Alkylating agents:

1. Alkylating agents: • Platinum analogs • Carboplatin • Cisplatin • Oxaliplatin • Triazenes • Dacarbazine • Procarbazine • Temozolomide • Nitrogen Mustards • Bendamustine • Cyclophosphamide • Estramustine • Ifosfamide • Mechlorethamine • Melphalan

2. Miscellaneous 13) Busulfan 14) Chlorambucil 15) Lomustine

3. Alkylating agents • -Transfer alkyl group to cellular elements • Alkylation of DNA • Drug – Cyclization – ethyleimonium ion – transfer alkyl group to DNA • Nitrosoureas • -Carbamoylation of lysine of proteins • -Single strand or both strands – BIFUNCTIONAL

4. -DNA Strand breakage • Cross linking of DNA • CCNS. • Mostly in late G1 & S • Pharmacological effects : • Dose related ADR. On rapidly growing tissue • Carinogenic – Secondary esp. AML • VESICANT

5. CYCLOPHOSPHAMIDE • NITROSOUREAS: • Not cross resistant with other alkylating agents • Enter BBB- lipid soluble – Brain tumors • Oral administration • STREPTOZOCIN

6. 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 SIADH and pulmonary toxicity

8. NON CLASSICAL ALKYLATING AGENTS: • PROCARBAZINE: Hodgkin's, Non – Hodgkin's, Brain • -Microsomal enzymes – azoprocarbazine + H2O2 • One metabolite – weak MAOI • Increase risk of secondary cancer

9. DACARBAZINE • Activation in liver  monomethyl derivative  diazomethane,  methyl Carbonium ion cytotoxic • Malignant melanoma, HL, Soft tissue sarcomas, neuroblastoma. • Potent vesicant

10. BENDAMUSTINE: • Bi functional • PLATINUM ANALOGS: Cisplatin • Carboplatin • Oxatiplatin • -Kill cells in all stage of cell cycle • -Synergism with alkylating agents, fluoropyrimidines & taxanes. • -vigorous hydration – Renal toxicity.

11. -Oxaliplatin + 5-FU + leucovorin – FOLFOX regimen – metastatic colorectal cancer - Severe nausea & vomiting Neurotoxicity- dose limiting.

12. Trimetrexate Pemetrexed Cytarabine Gemcitabine Capecitabine Thioguanine Fludarabine Phosphate Cladribine

13. Anti metabolites: • Folate antag:- • Methotrexate • Pemetrexed • Punine analogs:- • 3) Cladribine • 4) Clofarabine • 5) Fludarabine • 6) Mercaptopurine • 7) Pentostatin Pyramiding analogs. 8) Azacitidine 9) Capecitabine 10) Cytarabine 11) Decitabine 12) Fluorouracil 13) Gemcitabine

14. Antimetabolits: sites of drug action

15. 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.

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

17. Contd.. • 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

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

19. Anti-metabolites:- • Methotrexate:- Mechanism of action • Leucovorin rescue • Resistance:- • Uses:- ALL, Choric cancer , Burkitt's, breast cancer, • Head & Neck Cancer • Inflammatory diseases • PR:- Intrathecal – Pharmacological sanctuary • ADR:- Renal damage, Cirrhosis, Pulmonary infiltrates

20. 2) 6 – MP:- Azathioprine – 6MPPK:- DI MOA Allopurinol 3) 6 – TG – Purine Analog Acute nonlymhocytic leukemia + daunorubicin + Cytarbine 6 – TG  HGPRT TGMP  di & tri PO4  Θ Biosynthesis of Purines Cancer abc admin by allopurinol

21. 4) Fludarabime:- CLL, hairy cell leukemia, indolent NHL high doses – encephalopathy, blindness and death. 5) Hairy cell leukemia, CLL, NHL

22. Enzyme inhibitors • Anthracy clines • Damorubicin • Doxorubicin • Epirubicin • Idraubicin • Mitoxantrone • Topoismerase inhibitors • Etoposide • Irinotecarn • Topotecam

23. Anthracy clines • Inhibit topoisornerase • High –affinity binding to DNA through intercalation – blockade of synthesis of DNA & RNA, & DNA strand scission • Generation of Seniquinone & O2 free radicals though Fe dependent process • Binding to cellular membranes to alter fluidity & non tram sport

24. Doxorubicin - Used in Many Cancer Carditoxi city -  Acute  Chronic  DEXRAZOXANE “ Radiation recall reaction”