Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864)

• Published in: Cancer research (Chicago, Ill.) Vol. 51; no. 21; pp. 5813 - 5816
• Main Authors: MATTERN, M. R, HOFMANN, G. A, MCCABE, F. L, JOHNSON, R. K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.1991
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cell Survival - drug effects; Cell Survival - radiation effects; CHO Cells; Cricetinae; Dose-Response Relationship, Radiation; Drug Screening Assays, Antitumor; Gamma Rays; General aspects; Leukemia P388; Medical sciences; Mice; Pharmacology. Drug treatments; Topoisomerase I Inhibitors; Topotecan; Tumor Cells, Cultured; Antineoplastic agent; Enzyme; DNA topoisomerase; P388-Leukemia; Enzyme inhibitor; Cytotoxicity; Radiotherapy; In vitro; CHO cell line; Chemotherapy; Gamma irradiation; Combined treatment; Tumor cell
• ISSN: 0008-5472; 1538-7445

Topotecan (SK&F 104864), a water-soluble analogue of the topoisomerase I inhibitor camptothecin, is currently in Phase II clinical trial for solid tumors. We have characterized topotecan in terms of its effect upon gamma-radiation-induced cell killing. In colony formation experiments, subtoxic concentrations of topotecan (2 microM) potentiated radiation-induced killing of exponentially growing Chinese hamster ovary or P388 murine leukemia cultured cells. Survival curve shoulders were reduced; the slopes of the exponential portions of the curves were decreased to a small extent. D37 and D10 (radiation dose resulting in 37 and 10% survival of colony-forming ability) values were reduced by approximately 60 and 50%, respectively, in the case of Chinese hamster ovary cells. In P388 cells, topotecan reduced D37 by 35 to 40% and D10 by 20 to 25%. Potentiation of radiation-induced cell killing by topotecan was absolutely dependent upon the presence of the topoisomerase I inhibitor during the first few (less than 30) min after irradiation. Association of topoisomerase I with this effect was confirmed in studies of Chinese hamster ovary cells previously made resistant to camptothecin (and cross-resistant to topotecan), resulting in decreased cellular content of topoisomerase I. These cells were found to be 2- to 3-fold hypersensitive to gamma-radiation-induced killing. P388 camptothecin-resistant cells were further sensitized to the lethal effects of ionizing radiation by nontoxic treatment with the topoisomerase II inhibitor novobiocin, consistent with increased dependence of topoisomerase I-deficient cells upon topoisomerase II.