R. Mulcahy
May 1, 1985
Citations
0
Influential Citations
4
Citations
Journal
British Journal of Cancer
Abstract
The in vitro cytotoxicity and in vivo efficacy of 1-(2chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) can be markedly enhanced in combination with certain radiation sensitizing compounds (reviewed by Siemann, 1982), most notably Misonidazole (MISO). CCNU, like other nitrosoureas, undergoes a spontaneous chemical decomposition to yield two active species, an alkylating chloroethyl carbonium ion as well as a carbamoylating isocyanate (Montgomery et al., 1967). Alkylation is considered to be responsible for cytotoxicity (Wheeler et al., 1974), while carbamoylation can account for the inhibition of protein-mediated processes such as the repair of DNA damage (Kann et al., 1980) and the regeneration of intracellular glutatione (Babson & Reed, 1978). When administered in vivo certain nitrosoureas, including CCNU, are modified by hepatic mixed-function oxidases prior to their decomposition to therapeutically active species. In the case of CCNU, the cyclohexyl ring of the parent drug is rapidly hydroxylated at multiple sites to yield a mixture of cisand transhydroxylated analogs, some of which have properties significantly different from those of the parent compound (May et al., 1974; Hilton & Walter, 1975; Wheeler et al., 1977). As these analogs are believed to be the immediate precursors of active moieties, it is likely that the chemopotentiation observed when MISO is combined with CCNU in vivo represents a composite of the interactions of MISO with the individual hydroxylated CCNUs or the damage induced by these agents. In order to determine whether MISO can potentiate the cytotoxicity of individual CCNU metabolites EMT-6/Ro tumour cells were treated in vitro with MISO combined with four hydroxylated metabolites of CCNU: cis: and trans-2-OH CCNU and cisand trans-4-OH CCNU. The latter represent the major metabolites recovered from the plasma of humans and rodents treated with CCNU. Although chemopotentiation can be induced in EMT-6/Ro cell cultures treated at oxygen tensions