Mechanism of resistance of noncycling mammalian cells to 4'-(9-acridinylamino)methanesulfon-m-anisidide: comparison of uptake, metabolism, and DNA breakage in log- and plateau-phase Chinese hamster fibroblast cell cultures.
Resistance of noncycling cells to amsacrine (m-AMSA) has been widely reported and may limit the activity of this drug against solid tumors. The biochemical mechanism(s) for this resistance have been investigated using spontaneously transformed Chinese hamster fibroblasts (AA8 cells, a subline of Chinese hamster ovary-cells) in log- and plateau-phase spinner cultures. In early plateau phase most cells entered a growth-arrested state with a G1-G0 DNA content and showed a marked decrease in sensitivity to cytotoxicity induced by a 1-h exposure to m-AMSA or to its solid tumor-active analogue, CI-921. Studies with radiolabeled m-AMSA established that similar levels of drug were accumulated by log- and plateau-phase cells and that there was no significant drug metabolism in either of these cultures after 1 h. However, marked differences in sensitivity to m-AMSA-induced DNA breakage were observed using a fluorescence assay for DNA unwinding (Kanter P.M., and Schwartz, H.S., Mol. Pharmacol., 22: 145-151, 1982). Changes in sensitivity to DNA breakage occurred in parallel with changes in sensitivity to m-AMSA-induced cell killing. DNA breaks disappeared rapidly after drug removal (half-time approximately 4 min), suggesting that these lesions were probably mediated by DNA topoisomerase II. Resistance to m-AMSA may therefore be associated with changes in topoisomerase II activity in noncycling cells.
Robbie
M A
MA
Section of Oncology, University of Auckland School of Medicine, Private Bag, New Zealand.
Baguley
B C
BC
Denny
W A
WA
Gavin
J B
JB
Wilson
W R
WR
D000677:Amsacrine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002250:Carbon Radioisotopes; D002452:Cell Count; D002453:Cell Cycle; D002478:Cells, Cultured; D006224:Cricetinae; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000502:physiology; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism
D002250:Carbon Radioisotopes; D000677:Amsacrine; D004250:DNA Topoisomerases, Type II