Topoisomerase II-mediated DNA damage of episomes in tumor-bearing mice.
Observations of cells in culture have demonstrated that, for many antitumor agents, topoisomerase II-mediated DNA damage relates to cytotoxicity. However, there is no evidence in tumor-bearing animals to suggest that such agents induce topoisomerase II-mediated damage of DNA in solid tumors or that such damage reflects inhibition of tumor growth. To address this question, a mouse fibroblast cell line neoplastically transformed by an episomal element containing the v-Ha-ras and bovine papillomavirus genes was utilized to measure topoisomerase II-induced DNA damage and growth inhibition of solid tumors derived from this line. Using the topoisomerase II inhibitor amsacrine, the episomal element was found to be a sensitive indicator of topoisomerase II-mediated damage in vivo. The DNA breaks induced by single i.v. injections of amsacrine were protein linked and occurred preferentially in episomal regulatory regions. A strong correlation between suppression of tumor growth and topoisomerase II-mediated damage of the episome was demonstrated.
Cullinan
E B
EB
Department of Pharmacology, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263.
Gawron
L S
LS
Rustum
Y M
YM
Beerman
T A
TA
D000677:Amsacrine / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D052688:Bovine papillomavirus 1 / Q000235:genetics; D002461:Cell Line, Transformed; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects*; D004278:DNA, Superhelical / Q000032:analysis / Q000187:drug effects; D011905:Genes, ras; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004250:DNA Topoisomerases, Type II