Unusual dynamics of killing of cultured Lewis lung cells by the DNA-intercalating antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.
The cytotoxicity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601,316), a new experimental DNA-intercalating antitumor drug, against a cultured Lewis lung adenocarcinoma cell line was compared with that of the DNA-intercalating antitumor drug amsacrine. In contrast to amsacrine, AC demonstrated self-inhibition of cytotoxicity following short (3-9 h) incubation periods and exponential killing (with a shoulder) after long (24-72 h) periods of incubation. The difference between these drugs was best demonstrated using a constant concentration x time (C x T) exposure (AC, 12 mumol h l-1; amsacrine, 3 mumol h l-1). In contrast to amsacrine, AC was minimally effective over exposure periods of less than or equal to 1 h and maximally effective over intermediate periods (4-6 h). The results suggest the possibility of designing AC administration protocols that maximise the drug's cytotoxicity towards solid tumors, which, because of diffusion barriers, are subjected to longer drug exposures than are well-vascularised tumours.
Haldane
A
A
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Finlay
G J
GJ
Gavin
J B
JB
Baguley
B C
BC
D000166:Acridines; D000609:Aminoacridines / Q000494:pharmacology* / Q000633:toxicity; D000677:Amsacrine / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D007364:Intercalating Agents / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000473:pathology
D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D000677:Amsacrine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide