By: Abdulaziz bin Saeedan P h.D. Department of Pharmacology E mail: a.binsaeedan@sau.sa

1. By:Abdulaziz bin SaeedanPh.D.Department of PharmacologyE mail: a.binsaeedan@sau.edu.sa Pharmacology – IVPHL-425 Chapter 3:CANCER CHEMOTHERAPY

2. Classification

3. Alkylating agents • Cyclophosphamide • Cisplatin • Procarbazine • Busulfan • Mechlorethamine

4. MOA • Contain chemgrps that covalently bind cell nucleophiles • Impt properties of drugs • Can form carbonium ions • Bifunctional (2 reactive grps) • Allow cross-linking • DNA becomes cross-linked w/ agent • Intra- or inter-strand •  Decr’dtranscr’n, repl’n •  Chain scission, so strand breaks • Alkylating agents

5. Alkylating Agents- Used in wide variety of hematologic and solid tumors Thiotepa – ovarian cancer ***Nitrosoureas (Carmustine and lomustine ) - brain tumors Highly lipid soluble drugs hence reach high concentration in the brain and CSF. Streptozocin – insulin-secreting islet cell carcinoma of the pancreas Mechlorethamine– Prodrug. It is a highly irritant drug so care should be taken to avoid extravasation during IV administration Chlorambucil (Leukeran): Slow acting and least toxic nitrogen mustard.

6. Cyclophosphamide • It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard • The active drug alkylates nucleophilic groups on DNA bases • Particularly at the N-7 position of guanine • This leads to cross linking of bases, abnormal base pairing and DNA strand breakage

9. Mechanism of resistance • The mechanisms mentioned below are common for all the alkylyting agents • Increased DNA repair • Decreased drug permeability • Production of “trapping” agents (thiols)

10. Uses • Non-Hodgkin’s lymphoma • Breast Cancer • Ovarian Cancer • Neuroblastoma

11. ADR • Acrolein is the metabolite • Responsible for causing hemorrhagic cystitis • Suprapubic pain • Hematuria • Cyctoscopic findings • This is prevented/treated by MESNA (mercaptoethanesulfonate) • Rarely cyclophosphamide can cause pulmonary toxicity

13. Cisplatin • Platinum analog • Same MOA as cyclophosphamide • **Used in testicular carcinoma • Also used for Ca of bladder, lung and ovary • Carboplatin is new drug with better safety profile ADR • Nephrotoxicity (prevented by Amifostine) • Ototoxicity (acoustic nerve damage) • Peripheral neuritis • Severe nausea and vomiting

14. Procarbazine • MOA: forms hydrogen peroxide, which generates free radicals that cause DNA damage • Important component of regimens especially for Hodgkin’s lymphoma ADR • Disulfiram like reactions

15. They are structurally similar to endogenous compounds • They act as antagonists of: • Folic acid (methotrexate) • Purines (Mercaptopurine and thioguanine) • Pyrimidine (fluorouracil, cytarabine)

16. Antimetabolits: sites of drug action

17. Methotrexate

18. Methotrexate (MTX) • MTX is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR) • Thus it interferes with the synthesis of tetrahydrofolate (THF) • THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. • Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins.

19. Mechanism of Resistance 1. Decreased drug transport 2. Altered DHFR 3. Decreased polyglutamate formation 4. Increased levels of DHFR

20. MTX • Most commonly used anticancer drug. • Cell cycle specific (CCS) drug and acts during S phase of the cell cycle. • Antineoplastic, immunosuppressant and antiinflammatory • Used in RA, psoriasis • Well absorbed orally; can also be given IM, IV or intrathecally. • It is bound to plasma proteins, does not cross the BBB and most of the drug is excreted unchanged in urine. • It is a weak acid and so is excreted better at high urine pH. Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTX ADR: • Bone marrow suppression (BMS) • Folic acid deficiency • The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin) • This is called leucovorin rescue **** • Higher the dose of MTX more the leucovorin you give**

21. Mechanism of action of methotrexate and the effect of administration of leucovorin. FH2 = dihydrofolate FH4 = tetrahydrofolate dTMP = deoxythymidine monophosphate dUMP = deoxyuridine mono phosphate. Leucovorin Rescue

22. Both 6-MP and Thioguanine are activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism ***Resistance is due to cancer cells having d activity of HGPRT Cancer cells also es alkaline phosphatase that inactivate toxic nucleotides 6-Mercaptopurine (6-MP) & Thioguanine

23. 6-MP & Allopurinol • 6-MP is metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine • Allopurinol is used frequently to treat/prevent hyperuricemia caused by many anticancer drugs. • If Allopurinol is used with 6-MP then the dose of 6-MP is reduced by more than 75%

24. Cytarabine (Ara-C) • Cytarabine arabinoside is a pyrimidine antimetabolite • The drug is activated by kinases to AraCTP • This acts as an inhibitor of DNA polymerase • Of all antimetabolites, this is the most specific for S phase of tumor cell cycle • It is an important component in acute lukemia regimens ADR: • High doses cause neurotoxicity (cerebellar dysfunction and peripheral neuritis) • Hand-foot syndrome

25. Mechanism of the cytotoxic action of 5-FU 5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase. 5-FU = 5-fluorouracil 5-FUR = 5-fluorouridine 5-FUMP = 5-fluorouridine monophosphate 5-FUDP = 5-fluorouridine diphosphate 5-FUTP = 5-fluorouridine triphosphate dUMP = deoxyuridine monophosphate dTMP = deoxythymidine monophosphate 5-FdUMP = 5-fluorodeoxyuridine monophosphate. 5-FU

26. 5-FU causes, “thymidineless death” of cells Resistance is due to d activation of 5-FU and increased thymidylatesynthase activity Uses Metastatic carcinomas of the breast and the GI tract, hepatoma Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas Combined with levamisole for Rx of colon cancer ADR: nausea, mucositis, diarrhea, hand and foot syndrome, Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression

27. THANK YOU