Al-Mustaqbal University College
Department of Pharmacy
4th stage
Pharmacology III
Lecture: 2
ANTICANCER DRUGS
Dr Qassim A zigam
2. ANTITUMOR ANTIBIOTICS
• Their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA
function.
• In addition to intercalation, their abilities to inhibit topoisomerases (I and II) and produce
free radicals also play a major role in their cytotoxic effect.
• With the exception of bleomycin they are cell cycle nonspecific and include:
✓Anthracyclines: Doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone
✓Bleomycin
✓Mitomycin
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
2. ANTITUMOR ANTIBIOTICS
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Anthracyclines
• They include Doxorubicin (hydroxylated analog of daunorubicin )and daunorubicin,
Idarubicin (4-demethoxy analog of daunorubicin), epirubicin, and mitoxantrone.
• Applications for these agents differ despite their structural similarity and their 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 the treatment of sarcomas and a variety of
carcinomas, including breast and lung, as well as for the treatment of ALL and lymphomas.
• Daunorubicin and idarubicin are used in the treatment of acute leukemias, and
mitoxantrone is used in prostate cancer.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Anthracyclines
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 the
direct oxidation of purine or pyrimidine bases, thiols, and
amines.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Anthracyclines
2. Pharmacokinetics:
• All these drugs must be administered IV because they are inactivated in the
GI tract.
• Extravasation is a serious problem that can lead to tissue necrosis.
• The anthracycline antibiotics bind to plasma proteins as well as to other
tissue components, where they are widely distributed.
• They do not penetrate the BBB 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.
• Some renal excretion also occurs, but dosage adjustments are generally not
needed in renal dysfunction.
• Because of the dark red color of the anthracycline drugs, the veins may
become visible surrounding the site of infusion, and red discoloration of urine
may occur.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Anthracyclines
3. Adverse effects:
• Irreversible, dose-dependent cardiotoxicity, apparently a result of the generation of free
radicals and lipid peroxidation, is the most serious adverse reaction and is more common with
daunorubicin and doxorubicin than with idarubicin and epirubicin.
• Addition of trastuzumab (Herceptin®) to protocols with doxorubicin or epirubicin increases
congestive heart failure.
• There has been some success with the iron chelator dexrazoxane in protecting against the
cardiotoxicity of doxorubicin.
• The liposomal-encapsulated doxorubicin is reported to be less cardiotoxic than the usual
formulation.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Bleomycin
• Bleomycin is a mixture of different copper-chelating glycopeptides, that
cause the scission of DNA by an oxidative process.
• Bleomycin is cell cycle specific and causes cells to accumulate in the G2
phase.
• It is primarily used in the treatment of testicular cancers and Hodgkin
lymphoma.
1. Mechanism of action:
• A DNA–bleomycin–Fe2+ complex appears to undergo oxidation to
bleomycin–Fe3+.
• 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.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Bleomycin
2. Resistance:
• Increased levels of bleomycin hydrolase (or deaminase), glutathione S-transferase, increased
efflux of the drug have been implicated, and DNA repair also may contribute.
3. Pharmacokinetics:
• Bleomycin is administered by a number of routes such as SC, IM, IV, and IP.
• The bleomycin-inactivating enzyme (a hydrolase) is high in a number of tissues (for example,
the liver and spleen) but is low in the lung and is absent in the skin (accounting for the drug’s
toxicity in those tissues).
• Most of the parent drug is excreted unchanged in the urine, necessitating dose adjustment in
patients with renal failure.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Bleomycin
4. Adverse effects:
• Mucocutaneous reactions such as (rash, erythema, hyperpigmentation, & urticaria) and
alopecia are common.
• Hypertrophic skin changes and hyperpigmentation of the hands are prevalent.
• There is a high incidence of fever and chills and a low incidence of serious anaphylactoid
reactions.
• 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 to as “bleomycin lung.”
• Bleomycin is unusual in that myelosuppression is rare.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
3. ALKYLATING AGENTS
• Alkylating agents exert their cytotoxic effects by covalently binding to nucleophilic (electron-
rich) groups on various cell constituents.
• Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells.
• Agents do not discriminate between cycling and resting cells, even though they are more
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.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
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 the generation of their alkylating species, which are produced
through hydroxylation by cytochrome P450 (CYP450).
• These agents have a broad clinical spectrum, being used either singly or as part of a regimen
in the treatment of a wide variety of neoplastic diseases, such as non-Hodgkin lymphoma,
sarcoma, and breast cancer.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Cyclophosphamide and ifosfamide
1. Mechanism of action:
• Cyclophosphamide is the most commonly used alkylating agent.
• Both cyclophosphamide and ifosfamide are first biotransformed to
hydroxylated intermediates primarily in the liver by the CYP450 system.
• Then hydroxylated intermediates then undergo breakdown to form the
active compounds, phosphoramide mustard, and acrolein.
• Reaction of the phosphoramide mustard with DNA is considered to be the
cytotoxic step.
• The parent drug and its metabolites are primarily excreted in the urine.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Cyclophosphamide and ifosfamide
2. Pharmacokinetics:
• Cyclophosphamide is available in oral or 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 an unchanged drug.
• Ifosfamide (prodrug) is metabolized primarily by CYP450 3A4 and 2B6 isoenzymes, it is
mainly renally excreted.
3. Resistance:
• Resistance results from increased DNA repair, decreased drug permeability, and the
reaction of the drug with thiols (for example, glutathione).
• Cross-resistance does not always occur.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Cyclophosphamide and ifosfamide
4. 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 cyclophosphamide
and to toxic metabolites of ifosfamide.
• Adequate hydration as well as IV injection of MESNA (sodium 2-mercaptoethane sulfonate),
which neutralizes the toxic metabolites, can minimize this problem.
• A fairly high incidence of neurotoxicity has been reported in patients on high-dose
ifosfamide, probably due to the metabolite chloroacetaldehyde.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Nitrosoureas
• Carmustine and lomustine are closely related nitrosoureas.
• Because of their ability to penetrate the CNS, 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 protein synthesis.
• Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily on 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.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Nitrosoureas
2. Pharmacokinetics:
• In spite of the similarities in their structures, carmustine is administered IV and as
chemotherapy wafer implants, whereas lomustine is given orally.
• Because of their lipophilicity, they distribute widely in the body, but their most striking
property is their ability to readily penetrate the CNS.
• The drugs undergo extensive metabolism.
• Lomustine is metabolized to active products.
• The kidney is the major excretory route for the nitrosoureas.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
C. Dacarbazine
• Dacarbazine is an alkylating agent that must undergo biotransformation
to an active metabolite, methyltriazenoimidazole carboxamide (MTIC).
• This metabolite is responsible for the drug’s activity as an alkylating
agent by forming methylcarbonium ions that can attack the nucleophilic
groups in the DNA molecule.
• The cytotoxic action of dacarbazine has been attributed to the ability of
its metabolite to methylate DNA on the O6 position of guanine.
• Dacarbazine has found use in the treatment of melanoma and Hodgkin
lymphoma.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
D. Temozolomide
• Temozolomide, a triazene agent, has been approved for use against glioblastomas,
anaplastic astrocytomas, and metastatic melanoma.
• Temozolomide also undergoes biotransformation to an active metabolite, MTIC, which
probably is responsible for the methylation of DNA on the 6 position of guanine.
• Temozolomide also has the property of inhibiting the repair enzyme, O6-guanine-DNA alkyl
transferase.
• Temozolomide differs from dacarbazine in that it crosses the BBB.
• Temozolomide is administered intravenously or orally and has excellent bioavailability after
oral administration.
• The parent drug and metabolites are excreted in urine.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
OTHER ALKYLATING AGENTS
Melphalan:
• Melphalan 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 melphalan can be given orally, the plasma concentration differs from patient to
patient due to variations in intestinal absorption and metabolism.
• The dose of melphalan is carefully adjusted by monitoring the platelet and white blood cell
counts.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
OTHER ALKYLATING AGENTS
• Mechlorethamine:
• It was developed as a vesicant (nitrogen mustard) during World War I. Its ability to cause
lymphocytopenia led to its use in lymphatic cancers.
• Chlorambucil:
• It is another bifunctional alkylating agent that is used in the treatment of chronic
lymphocytic leukemia.
• Both melphalan and chlorambucil have moderate hematologic toxicities and GIT upset.
• Busulfan:
• It is another oral agent that is effective against chronic granulocytic leukemia.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
4. MICROTUBULE INHIBITORS
• The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for
the movements of structures occurring in the cytoplasm of all eukaryotic cells.
• The mitotic spindle consists of chromatin 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 equilibrium between the polymerized and depolymerized forms of the microtubules,
thereby causing cytotoxicity.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Vincristine, vinblastine, and vinorelbine
• Vincristine (VX) and vinblastine (VBL) are structurally related
compounds derived from the periwinkle plant, Vinca rosea,
therefore, referred to as the Vinca alkaloids.
• A less neurotoxic agent is vinorelbine (VRB).
• Although the Vinca alkaloids are structurally similar to one
another, their therapeutic indications are different.
• They are generally administered in combination with other
drugs.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Vincristine, vinblastine, and vinorelbine
• 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.
• 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.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Vincristine, vinblastine, and vinorelbine
1. Mechanism of action:
• VX, VRB, and VBL are all 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
segregation and cell proliferation.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Vincristine, vinblastine, and vinorelbine
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 concentrated and metabolized in the liver by the CYP450 pathway
and eliminated in bile and feces.
• Doses must be modified in patients with impaired hepatic function or biliary obstruction.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
A. Vincristine, vinblastine, and vinorelbine
3. Adverse effects:
• VX and VBL have certain toxicities in common, these include phlebitis or cellulitis, if the
drugs extravasate during injection, as well as N/V/D and alopecia.
• However, the adverse effects of VX and VBL are not identical.
• VBL is a more potent myelosuppressant than VX, whereas peripheral neuropathy
(paresthesias, loss of reflexes, foot drop, and ataxia) is associated with VX.
• Constipation is more frequently encountered with VX.
• These agents should not be administered intrathecally, this potential drug error can result in
death, and special precautions should be in place for administration.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Paclitaxel and docetaxel
• Paclitaxel was the first member of the taxane family to be used in cancer chemotherapy.
• A semisynthetic paclitaxel is now available through chemical modification of a precursor
found in the needles of Pacific yew species.
• An albumin-bound form is also available.
• Substitution of a side chain has resulted in docetaxel, which is the more potent of the two
drugs.
• Paclitaxel has shown good activity against advanced ovarian cancer and metastatic breast
cancer.
• Favorable results have been obtained in non–small cell lung cancer when administered with
cisplatin.
• Docetaxel is commonly used in prostate, breast, GI, and non–small cell lung cancers.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Paclitaxel and docetaxel
1. Mechanism of action:
• Both drugs are active in the G2/M-phase of the cell cycle, but
unlike the Vinca alkaloids, they promote polymerization and
stabilization of the polymer rather than disassembly, leading to
the accumulation of microtubules.
• The overly stable microtubules formed are nonfunctional, and
chromosome desegregation does not occur, this results in
death of the cell.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
B. Paclitaxel and docetaxel
2. Pharmacokinetics:
• These agents undergo hepatic metabolism by the CYP450 system and are excreted via the
biliary system.
• Dose modification is not required in patients with renal impairment, but doses should be
reduced in patients with hepatic dysfunction.
3. Adverse effects:
• The dose-limiting toxicities of paclitaxel and docetaxel are neutropenia and leukopenia.
• Alopecia occurs, but vomiting and diarrhea are uncommon.
• 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 H2 blocker.
Pharmacology III 4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
THANK YOU FOR
YOUR ATTENTION
Pharmacology III/4th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A Zigam
