Enhancement of tumor radio-response by irinotecan in human lung tumor xenografts

Abstract

We investigated the ability of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) to increase tumor radio-response in vivo using human lung tumor xenografts. The xenografts were treated with (1) CPT-11 (10 mg/kg) intraperitoneally on days 1, 5 and 9, (2) single dose radiation (10 Gy/leg) on day 1, or (3) a combination regimen of both treatments in which radiation was given 1 h after the first dose of CPT-11, DNA flow cytometry studies were performed to define the cell cycle changes following treatment for 1 to 12 h with 0, 0.5, 2.0 or 8.0 ng/ml SN-38, the major active metabolite of CPT-11. In both small cell lung cancer (MS-1) and small cell/large cell carcinoma (LX-1) xenografts, combination treatment resulted in significant tumor regression compared with the use of CPT-11 (P = 0.0005, 0.0053) or radiation treatment (P = 0.00221, 0.0035) alone. Neither severe body weight loss nor enhanced skin reaction was observed following the combined treatment. In flow cytometry studies, the proportion of cells in G2/M-phase, the most radio-sensitive phase, increased after 1 h exposure to the lowest dose of SN-38 (0.5 ng/ml). These findings suggest that CPT-11 is a potent radiosensitizing agent, and that its activity is related to the cell cycle. This is the first report to indicate that CPT-11 serves as a radiosensitizer in vivo.