NOVEL CARBAMATE ANALOGS OF AMSACRINE WITH ACTIVITY AGAINST NON-CYCLING MURINE AND HUMAN TUMOR-CELLS

The cytotoxicity of a class of compounds related to the topoisomerase- II poison amsacrine was investigated against plateau-phase murine Lewi s lung carcinoma cells (LLTC), HCT-8 human colon carcinoma cells and o ther cell lines. Methyl N-[4-(9-acridinylamino)-2-methoxy-phenyl]carba mate hydrochloride and the corresponding demethoxy compound, which con tain a methylcarbamate instead of the methylsulphonylamino group, mani fested relatively high cytotoxic activity against plateau-phase cells as measured by clonogenic survival. The concentration of drug required for a given cytotoxic effect on plateau-phase cells was about 2 times higher than that required for an equitoxic effect on actively prolife rating cells. In contrast, at least 5 times more amsacrine, doxorubici n or etoposide was needed for an equitoxic effect on plateau-phase cel ls. Cells taken directly from subcutaneous LLTC tumours and exposed to drugs displayed the same differential drug sensitivity to the carbama te compounds, suggesting that the plateau-phase cells provide an appro priate model for cells growing in vivo. The greater cytotoxicity of th e carbamate drugs was shown to depend critically on the provision of a n energy source such as glucose, suggesting that nutrient starvation b oth in plateau-phase cells and in tumours induced a glucose-sensitive resistance mechanism. It is suggested that the carbamate analogues of amsacrine recognize a form of topoisomerase II, possibly topoisomerase II beta, the activity of which increases relative to that of topoisom erase II alpha in non-cycling cells, and might be used to devise new s trategies for the treatment of solid tumours.