抗癌药（Anti-CancerDrugs）.ppt

Procarbazine hydrochloride (MIH, Matulane) Procarbazine has the ability to alkylate through free radical formation. The compound in initially activated in vivo to active form in which methylhydrazine is formed and is farther oxidized to methyldiazine which results in the formulation of the hydrogen and methyl radicals. Procarbazine is used in capsules form and it is active against Hodgkin’s disease and for this, it is used in the MOPP regimen or program. It has weak MAD inhibiting activity and may cause hypertension. Procarbazine hydrochloride (MIH, Matulane) Dacarbazine (DTIC) and Temozolomide Dacarbazine is a dimethyl triazenyl imidazole carboxamide (DTIC) which is though to act as an alkylating agent. It must be administered via intravenous route and it is bioactivated through reactions involving CYP 450. DACARBAZINE Activation of the agent occurs through the action of CYP (isozymes 1A1, 1A2, and 2E1) to give the demethylated product monomethyl triazeno imidazole carboxamide (MTIC) (Scheme 10.14). Tautomerization allows for decomposition to give the amino- carboxamido-imidazole and diazomethane, which is capable of alkylating DNA. An alternative pathway involves acid catalyzed or photoinduced loss of dimethylamine to give an alternative diazo compound (diazo-IC), which may not only generate a carbocation but also undergoes internal cyclization to give 2-azo-hypoxanthine. Formation of diazo-IC has been associated with pain at the injection site, which is often seen during dacarbazine administration. Methylation of DNA occurs at N-7, N-3 and O-6 of guanine among other sites. Dacarbazine proved to be more active against murine tumors than against human tumors. This was attributed to the enhanced ability of mice to metabolize the agent to MTIC and the subsequent conversion to a methylating species. Dacarbazine (DTIC) and Temozolomide Temozolomide is a prodrug which is non-enzymatically converted into MTIC which alkylate DNA in a manner similar to that o