Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts
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Purpose: To further evaluate the activity of irinotecan (CPT-11) plus 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU) in the treatment of central nervous system tumor-derived xenografts in athymic nude mice. Methods: We report studies evaluating the schedule- dependence of this regimen in the treatment of the malignant glioma xenograft D-54 MG. Results: The combination of BCNU and CPT-11 showed the highest enhancement index (2.0–3.3) when BCNU was given on day 1 and CPT-11 was given on days 1–5 and 8–12. Delay of CPT-11 administration to day 3 or day 5 substantially decreased activity with enhancement indices of 1.6–1.8 and 0.6–1.0, respectively. Delay of BCNU administration to day 8 also reduced the CPT-11 activity with enhancement indices of 1.2–1.4. Conclusions: These results suggest that the presence of a BCNU- induced adduct or possibly crosslink prior to administration of CPT-11 is critical for enhanced activity. Although the mechanism of this enhancement is not currently known, a phase I trial of CPT-11 plus BCNU for adults with recurrent malignant glioma based on these results is in progress.
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