BACKGROUND: Topotecan demonstrated radiosensitizing effects in vivo and in vitro, which are schedule- and cell line dependent. The underlying mechanisms are not fully understood. Topotecan interferes with DNA replication, transcription, and repair and may thus increase the frequency of radiation-induced lethal chromosome aberrations. MATERIAL AND METHODS: U-373 MG glioblastoma cells, WiDr colon adeno-carcinoma cells, as well as normal human fibroblasts and lymphocytes were irradiated (0-6 Gy) and exposed to varying topotecan doses (0.01-10 microM) always 15 minutes before and either 1 hour after (short-term) or 24 hours after (long-term) irradiation. Survival was measured by colony-forming assays, and chromosome aberrations were scored in Giemsa-stained metaphase spreads. Unirradiated cells served as specific controls. RESULTS: Topotecan alone reduced the clonogenic cell survival in a concentration- and time-dependent manner, and radiosensitization was observed for all cell lines tested. There was no correlation between clonogenic cell survival and the frequencies of treatment-induced chromosomal aberrations, neither in tumor cells nor in fibroblasts. In contrast, in lymphocytes increased frequencies of radiation-induced dicentric chromosomes were seen after the combined treatment. CONCLUSION: In certain cell types combined radiation/topotecan treatment may lead to increased frequencies of lethal chromosome aberrations. However, there is no evidence that the increased formation of lethal chromosome aberrations plays an important role in the topotecan-induced radiosensitization of human tumors.
BACKGROUND:Topotecan demonstrated radiosensitizing effects in vivo and in vitro, which are schedule- and cell line dependent. The underlying mechanisms are not fully understood. Topotecan interferes with DNA replication, transcription, and repair and may thus increase the frequency of radiation-induced lethal chromosome aberrations. MATERIAL AND METHODS: U-373 MG glioblastoma cells, WiDr colon adeno-carcinoma cells, as well as normal human fibroblasts and lymphocytes were irradiated (0-6 Gy) and exposed to varying topotecan doses (0.01-10 microM) always 15 minutes before and either 1 hour after (short-term) or 24 hours after (long-term) irradiation. Survival was measured by colony-forming assays, and chromosome aberrations were scored in Giemsa-stained metaphase spreads. Unirradiated cells served as specific controls. RESULTS:Topotecan alone reduced the clonogenic cell survival in a concentration- and time-dependent manner, and radiosensitization was observed for all cell lines tested. There was no correlation between clonogenic cell survival and the frequencies of treatment-induced chromosomal aberrations, neither in tumor cells nor in fibroblasts. In contrast, in lymphocytes increased frequencies of radiation-induced dicentric chromosomes were seen after the combined treatment. CONCLUSION: In certain cell types combined radiation/topotecan treatment may lead to increased frequencies of lethal chromosome aberrations. However, there is no evidence that the increased formation of lethal chromosome aberrations plays an important role in the topotecan-induced radiosensitization of humantumors.