Cell cycle stage dependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity
The DNA cleavage produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in mammalian cells is putatively mediated by topoisomerase II. The authors found that in synchronized HeLa cells the frequency of such cleavage was 4-15-fold greater in mitosis than in S while the DNA of G/sub 1/ and G/sub 2/ cells exhibited an intermediate susceptibility to cleavage. The hypersensitivity of mitotic DNA to m-AMSA-induced cleavage was acquired relatively abruptly in late G/sub 2/ and was lost similarly abruptly in early G/sub 1/. The susceptibility of mitotic cells to m-AMSA-induced DNA cleavage was not clearly paralleled by an increase in topoisomerase II activity in 350 mM NaCl extracts from mitotic cells compared to similar extracts from cells in G/sub 1/, S, or G/sub 2/. Furthermore, equal amounts of decatenating activity from cells in mitosis and S produced equal amounts of m-AMSA-induced cleavage of simian virus 40 (SV40) DNA; i.e., the interaction between m-AMSA and extractable enzyme was similar in mitosis and S. The DNA of mitotic cells was also hypersensitive to cleavage by 4'-demethylepipodophyllotoxin 4-(4,6-O-ethylidene-..beta..-D-glucopyranoside) (etoposide), a drug that produces topoisomerase II mediated DNA cleavage without binding to DNA. Cell cycle stage dependent fluctuations in m-AMSA-induced DNA cleavage may result from fluctuations in the structure of chromatin per se that occur during the cell cycle. Surprisingly, cell cycle stage dependent differences in m-AMSA-induced DNA cleavage did not correlate with differences in the susceptibility to the cytotoxic effects of the drug. In fact, cells in S were most sensitive to these effects. These results are an exception to the previously observed parallel between the susceptibility of mammalian cells to drug-induced DNA cleavage and the susceptibility of the cells to drug-induced cytotoxicity and indicate the complexity of any relationship between the two phenomena.
- Research Organization:
- Univ. of Texas M.D. Anderson Hospital and Tumor Institute, Houston
- OSTI ID:
- 5898423
- Journal Information:
- Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 26:14; ISSN BICHA
- Country of Publication:
- United States
- Language:
- English
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560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ACRIDINES
AROMATICS
AZAARENES
AZINES
BIOLOGICAL EFFECTS
CARBON 14 COMPOUNDS
CELL CYCLE
DNA
ENZYME ACTIVITY
ENZYMES
GENETIC EFFECTS
HELA CELLS
HETEROCYCLIC COMPOUNDS
ISOMERASES
LABELLED COMPOUNDS
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIDINES
PYRIMIDINES
RIBOSIDES
STRAND BREAKS
THYMIDINE
TOXICITY
TRITIUM COMPOUNDS
UPTAKE