Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice

The anti-tumor activity of irinotecan (CPT-11), a DNA-topoisomerase 1 inhibitor, was evaluated in 5 advanced stage subcutaneous medulloblastoma xenografts in nude mice, using different schedules of administration, With a 5-day schedule, the highest i.v. dose tested (40 mg kg(-1) day(-1)) induced complete regressions in all xenografts but 1, and delays in tumor growth always exceeded 30 days, Two xenografts, IGRM11 acid IGRM33, were highly sensitive, and animals survived tumor-free beyond 120 days after treatment, CPT-11 clearly retained its anti-tumor activity at a lower dosage (27 mg kg(-1) day(-1)), CPT-11 was significantly more active than cyclophosphamide, thiotepa and etoposide against the 3 xenografts evaluated, To study the schedule dependency of its anti tumor activity, CPT-11 was given i.v. at the same total doses over the same period (33 days) using either a protracted or a sequential schedule in IGRM34-bearing mice. With a dose of 10 mg kg(-1) day(-1) given on days 0-4, days 7-11, days 21-25 and days 28-32 (total dose, 200 mg kg(-1)), 3 of 6 animals were tumor free on day 378, The same total dose given with a sequential schedule, i.e., 20 mg kg(-1) day(-1) on days 0-4 and days 28-32, failed to induce complete regression. The plasma pharmacokinetics of CPT-11 and SN-38 were studied in IGRM34-bearing animals after a single i.v. dose of 10 and 40 mg kg(-1). The plasma clearance rate of CPT-11 was dose dependent. The ratio between the SN-38 and CPT-11 area under the curve in plasma was 0.4-0.65, i.e., significantly higher than that observed in humans at the maximum tolerated dose (0.01-0.05), Conversely, this ratio was 10-fold lower in tumor than in plasma, Clinical development of irinotecan is warranted in pediatric malignancies. (C) 1997 Wiley-Liss, Inc.