LS 1727, a
nitrosocarbamate of
19-nortestosterone, was active against lymphoid,
antimetabolite-sensitive, cell lines in vitro especially L1210 and Ehrlich
ascites tumour lines. It was less effective against
alkylating agent-sensitive lines such as the Walker 256
carcinosarcoma. These results suggested a possible
antimetabolite mode of action but
LS 1727 had no effect on deoxy-or
ribonucleotide pool sizes in L1210 cells. Studies on macromolecular synthesis showed an early inhibition of
DNA synthesis whilst
RNA and
protein synthesis continued for 24-48 hours. This was reminiscent of a classic
alkylating agent-like effect. In vivo studies with specific
alkylating agent-sensitive, or
antimetabolite-sensitive tumours showed no antitumour activity although significant inhibition of Ehrlich
ascites tumour cell growth was observed at high doses. In vitro cytotoxicity studies showed
LS 1727 to be inactivated in the presence of mouse, rat and dog liver supernatants. This would explain the poor antitumour effects in vivo compared with the in vitro observations. Because
LS 1727 is a
nitrosocarbamate its possible mutagenic activity was investigated.
LS 1727 was highly mutagenic but this property was also lost in the presence of a rat liver microsomal fraction. Although an effective
cytotoxic agent in vitro
LS 1727 is only effective in vivo at toxic doses.