Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts

Purpose: To further evaluate the activity of irinotecan (CPT-11) plus 1,3-b is-(chloroethyl)-1-nitrosourea (BCNU) in the treatment of central nervous s ystem tumor-derived xenografts in athymic nude mice. Methods: We report stu dies evaluating the schedule-dependence of this regimen in the treatment of the malignant glioma xenograft D-54 MG. Results: The combination of BCNU a nd CPT-11 showed the highest enhancement index (2.0-3.3) when BCNU was give n on day 1 and CPT-11 was given on days 1-5 and 8-12. Delay of CPT-11 admin istration to day 3 or day 5 substantially decreased activity with enhanceme nt indices of 1.6-1.8 and 0.6-1.0, respectively. Delay of BCNU administrati on 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-induc ed adduct or possibly crosslink prior to administration of CPT-11 is critic al 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 recur rent malignant glioma based on these results is in progress.