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7.06.3.2 Resistance to Oxazaphosphorine-Based Chemotherapy

The primary mode of resistance to oxazaphosphorine-based therapies is the increased expression of aldehyde dehydrogenase activity, thereby increasing the concentration of inactive metabolite 20 that is generated from cyclophosphamide.50 To underscore the complexity of how a cell might become resistant, the characterization of a cyclophosphamide-resistant breast cell line (MCF-7) revealed not only overexpression of ALDH1, but also increased levels of GSH and increased GSTactivity.51'51a'51b Recent reports have indicated that the activity of the O6-alkylguanine alkyltransferase (AGT) and defective DNA repair can lead to resistance.52 The role of AGT is to irreversibly remove an alkyl group from the O6-position of guanine. For the triazene and nitrosourea class of therapeutics, the inability of the cell to repair these lesions has been correlated to their cytotoxicity and mutagenicity.53 However, these types of lesions have not been isolated from cells treated with cyclophosphamide. As a result, the exact manner in which the expression of AGTconfers resistance to 12 is unknown. A possible explanation is that AGTacts to remove acrolein-derived lesions from the O6-guanine,54 and/or acts as a molecular scavenger for acrolein.55

7.06.4 Triazenes

The development of the triazene class of therapeutics can trace its beginnings to the mid-1950s, where early predecessors of the triazenes (aryl-dimethyl triazenes) were metabolic precursors to cytotoxic agents. Contemporaneously, the pyrazolo-triazines were reported to have modest activity in a mouse model of sarcoma. Over nearly 60 years of research, three compounds have been widely studied for their anticancer properties: temozolomide (37, TMZ, Temodar), mitozolomide (38), and dacarbazine (42, DTIC-Dome). Preclinical evaluation of 38 in mice demonstrated promising cytotoxic activity. However, mitozolomide exhibited dose-limiting thrombocytopenia and hematological toxicities in phase I studies, even after dose reduction. The unpredictable toxicity of mitozolomide rendered further development impractical (for a discussion of the historical development of the triazene class of therapeutics see 56,56a); consequently, the following discussion is restricted to 37 and 42.

7.06.4.1 Mechanism of Action

The minor structural difference between the bicyclic agents (37, 38) and the monocyclic agent 42 yields major differences in the manner in which the agents exert their cytotoxic effects. For example, TMZ possesses good aqueous stability at low pH, making oral administration of TMZ possible. However, at pH > 7, base promoted attack of the C-4 carbonyl generates the intermediate 39 and subsequent decomposition yields 40 (Figure 9). The decomposition of h2noc h2noc

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