The document provides an overview of various anticancer drugs, categorizing them into groups such as antimetabolites, alkylating agents, antibiotics, and microtubule inhibitors. It details specific drugs within these categories, including their mechanisms of action, therapeutic uses, and effects on DNA synthesis and cell division. Key drugs discussed include methotrexate, 6-mercaptopurine, and cisplatin, highlighting their roles in treating different types of cancers.

1. Cancer Chemotherapy
Lecture 10

2. Anticancer drugs
 Antimetabolites
 Alkylating agents
 Antibiotics
 Microtubule inhibitors
 Miscellaneous agents
Lecture 10

3. Lecture 10
Antimetabolites
 Methotrexate
 6-marcaptopurine
 5-fluorouracil
 Cytrabine

4. 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.

5. Lecture 10
Methotrexate

6. 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.

7. 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

8. Lecture 10
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

9. Lecture 10
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

10. 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
Lecture 10
+) 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

11. 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

12. Lecture 10
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

13. 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

14. Antibiotics
 Dactinomycin
 Doxorubicine and donorubicine
Lecture 10

15. 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

16. 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
Lecture 10

17. Microtubule inhibitors
Background:
 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
Lecture 10
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

18. Microtubule inhibitors
Lecture 10
 Vincristin and Vinblastin
 Taxols

19. 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
Lecture 10
metaphase stage
 Prevents chromosomal segregation and cell proliferation

20. Lecture 10
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

21. Lecture 10
Miscellaneous agents
 Cisplatin
 Etoposide
 Bleomycin

22. Lecture 10
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

23. Lecture 10
Etoposide
 A semi-synthetic derivative of the plank alkaloid
podophylotoxin
 Blocks cell cycle at S -- G2 phase
 Major target is topoisomerage II

24. Lecture 10
Bleomycin
 Mixture of different copper chelating glycoproteins

25. Sites of Action of Cytotoxic Agents – Cellular Level
25
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