Interaction of topoisomerase I inhibitors with radiation in cis‐diamminedichloroplatinum(II)‐sensitive and ‐resistantcells 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.

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

“…The most promising of these agents are oxaliplatin and irinotecan. We added irinotecan to 5-fluorouracil in our study for two reasons: Owing to its high activity in advanced colorectal cancer (Douillard et al, 2000;Saltz et al, 2000) irinotecan appears particularly suited for intensified induction therapy; in addition, several studies have documented the radiosensitising properties of irinotecan (Boothmann et al, 1987;Boscia et al, 1993;Omura et al, 1997;Chen et al, 1999) that were observed even under hypoxic conditions (Boscia et al, 1993). As hypoxia may have an adverse effect on the radiosensitivity of cells (Kumar, 2000;Fyles et al, 2000), irinotecan may be particularly useful as a constituent of chemoradiotherapy programmes in patients with bulky pelvic tumours and poor blood supply that often contain hypoxic regions.…”

Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study

“…Also radiosensitizing properties even under hypoxic conditions were documented (Boothmann et al, 1987;Boscia et al, 1993), and Irinotecan has also shown in combination with 5-FU and radiation preoperatively in patients with LARC consistent efficacy in local control and DFS (Mehta et al, 2003;Klautke et al, 2005). As a result of that, it was a logical step to investigate the combination of capecitabine and irinotecan in patients with LARC.…”

A phase I/II study of irinotecan when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group Study

“…Preclinical studies have demonstrated irinotecan to be a potent radio-sensitising agent in human lung tumour xenografts (Tamura et al, 1997) and colorectal cancer (Wang et al, 1996;Omura et al, 1997;Chen et al, 1999), even under hypoxic conditions, which normally render tumours radio-resistant (Boscia et al, 1993). The mechanism of this interaction may reflect the attachment of the DNA-topoisomerase I adducts at sites of DNA single-strand breaks, or radiation-induced synchronization of the tumour cell population in the S phase of the cell cycle, where cells are more sensitive to irinotecan chemotherapy (Falk and Smith, 1992).…”