Enhancement of Tumor Radio‐response by Irinotecan in Human Lung Tumor Xenografts

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Abstract
We investigated the ability of 7‐ethyl‐10‐[4‐(l‐piperidino)‐l‐piperidmo]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.