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

Journal Article · Fri Jan 15 04:00:00 EST 1988 · Cancer Res.; (United States)

OSTI ID:5509568

Robbie, M A; Baguley, B C; Denny, W A; Gavin, J B; Wilson, W R

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. 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.

• Research Organization: Univ. of Auckland School of Medicine, Private Bag, New Zealand
• OSTI ID: 5509568
• Journal Information: Cancer Res.; (United States), Journal Name: Cancer Res.; (United States) Vol. 48:2; ISSN CNREA
• Country of Publication: United States
• Language: English

Related Subjects

550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANIMALS
ANTINEOPLASTIC DRUGS
CELL CULTURES
CELL CYCLE
CELL KILLING
CONNECTIVE TISSUE CELLS
DNA
DRUGS
ENZYMES
FIBROBLASTS
HAMSTERS
ISOMERASES
ISOTOPE APPLICATIONS
ISOTOPES
LABELLED COMPOUNDS
MAMMALS
METABOLISM
NUCLEIC ACIDS
ORGANIC COMPOUNDS
RADIOISOTOPES
RODENTS
SENSITIVITY
SOMATIC CELLS
STRAND BREAKS
TRACER TECHNIQUES
UPTAKE
VERTEBRATES