Lecture 10

Cancer Chemotherapy

Lecture 10

Anticancer drugs

Antimetabolites Alkylating agents Antibiotics Microtubule inhibitors Miscellaneous agents

Lecture 10

Antimetabolites

Methotrexate 6-marcaptopurine 5-fluorouracil Cytrabine

Lecture 10

Methotrexate

Structurally related to folic acid Inhibitor of an enzyme dihydrofolate reductase (DHFR) DHFR reduces duhydrofolate (FH2) to tetrahydofolate (FH4)

using NADH as electron donor The affinity of MTX for DHFR is thousand times higher than

that of folate for DHFR Therefore the enzyme is competitively inhibited Acts mainly on S phase.

Lecture 10

Methotrexate

Lecture 10

Methotrexate

Inhibition of DHFR deprive the cell of folic acid Folic acid is required for the de novo synthesis of thymidine Folate is also needed for the synthesis of purine nucleotides MTX therefore, inhibit the synthesis of DNA, RNA,

thymidylates and protieins. MTX acts specifically during DNA and RNA synthesis and

thus cytotoxic during the S-phase of cell cycle and has a great effect on rapidly dividing cells.

Effective against Burkitt’s lymphoma, Breast cancer, Head and neck carcinoma.

Lecture 10

6-Marcaptopurine

Purine analogue, structural analogue of hypoxanthine Inhibits 1st step of de novo prurine biosynthesis, thereby inhibiting

their synthesis The thiol anallogues are also incorporated into DNA and RNA Used in acute lymphoblastic leukemia

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5-Fluorouracil

Pyrimidine analogue, fluorine substituted analogue of uracil Has a stable fluorine at position 5 in place of hydrogen atom Interferes with the conversion of deoxyuridylic acid to thymidylic acid

by inhibiting Thymudylate synthase Inhibits cells ability to synthesize DNA Used in colorectal, ovarian, pancreatic and gastric carcinoma

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Cytrabine

Analogue of 2’ deoxycytidine in which natural ribose is replaced by D-arabinose

Acts as a pryrimidine antagonist Biotransformed to its active form – ara CTP Competitively inhibits DNA polymerase No effect on protein or RNA synthesis Used in acute myelogenous leukemia

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Alkylating agent

Exert their cytotoxic effect by covalently binding with nucleophilic group of various cell constituents.

Act via a reactive alkyl group (R-CH2-CH2+) to form covalent bond

Alkylation of DNA is the crucial cytotoxic reaction that is lethal to tumor cell

They are phase non-specific. Do not discriminate between dividing and resting cells but are most

toxic for rapidly dividing cells.

Alkylating agents include: Cyclophosphamide Nitrosuria Nitrogen mustard

Lecture 10

Cyclophosphamide

Pro-drug, requires metabolic activation Cyt P450 system converts it into a hydroxylated intermediate Alkylation of DNA is considered to be the cytotoxic step Inter- and intra-strand cross-linking of DNA at N7 of guanine causes

cell death Used in Burkitt’s Lymphoma and breast cancer

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Nitrogen mustard

First developed during World War II as a vesicant or blister agent They are transported into the cell by a chloride uptake process The drug lose a chloride ion and forms a reactive intermediate that

alkylates N7 of guanine residue in one or both the strand of DNA Leads to cross-linkages between guanine residues in DNA strands Leads to depurination that facilitates DNA strand breakage Predominantly used in Hodgkin’s disease

Lecture 10

Nitrosurea

Exert cytotoxic effect by alkylation that crosslink DNA strands Inhibits DNA replication Because of their ability to penetrate CNS, they are primarily

used in the treatment of brain tumors Limited in the treatment of other cancer

Lecture 10

Antibiotics

Dactinomycin Doxorubicine and donorubicine

Lecture 10

Dactinomycin

Intercalates into the minor groove of the double helix between G-C base pairs of DNA

Forms a stable dactinomycin-DNA complex Inhibits DNA-dependent RNA synthesis Blocks protein synthesis Used in gastric carcinoma and soft tissue carcinoma

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Doxorubicine and donorubicine

Inserted non-specifically between adjacent base pairs Binds to sugar-phosphate backbone of DNA Causes a local uncoiling of the DNA molecule Blocks DNA and RNA synthesis

Doxorubicin Daunorubicin

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Microtubule inhibitors

Mitotic spindle is a part of cytoskeleton Essential for the internal movement of cytoplasm in all eukaryotic cells It is also essential for the equal partitioning of DNA into daughter cells during cell

division Mitotic spindle consists of chromatin and a protein tubulin Polymerization of tubulin molecule is a necessary step in the formation of mitotic

spindle Several plant alkaloids used as anticancer drugs that disrupt this process by affecting

the equilibrium between polymerized and depolymerized formd of tubulin

Background:

Lecture 10

Microtubule inhibitors

Vincristin and Vinblastin Taxols

Lecture 10

Vincritine and vinblstine

Isolated form a plant Vinca rosea Sometimes referred to as vinca alkaloids Both vincristine and vinblastin binds to tubulin Blocks the ability of tubulin to polymerize An aggregate of tubulin-dimer and the drug is formed Resulting dysfunctional spindle apparatus that are frozen at

metaphase stage Prevents chromosomal segregation and cell proliferation

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Taxol

Isolated for the needle of yew species Binds reversibly to tubulin Unlike vinca alkaloids it promotes tubulin polymerization Stabilize the polymer which is non functional

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Miscellaneous agents

Cisplatin Etoposide Bleomycin

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Cisplatin

The drug is a platinum complex Has synergistic cytotoxicity with radiation and other

chemmotherapeutic agents Mechanism of action is similar to alkylating agents Binds to N7 of guanine

Forms inter- and intra-strand cross-linkage in the DNA strands

Used in Testicular, bladder and ovarian cancer

Lecture 10

Etoposide

A semi-synthetic derivative of the plank alkaloid podophylotoxin

Blocks cell cycle at S -- G2 phase

Major target is topoisomerage II

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Bleomycin

Mixture of different copper chelating glycoproteins

25

DNA synthesis

AntimetabolitesAntimetabolites

DNA

DNA transcription DNA duplication

Mitosis

Alkylating agentsAlkylating agents

Spindle poisonsSpindle poisons & &

Microtuble StablizersMicrotuble Stablizers

Intercalating agentsIntercalating agents

Sites of Action of Cytotoxic Agents – Cellular Level