Carmethizole, a novel bis-
carbamate alkylating agent, was evaluated in vitro for potential mechanisms of interaction with
DNA and in vivo for spectrum and degree of antitumor activity. In vitro, the concentration of
carmethizole required to produce a 50% reduction in clonogenic cell survival was identical in O6-alkylguanine
DNA alkyltransferase-positive and -negative human cell lines. The CHO cell line UV4, hypersensitive to mono- and bifunctional
alkylating agents, was 37-fold more sensitive to
carmethizole than normal cells. The UV5 cell line, which is not hypersensitive to cross-linkers, was 13-fold more sensitive to
carmethizole than normal cells. Alkaline elution studies in L1210 cells exposed to
carmethizole showed the presence of
DNA-
protein and
DNA-
DNA cross-links but not
DNA strand breaks. These data suggested that the interaction of
carmethizole with
DNA produces monoadducts,
DNA-
protein, and
DNA-
DNA interstrand cross-links at several sites. In vivo,
carmethizole was not cross-resistant with
1,3-bis(2-chloroethyl)-1-nitrosourea or
Cytoxan as determined by testing against P388
leukemias resistant to the latter 2 agents.
Carmethizole activity was similar to that of
melphalan across the murine solid
tumor panel, which consisted of
B16 melanoma;
colon adenocarcinomas 11a, 26, and 36; and the KHT
sarcoma.
Carmethizole,
Cytoxan, and
melphalan were all active and had comparable activity against the HCT-8 and MX-1 human
tumor xenografts. The in vivo spectrum of activity and efficacy of
carmethizole was similar to that of
melphalan.