Interaction of topoisomerase I inhibitors with radiation in cis-diamminedichloroplatinum(II)-sensitive and -resistant cells in vitro and in the FSAIIC fibrosarcoma in vivo

Abstract

The cytotoxicity of the topoisomerase-I inhibitors, camptothecin and topotecan, toward the SCC-25 human head-and-neck squamous-carcinoma cells and the SCC-25/CDDP sub-line made resistant to cis-diamminedichloroplatinum(II) was assessed alone and in combination with radiation. Topotecan was less cytotoxic than camptothecin in cell culture and the SCC-25/CDDP cell line was more sensitive to either topoisomerase-I inhibitor than was the parental SCC-25 cell line. Both camptothecin and topotecan were effective radiation sensitizers of hypoxic SCC-25 and SCC-25/CDDP cells under normal pH or acidic pH conditions. Sensitizer-enhancement ratios ranged between 1.5 and 1.6 for hypoxic SCC-25 cells and between 1.3 and 1.5 for hypoxic SCC-25/CDDP cells. When the ability of camptothecin or topotecan to sensitize the FSallC fibrosarcoma to single-dose radiation was assessed using the tumor-cell-survival assay, a sensitizer-enhancement ratio of 1.2 was found with each drug. However, using tumor growth delay of the FSaIIC fibrosarcoma to determine the effect of camptothecin or topotecan to enhance the efficacy of a daily fractionated radiation regimen, topotecan produced a sensitizer-enhancement ratio of 1.4, while that for camptothecin was 1.2. These results indicate that topoisomerase-I inhibitors may retain activity in CDDP-resistant cells and may be effective adjuncts to radiation therapy.