‫كناشة الفارما‬

ANTICANCER
DRUGS
-AbdulHakeem Emad
taktom ali

part 2
 ANTIBIOTICS
The antitumor antibiotics (Figure 35.14) owe their
cytotoxic action primarily to their interactions
with DNA, leading to disruption of DNA function.
In addition to intercalation, their abilities to inhibit
topoisom- erases (I and II) and produce free
radicals also play a major role in their cytotoxic
effect. They are cell cycle nonspecific, with
bleomycin. as an exception
 A. ANTHRACYCLINES:
Doxorubicin, daunorubicin, Idarubicin, epirubi- cin, and mitoxantrone

Doxorubicin (dox-oh-ROO-bi-sin) and daunorubicin [daw-noe-ROO- bi-sin) are

classified as anthracycline antibiotics. Doxorubicin is the hydroxylated analog
of daunorubicin. Idarubicin (eye-da-ROO-bi-sin]. the 4-demethoxy analog of
daunorubicin, epirubicin [eh-pee-ROO- bih-sin), and mitoxantrone [mye-toe-
ZAN-trone] are also available. Therapeutic uses for these agents differ despite
their structural simi larity and apparently similar mechanisms of action.
Doxorubicin is one of the most important and widely used anticancer drugs. It
is used in combination with other agents for treatment of sarcomas and a
variety of carcinomas, including breast cancer, as well as for treat- ment of
acute lymphocytic leukemia and lymphomas. Daunorubicin and idarubicin
are used in the treatment of acute leukemias, and mito- xantrone is used in
prostate cancer.
1. Mechanism of action: Doxorubicin and other anthracyclines induce cytotoxicity through several
different mechanisms. For example, doxorubicin-derived free radicals can induce membrane lipid
peroxidation, DNA strand scission, and direct oxidation of purine or pyrimidine bases, thiols, and amines
(Figure 35.15).
2. Pharmacokinetics: These agents must be administered intrave- nously, because they are inactivated in
the Gl tract. Extravasation is a serious problem that can lead to tissue necrosis. The anthracy- cline
antibiotics bind to plasma proteins as well as to other tissue components, where they are widely
distributed. They do not pen- etrate the blood-brain barrier or the testes. These agents undergo extensive
hepatic metabolism, and dosage adjustments are needed in patients with impaired hepatic function.
Biliary excretion is the major route of elimination. Because of the dark red color of the anthracycline
drugs, the veins may become visible surround- ing the site of infusion, and red discoloration of urine may
occur.
3. Adverse effects: Irreversible, dose-dependent cardiotoxicity
is the most serious adverse reaction and is more common with daunorubicin and doxorubicin than with
idarubicin and epirubicin. Cardiotoxicity apparently results from the generation of free radi- cals and lipid
peroxidation. Addition of trastuzumab to protocols with doxorubicin or epirubicin increases the risk of
congestive heart failure. There has been some success with the iron chelator dexrazoxane in protecting
against the cardiotoxicity of doxorubi- cin. The liposomal-encapsulated doxorubicin is reported to be less
cardiotoxic than the standard formulation.
B. Bleomycin

Bleomycin [blee-oh-MYE-sin] is a mixture of different copper-chelat- ing glycopeptides that, like the
anthracycline antibiotics, cause scis- sion of DNA by an oxidative process. Bleomycin is cell cycle specific
RIMBERIO
and causes cells to accumulate in the G, phase. It is primarily used in the treatment of testicular cancers
and Hodgkin lymphoma.

1. Mechanism of action: A DNA-bleomycin-Fe complex appears to undergo oxidation to bleomycin-Fe.

The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which, in turn. attack
the phosphodiester bonds of DNA, resulting in strand breakage and chromosomal aberrations (Figure
35.16).

2. Pharmacokinetics: Bleomycin is administered by a number of routes. The bleomycin-inactivating

enzyme (a hydrolase) is high in a number of tissues (for example, liver and spleen) but is low in the lung
and absent in the skin, accounting for toxicity in those tissues. Most of the parent drug is excreted
unchanged in the urine, neces sitating dose adjustment in patients with renal failure.

3. Adverse effects: Pulmonary toxicity is the most serious adverse effect, progressing from rales, cough,
and infiltrate to potentially fatal fibrosis. The pulmonary fibrosis that is caused by bleomycin is often
referred as "bleomycin lung." Hypertrophic skin changes and hyperpigmentation of the hands are
prevalent. Bleomycin is unusual in that myelosuppression is rare.
RIMBERIO
ALKYLATING AGENTS

