title: Interleukin-1 alpha-induced modulation of topoisomerase I activity and DNA damage: implications in the mechanisms of synergy with camptothecins in vitro and in vivo.
abstract: Studies have shown that cytokines are directly cytotoxic to tumor cells in vitro and in vivo and that interleukin-1 alpha (IL-1 alpha) potentiates the cytotoxicity of certain clinically active drugs in a number of human tumor cells, including carcinomas of breast and ovary. We found that interleukin-1 alpha potentiated cytotoxicity of camptothecin (4-5-fold) during simultaneous drug exposure in human ovarian NIH:OVCAR-3 cancer cells in vitro. Studies indicated that IL-1 alpha significantly increased topoisomerase I-catalyzed camptothecin-induced DNA cleavable complexes in the ovarian cell line, which was not due increased intracellular camptothecin as IL-1 alpha failed to effect cellular uptake of camptothecin. Pretreatment of the ovarian cells with IL-1 alpha did not result in increased expressions of mRNA for the topoisomerase I gene, whereas a small increase (approximately 1.5-fold) in the expression of topoisomerase I protein was observed, suggesting that IL-1 modulated the activity of topoisomerase I for the observed increase in cleavable complex formation. Treatment of human ovarian tumor cells grown as xenografts in nude mice with IL-1 alpha followed by CPT-11 at minimally toxic doses significantly (5-6-fold) enhanced antitumor activity of either agent alone. Because camptothecins are active against solid tumors in vivo, combinations of IL-1 alpha with these active drugs may lead to more effective treatment of ovarian cancers in the clinic.
authors.affiliation: Biochemical and Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: B K
authors.initials: BK
authors.lastname: Sinha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000627:therapeutic use / Q000633:toxicity*; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D014176:Protein Biosynthesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007375:Interleukin-1; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin