disruption of signal transduction. Breast Cancer 2002; 9(1): 50–54.

Senderowicz AM. The cell cycle as a target for cancer therapy: basic and clinical findings
with the small molecule inhibitors flavopiridol and UCN-01. Oncologist 2002; 7(Suppl 3):
12–19.

Rose WC, Long BH, Fairchild CR, Lee FY, Kadow JF. Preclinical pharmacology of BMS-
275183, an orally active taxane. Clin Cancer Res 2001; 7(7): 2016–2021.

Lee FY, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos-Suarez C, et al. BMS-
247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing
superior antitumor efficacy. Clin Cancer Res 2001; 7(5): 1429–1437.

Stachel SJ, Biswas K, Danishefsky SJ. The epothilones, eleutherobins, and related types of
molecules. Curr Pharm Des 2001; 7(13): 1277–1290.

Neben K, Moehler T, Egerer G, Kraemer A, Hillengass J, Benner A, et al. High plasma basic
fibroblast growth factor concentration is associated with response to thalidomide in
progressive multiple myeloma. Clin Cancer Res 2001; 7(9): 2675–2681.

Raje N, Anderson KC. Thalidomide and immunomodulatory drugs as cancer therapy. Curr
Opin Oncol 2002; 14(6): 635–640.

Figg WD, Kruger EA, Price DK, Kim S, Dahut WD. Inhibition of angiogenesis: treatment
options for patients with metastatic prostate cancer. Invest New Drugs 2002; 20(2): 183–194.

Waselenko JK, Shinn CA, Willis CR, Flinn IW, Grever MR, Byrd JC. Carboxyamido-triazole
(CAI)—a novel ‘‘static’’ signal transduction inhibitor induces apoptosis in human B-cell
chronic lymphocytic leukemia cells. Leukemia Lymphoma 2001; 42(5): 1049–1053.

Dreau D, Foster M, Hogg M, Swiggett J, Holder WD, White RL. Angiogenic and immune
parameters during recombinant interferon-a2b adjuvant treatment in patients with melanoma.
Oncol Res 2000; 12(5): 241–251.

Kawano Y, Matsui N, Kamihigashi S, Narahara H, Miyakawa I. Effects of interferon-gamma

on secretion of vascular endothelial growth factor by endometrial stromal cells. Am J Reprod
Immunol 2000; 43(1): 47–52.

20
Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL. Cyclooxygenase-2
inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial
cells in vivo. Cancer Res 2002; 62(3): 625–631.

Wang Z, Fuentes CF, Shapshay SM. Antiangiogenic and chemopreventive activities of

celecoxib in oral carcinoma cell. Laryngoscope 2002; 112(5): 839–843.

Bevacizumab. Anti-VEGF monoclonal antibody, avastin, rhumab-VEGF. Drugs R D 2002;

3(1): 28–30.

Chen HX, Gore-Langton RE, Cheson BD. Clinical trials referral resource: Current clinical
trials of the anti-VEGF
monoclonal antibody bevacizumab. Oncology (Huntingt) 2001; 15(8): 1017, 1020, 1023–
1026.
Stopeck A, Sheldon M, Vahedian M, Cropp G, Gosalia R, Hannah A. Results of a Phase I
dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced
malignancies. Clin Cancer Res 2002; 8(9): 2798–2805.
Fabbro D, Manley P. Su-6668. SUGEN. Curr Opin Investig Drugs 2001; 2: 1142–1148.
Hoekman K. SU6668, a multitargeted angiogenesis inhibitor. Cancer J 2001; 7(Suppl 3):
S134–S138.
Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, et al. A phase I
pharmacokinetic and translational study of the novel vascular targeting agent combretastatin
a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer.
Cancer Res 2002; 62(12): 3408–3416.
Ohno T, Kawano K, Sasaki A, Aramaki M, Tahara K, Etoh T, et al. Antitumor and
antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer. Int
J Clin Oncol 2002; 7(3): 171–176.

Hoekstra R, Eskens FA, Verweij J. Matrix metalloproteinase inhibitors: current developments

and future perspectives. Oncologist 2001; 6(5): 415–427.

Bramhall SR, Hallissey MT, Whiting J, Scholefield J, Tierney G, Stuart RC, et al. Marimastat
as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J
Cancer 2002; 86(12): 1864–1870.

Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. A double-blind
placebo-controlled, randomised study comparing gemcitabine and marimastat with
gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br
J Cancer 2002; 87(2): 161–167.

Groves MD, Puduvalli VK, Hess KR, Jaeckle KA, Peterson P, Yung WK, et al. Phase II trial
of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and
progressive glioblastoma multiforme. J Clin Oncol 2002; 20(5): 1383–1388.

21
Batist G, Patenaude F, Champagne P, Croteau D, Levinton C, Hariton C, et al. Neovastat
(AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose
levels. Ann Oncol 2002; 13(8): 1259–1263.

Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E. Neovastat, a naturally occurring

multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 2001; 28(6):
620–625.

Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, et al. Targeted
antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the
integrin avb3. Clin Cancer Res 2000; 6(8): 3056–3061.

Patel SR, Jenkins J, Papadopolous N, Burgess MA, Plager C, Gutterman J, et al. Pilot study
of vitaxin—an angiogenesis inhibitor—in patients with advanced leiomyosarcomas. Cancer
2001; 92(5): 1347–1348.

Coleman RE. Treatment of skeletal complications of cancer with zoledronic acid. Semin
Oncol 2002; 29(Suppl 21): 1–49.

Body JJ, Mancini I. Bisphosphonates for cancer patients: why,

how, and when? Support Care Cancer 2002; 10: 399–407.

Body JJ, Greip P, Coleman RE, et al. A phase I study of AMGN-0007, a recombinant
osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related
bone metastases. Cancer 2003; 97(Suppl 3): 887–892.

22
 NEKEMTE HEALTH SCIENSE
COLLEGE
Department of : Health Informatics
COURSE :
PHARMAC
OLOGY
Tittle
INDIVIDUA
:
L
Classific
Prepere
ASSIGNME
ation of
daby : NT
nti
Temesg
cancer
drugs
en Tirri 17|2016
Abdisa
ID
Number 23