Novel carbamate analogues of amsacrine with activity against non-cycling murine and human tumour cells.
The cytotoxicity of a class of compounds related to the topoisomerase-II poison amsacrine was investigated against plateau-phase murine Lewis lung carcinoma cells (LLTC), HCT-8 human colon carcinoma cells and other cell lines. Methyl N-[4-(9-acridinylamino)-2-methoxy-phenyl]carbamate hydrochloride and the corresponding demethoxy compound, which contain a methylcarbamate instead of the methylsulphonylamino group, manifested 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 proliferating cells. In contrast, at least 5 times more amsacrine, doxorubicin or etoposide was needed for an equitoxic effect on plateau-phase cells. Cells taken directly from subcutaneous LLTC tumours and exposed to drugs displayed the same differential drug sensitivity to the carbamate compounds, suggesting that the plateau-phase cells provide an appropriate model for cells growing in vivo. The greater cytotoxicity of the carbamate drugs was shown to depend critically on the provision of an energy source such as glucose, suggesting that nutrient starvation both 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 topoisomerase II alpha in non-cycling cells, and might be used to devise new strategies for the treatment of solid tumours.
Finlay
G J
GJ
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Holdaway
K M
KM
Baguley
B C
BC
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D002277:Carcinoma / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000677:Amsacrine