N

excreted in the urine. The high lipophilicity and lack of highly charged metabolites allows the carmustine-derived agent to penetrate the blood-brain barrier. As a single agent, the compound is given i.v. over 2 h, every 6 weeks.98 The major dose-limiting toxicity of BCNU is delayed and there is cumulative bone marrow suppression, which necessitates dose individualization if the patient is currently taking other myelosuppressive agents.

7.06.6 Mitomycin C

The mitomycins are antitumor antibiotics first isolated from Streptomyces spp. bacteria in the 1950s. Mitomycin C (62, MC, Mutamycin; Figure 13) contains an unusual molecular architecture including an aziridine, a quinone, and a primary carbamate. This structure allows for a unique mechanism of bioactivation of MC.100 The quinone is reduced in vivo by one of a number of enzymatic reductases, followed by the elimination of methanol to give the mitocene 63 (Figure 13).101 The 2-amino group of a guanine residue of DNA opens the aziridine yielding 64. Nucleophilic displacement of the carbamate forms a 1,2-interstrand adduct to a guanine of the complementary strand 65. MC cross-linking of DNA is specific to dCpG CpG duplex sites in DNA.102'103

7.06.6.1 Clinical Use of Mitomycin C (62)

MC was initially approved for clinical use in 1974 for treatment of stomach and pancreatic cancers. It has since been used in several other cancer types, including bladder, breast, cervical, colorectal, head and neck, and nonsmall cell lung cancer.104 For example, although typically used in combination, MC has shown single-agent activity in breast cancer.105 In the FILM combination for first-line treatment of advanced breast cancer, 5-fluorouracil (750 mgm_2), ifosfamide (1 gm_2), leucovorin (200mgm_2), and mitomycin C (6mgm_2, alternate cycles) are given in 3-week cycles on an outpatient basis. From a trial cohort of 90 patients on the FILM regimen, 70% were in remission and 86% were alive after 5 years.106

One common side effect of MC is dose-dependent myelosuppression.107 This is evidenced by delayed leucopenia and thrombocytopenia. The dose-limiting toxicity is hemolytic uremic syndrome. The end result can be irreversible renal damage, which is usually lethal. This side effect can generally be avoided by maintaining a cumulative dose of <30 mgm _ 2.

7.06.6.2 Resistance to Mitomycin C

Resistance to MC can be caused by a lack of activation. Single electron reduction of MC by several enzymes can be reversed by molecular oxygen. However, under normoxic conditions, MC can be reduced in a two-electron process by DT-diaphorase (DTD) or xanthine dehydrogenase to an oxygen-insensitive intermediate.108 Thus, resistance is less pronounced under hypoxic conditions, but under normoxic conditions, downregulation of DTD can lead to resistance.109

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