Alkylating agents (Figure 35.17) exert their cytotoxic effects by

covalently binding to nucleophilic groups on various cell
constituents. Alkylation of DNA is probably the crucial
cytotoxic reaction that is lethal to the tumor cells. Alkylating
agents do not discriminate between cycling and resting cells,
even though they are most toxic for rapidly dividing cells. They
are used in combination with other agents to treat a wide
variety of lymphatic and solid cancers. In addition to being
cytotoxic, all are mutagenic and carcinogenic and can lead to
secondary malignancies such as acute leukemia.
A. Cyclophosphamide and ifosfamide
These drugs are very closely related mustard agents that share most of the same primary
mechanisms and toxicities. They are cytotoxic only after generation of their alkylating species,
which are produced through hydroxylation by cytochrome P450 (CYP450). These agents. have
a broad clinical spectrum and are used as single agents or in combinations in the treatment of
a wide variety of neoplastic dis- eases, such as non-Hodgkin lymphoma, sarcoma, and breast
cancer

1. Mechanism of action:
Cyclophosphamide [sye-kloe-FOSS- fah-mide] is the most commonly used alkylating agent.
Both cyclophosphamide and ifosfamide [eye-FOSS-fah-mide) are first biotransformed to
hydroxylated intermediates primarily in the liver by the CYP450 system (Figure 35.18). The
hydroxylated intermedi- ates then undergo metabolism to form the active compounds, phos-
phoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is
considered to be the cytotoxic step.
2. Pharmacokinetics:
Cyclophosphamide is available in oral and IV
preparations, whereas ifosfamide is IV only. Cyclophosphamide is metabolized in
the liver to active and inactive metabolites, and minimal amounts are excreted in
the urine as unchanged drug. Ifosfamide is metabolized primarily by CYP450 3A4
and 286 iso- enzymes. It is mainly renally excreted.

3. Adverse effects:
A unique toxicity of both drugs is hemorrhagic cystitis, which can lead to fibrosis
of the bladder. Bladder toxicity has been attributed to acrolein in the urine in the
case of cyclophos- phamide and to toxic metabolites of ifosfamide. Adequate
hydration as well as IV injection of mesna (sodium 2-mercaptoethane sulfo- nate),
which neutralizes the toxic metabolites, can minimize this problem. Neurotoxicity
has been reported in patients on high-dose ifosfamide, probably due to the
metabolite, chloroacetaldehyde.
B. Nitrosoureas

Carmustine [KAR-mus-teen, BCNU] and lomustine [LOE-mus-teen, CCNU] are closely related
nitrosoureas. Because of their ability to penetrate the CNS, the nitrosoureas are primarily employed
in the treatment of brain tumors.

1. Mechanism of action:
The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually,
RNA and agent protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is
expressed primarily in cells that are actively dividing. Therefore, nondividing cells can escape death
if DNA repair. occurs. Nitrosoureas also inhibit several key enzymatic processes by carbamoylation
of amino acids in proteins in the targeted cells

2. Pharmacokinetics:
Carmustine is administered IV and as chemotherapy wafer implants, whereas lomustine is given
orally. Because of their lipophilicity, these agents distribute widely in the body and readily penetrate
the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active prod- ucts. The
kidney is the major excretory route for the nitrosoureas (Figure 35.19
C. Dacarbazine and temozolomide

Dacarbazine [dah-KAR-bah-zeen] is an alkylating agent that must undergo biotransformation to

an active metabolite, methyltriazeno- imidazole carboxamide (MTIC). The metabolite is
responsible for the alkylating activity of this agent by forming methyl carbonium ions that attack
the nucleophilic groups in the DNA molecule. The cytotoxic action of dacarbazine has been
attributed to the ability of its metabo- lite to methylate DNA on the O-6 position of guanine.
Dacarbazine has found use in the treatment of melanoma and Hodgkin lymphoma.
Termozolomide [te-moe-ZOE-loe-mide] is related to dacarbazine, because both must undergo
biotransformation to an active metabolite, MTIC, which is likely responsible for the methylation
of DNA on the 0-6 and N-7 position of guanine. Unlike dacarbazine, temozolomide does not
require the CYP450 system for metabolic transformation, and it undergoes chemical
transformation at normal physiological PH. Temozolomide also inhibits the repair enzyme, O-6-
guanine- DNA alkyltransferase. Temozolomide differs from dacarbazine in that it crosses the
blood-brain barrier and, therefore, is used in the treatment of brain tumors such as
glioblastomas and astrocytomas. It is also used in metastatic melanoma. Temozolomide is
adminis- tered intravenously or orally and has excellent bioavailability after oral administration.
The parent drug and metabolites are excreted in urine (Figure 35.20).
D. Other alkylating agents

