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Potent therapeutic activity of irinotecan (CPT‐11) and its schedule dependency in medulloblastoma xenografts in nude mice
Author(s) -
Vassal Gilles,
Boland Isabelle,
Santos Alexandre,
Bissery MarieChristine,
TerrierLacombe MarieJosé,
Morizet Jackie,
SainteRose Christian,
LellouchTubiana Arielle,
Kalifa Chantal,
Gouyette Alain
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970926)73:1<156::aid-ijc24>3.0.co;2-d
Subject(s) - irinotecan , etoposide , medicine , medulloblastoma , camptothecin , pharmacokinetics , cyclophosphamide , pharmacology , topoisomerase , chemotherapy , biology , cancer , pathology , colorectal cancer , biochemistry , enzyme
The anti‐tumor activity of irinotecan (CPT‐11), a DNA‐topoisomerase I 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 and 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. Int. J. Cancer 73:156–163, 1997. © 1997 Wiley‐Liss, Inc.