Hyperthermic modulation of SN-38-induced topoisomerase I DNA cross-linking and SN-38 cytotoxicity through altered topoisomerase I activity
✍ Scribed by Dörthe M. Katschinski; H. Ian Robins
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- French
- Weight
- 128 KB
- Volume
- 80
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
The effect of different temperatures (37-42.5°C) on SN-38 (the active metabolite of CPT-11) cytotoxicity was examined in the human lung carcinoma cell lines H460 and Calu-6 as well as the murine fibrosarcoma cell line L929. The cytotoxicity of SN-38, determined by MTT cell survival assay, was significantly increased in each cell line in combination with 41.8°C hyperthermia (؋60-120 min); the combination of SN-38 with 40.5°C and 42.5°C, however, was unchanged compared to 37°C. Determination of topoisomerase (Topo) I DNA cross-linking in Calu-6 cells and L929 cells after treatment with SN-38 showed the same temperature profile as seen in the cell-survival assays with increased Topo I DNA cross-linking after treatment with the combination of SN-38 and 41.8°C hyperthermia and unchanged Topo I DNA crosslinking at 40.5°C and 42.5°C. To test the hypothesis that increased Topo I DNA cross-linking and SN-38 cytotoxicity at 41.8°C is caused by hyperthermia-modulated changes in Topo I activity, catalytic activity of Topo I extracted from each cell line and of purified human Topo I was determined at 20-42.5°C. Topo I activity was found to be gradually increased with rising temperatures, resulting in significantly higher activity at 41.8°C compared to 37°C; further increase of temperature past 41.8°C decreased Topo I activity back to levels found at 37°C. Our data are used to explain a series of events resulting in hyperthermic enhancement of Topo I DNA cross-linking and SN-38 cytotoxicity in combination with 41.8°C hyperthermia via increased Topo I activity.