title: Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Castellino
authors.forename: G B
authors.initials: GB
authors.lastname: Elion
authors.forename: S T
authors.initials: ST
authors.lastname: Keir
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: S P
authors.initials: SP
authors.lastname: Johnson
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002330:Carmustine / Q000008:administration & dosage / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002330:Carmustine; D002166:Camptothecin