N

a murine model of leukemia, L1210. The elevated expression of murine AGT relative to human AGTafforded a higher therapeutic window in this model than what would be witnessed in the clinic. Nevertheless, the predecessors of the nitrosoureas, namely N-methyl-N'-nitro-N-nitrosoguanidine (50, MNNG) and N-methyl-N-nitrosourea (51, MNU), showed moderate activity in the L1210 tumor model, the latter being more efficacious. The promising activity of 51 prompted Montgomery's group to synthesize >200 analogs, before finding one with superior activity to 51, which was N,jV-bis(2-chloroethyl)-N-nitrosourea (52, BCNU, BiCNU, Carmustine). Once again, the presence of 2-chloroethyl groups proved to be instrumental in providing increased efficacy for this class of therapeutics relative to 51. The preliminary in vivo results indicated that BCNU had cured mice from either intraperitoneally or intracerebrally implanted L1210 leukemia cells. Multiple compounds have been optimized for anticancer activity within this class, two such examples being Lomustine (53, CCNU) and streptozocin (54, STZ, Zanosar). For leading references regarding the chemical and biological properties of STZ, see93. The discussion will focus on the chemical and biological properties of the prototypical nitrosourea, BCNU.

7.06.5.1 Mechanism of Action of BCNU

Upon intravenous administration, 52 undergoes base catalyzed degradation, within as little as 5 min, to afford 55 and 56, the former being responsible for the cytotoxic activity of 52, and the latter acting as a carbamoylating agent (Figure 12).94 The mechanism of how BCNU generates interstrand cross-links, shown below, needs to address two seemingly conflicting pieces of data. First, research had shown that treating cells with BCNU results in formation of the G-C crosslink 61,95 which was formed by attack of the poorly nucleophilic N-1 position of guanine and the N-3 position of cytosine. Second, Erickson had demonstrated that the in vitro cytotoxic effects of the nitrosoureas were diminished with increased levels of AGT, which would imply that BCNU alkylates the O6 position of guanine.96 To address both of these issues Ludlum has proposed the following reaction mechanism, which begins with the bis-electrophilic ethylating agent 55 reacting initially with the O6 position of guanine 57, yielding 58. The N-1 position of guanine displaces the chloride, yielding the highly electrophilic intermediate 59, which is trapped by N-3 of the Watson-Crick paired cytosine to yield the interstrand cross-linked base pair 61.97 The cytotoxic activity of 52 is strongly correlated to its ability to generate 61.

7.06.5.2 Clinical Use and Administration of BCNU (52)

The dramatic activity of BCNU in preclinical rodent models has not translated into equally dramatic responses in man. Nevertheless, BCNU has been used clinically either alone or in combination for treating the following malignancies: primary or metastatic melanoma, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma. The compound is highly metabolized, with a half-life of 15 min, after intravenous administration. The majority of the metabolites are

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