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2 alkylating antimetabolties

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CANCER CHEMOTHERAPY: ALKYLATING AGENTS & ANTIMETABOLITES BY DR. HARSHIKA PATEL MEDB 335 BASIC PHARMACOLOGY AND TOXICOLOGY KEMU ALKYLATING AGENTS History • Sulfur mustard gas – potent vesicant • Clinical trials with SMG – penile tumor • Gillman and his colleagues work on nitrogen mustard against murine lymphoma • In 1942, clinical trials began → pt with lymphoma → treated by i.v. NM • Launching modern era of cancer chemo ALKYLATING AGENTS • Nitrogen Mustards (MCI) – Meclorethamine, Melphalan, Chlorambucil, Cyclophosphamide, Ifosfamide (M2C2I ) • Ethyleneimine : Thio-tepa • Alkyl Sulfonate: Busulfan • Nitrosoureas – Carmustine, lomustine, Streptozocin • Triazine /DNA methylating drugs -procarbazine,temozolomide, dacarbazine Other group of cytotoxic drugs Platinum compound…… Cisplatin Carboplatin Oxaliplatin Highly reactive intermediate – carbonium ions Structure activity relationship meclorethamine Chlorambucil melphalan MECHANISMS OF RESISTANCE OF ALKYLATING AGENTS • Acquired resistance –to alkylating agents • Mechanism: involved in ❑ Inc’ capability to repair DNA lesions, ❑ Dec’ permeability of the cell to drug, ❑ Inc’ production of glutathione* (cause higher metabolism rate) PHARMACOLOGICAL ACTIONS • Cytotoxic action – vesicant property • Hemopoietic system highly susceptible • Chlorambucil ✓ more against lymphoid series • Busulfan ✓ more against myeloid series ✓Epithelial tissues, ha ...
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