Mechlorethamine [mek-lor-ETH-ah-meen] was developed as a vesicant (nitrogen mustard)

during World War I. Its ability to cause lymphocytopenia led to its use in lymphatic cancers.
Melphalan [MEL- fah-lan], a phenylalanine derivative of nitrogen mustard, is used in the
treatment of multiple myeloma. This is a bifunctional alkylating agent that can be given orally,
although the plasma concentration differs from patient to patient due to variation in intestinal
absorption and metabolism. The dose of melphalan is carefully adjusted by monitor- ing the
platelet and white blood cell counts. Chlorambucil (clor-AM- byoo-sil] is another bifunctional
alkylating agent that is used in the treatment of chronic lymphocytic leukemia, Busulfan [byoo-
SUL-fan] is an alkylating agent that is effective against chronic myelogenous leukemia. This
agent can cause pulmonary fibrosis ("busulfan lung"). Like other alkylating agents, all of these
agents are leukemogenic
MICROTUBULE INHIBITORS
The mitotic spindle is part of a larger, intracellular skeleton
(cytoskel- eton) that is essential for the movements of structures
occurring in the cytoplasm of all eukaryotic cells. The mitotic
spindle consists of chroma- tin plus a system of microtubules
composed of the protein tubulin. The mitotic spindle is essential for
the equal partitioning of DNA into the two daughter cells that are
formed when a eukaryotic cell divides. Several plant-derived
substances used as anticancer drugs disrupt this process by
affecting the equilibriurn between the polymerized and
depolymerized forms of the microtubules, thereby causing
cytotoxicity. The microtubule inhibitors are summarized in Figure
35.21.
A. Vincristine and vinblastine

Vincristine [vin-KRIS-teen] (VX) and vinblastine [vin-BLAS-teen] (VBL) are structurally related
compounds derived from the periwin- kle plant, Vinca rosea. They are, therefore, referred to
as the Vinca alkaloids. A less neurotoxic agent is vinorelbine (vye-NOR-el-been) (VRB).
Although the Vinca alkaloids are structurally similar, their therapeutic indications are
different. They are generally adminis- tered in combination with other drugs. VX is used in
the treatment of acute lymphoblastic leukemia in children, Wilms tumor, Ewing soft tissue
sarcoma, and Hodgkin and non-Hodgkin lymphomas, as well as some other rapidly
proliferating neoplasms. (Note: VX (former trade name. Oncovin) is the "O" in the R-CHOP
regimen for lymphoma. Due to relatively mild myelosuppressive activity, VX is used in a
number of other protocols.] VBL is administered with bleomycin and cisplatin for the
treatment of metastatic testicular carcinoma. It is also used in the treatment of systemic
Hodgkin and non-Hodgkin lymphomas. VRB is beneficial in the treatment of advanced non-
small cell lung cancer, either as a single agent or with cisplatin.
1. Mechanism of action: These agents are cell cycle specific and phase specific, because they
block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, blocks
the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates
consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional
spindle apparatus, frozen in metaphase, prevents chromosomal segrega- tion and cell
proliferation (Figure 35.22).

2. Pharmacokinetics: IV injection of these agents leads to rapid cytotoxic effects and cell
destruction. This, in turn, can cause hyperuricemia due to the oxidation of purines that are
released from fragmenting DNA molecules. The Vinca alkaloids are con- centrated and
metabolized in the liver by the CYP450 pathway and eliminated in bile and feces. Dosage
adjustment is required in patients with impaired hepatic function or biliary obstruction.

3. Adverse effects: VX and VBL are both associated with phlebitis or cellulitis if extravasation
occurs during injection, as well as nau- sea, vomiting, diarrhea, and alopecia. VBL is a potent
myelosup- pressant, whereas peripheral neuropathy (paresthesias, loss of reflexes, foot drop, and
ataxia) and constipation are more common with VX. These agents should not be administered
intrathecally. This potential drug error can result in death, and special precau- tions should be in
place for administration
B. Paclitaxel and docetaxel
Paclitaxel [PAK-li-tax-el] was the first member of the taxane family to be used in cancer chemotherapy.
Semisynthetic paclitaxel is avail- able through chemical modification of a precursor found in the nee- dles
of Pacific yew species. An albumin-bound form is also available. Substitution of a side chain resulted in
docetaxel [doe-see-TAX-el), which is the more potent of the two drugs. Paclitaxel has good activity against
advanced ovarian cancer and metastatic breast cancer, as well as non-small cell lung cancer when
administered with cisplatin. Docetaxel is commonly used in prostate, breast, Gl, and non-small cell lung
cancers.

1. Mechanism of action: Both drugs are active in the G/M phase of the cell cycle, but unlike the Vinca
alkaloids, they promote polym erization and stabilization of the polymer rather than disassem bly, leading
to the accumulation of microtubules (Figure 35.23). The microtubules formed are overly stable and
nonfunctional, and chromosome desegregation does not occur. This results in cell death.
2. Pharmacokinetics: These agents undergo hepatic metabolism by the CYP450 system and are excreted
via the biliary system. Dosages should be reduced in patients with hepatic dysfunction.
3. Adverse effects: The dose-limiting toxicities of paclitaxel and docetaxel are neutropenia and leukopenia.
Peripheral neuropathy is also a common adverse effect with the taxanes. (Note: Because of serious
hypersensitivity reactions (including dyspnea, urticaria, and hypotension), patients who are treated with
paclitaxel should be premedicated with dexamethasone and diphenhydramine, as well as with an H,
receptor antagonis
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