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

Miscellaneous 13) Busulfan 14) Chlorambucil 15) Lomustine

Alkylating agents Nitrosoureas -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

Pharmacological effects : -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

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

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

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

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

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.

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

Trimetrexate Pemetrexed Cytarabine Thioguanine Gemcitabine Capecitabine Thioguanine Fludarabine Phosphate Cladribine

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

Antimetabolits: sites of drug action

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.

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

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

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.

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

2) 6 – MP:- Azathioprine – 6MP PK:- 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

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

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

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

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