Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models.
The activity of temozolomide combined with irinotecan (CPT-11) was evaluated against eight independent xenografts (four neuroblastomas, three rhabdomyosarcomas, and one glioblastoma). In all studies, temozolomide was administered p.o. daily for 5 consecutive days/cycle, found in preliminary studies to be the optimal schedule for administration. Irinotecan was administered i.v. for 5 days for 2 consecutive weeks/cycle. Treatment cycles were repeated every 21 days for a total of three cycles over 8 weeks. In combination, temozolomide and CPT-11 induced complete responses in four neuroblastomas, two rhabdomyosarcomas, and the glioblastoma line. The activity of the combination was significantly greater than the activity of either agent administered alone in four tumor lines. Of interest, the interaction appeared independent of tumor MGMT or mismatch repair phenotype, suggesting that the mechanism of synergy may be independent of O6-methylation by temozolomide. Pharmacokinetic studies indicated no detectable interaction between these two agents. Further, coadministration of CPT-11 appeared to reduce the toxicity of temozolomide in tumor-bearing mice.
Houghton
P J
PJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA. peter.houghton@stjude.org
Stewart
C F
CF
Cheshire
P J
PJ
Richmond
L B
LB
Kirstein
M N
MN
Poquette
C A
CA
Tan
M
M
Friedman
H S
HS
Brent
T P
TP
D000284:Administration, Oral; D000477:Alkylating Agents / Q000493:pharmacokinetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D020137:Base Pair Mismatch; D001932:Brain Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D000077146:Irinotecan; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D010641:Phenotype; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D000077204:Temozolomide; D013997:Time Factors
D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide; D002166:Camptothecin; D000077204:Temozolomide