Efficacy of systemic administration of irinotecan against neuroblastoma xenografts.
The efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11) has been examined against a panel of six independently derived neuroblastoma xenografts. Intensive courses of therapy, where irinotecan was administered i.v. daily 5 days per week for two consecutive weeks [(dx5)2; defined as 1 cycle], were compared to more protracted low-dose schedules where cycles were repeated every 21 days for a total of three courses ¿abbreviated [(dx5)2]3¿. When administered (dx5)2 for a single cycle, the maximum tolerated daily dose was 40 mg/kg. Irinotecan induced a high frequency of complete regressions (CRs) in four of the six lines examined; however, most tumors achieving CR regrew during the period of observation (12 weeks). Furthermore, there was no advantage in high-dose regimens as compared to low dose (10 mg/kg) on the same schedule. Protracted schedules of administration, where three courses of therapy were given at 21-day intervals ¿[(dx5)2]3¿ i.v. were examined at 10 and 5 mg/kg/dose. Even at the lower dose level, irinotecan caused 100% CR in all tumor lines that were maintained at 12 weeks. To determine the minimum dose levels required to induce objective regressions of neuroblastoma xenografts, decreasing doses were examined using the [(dx5)2]3 i.v. schedule. At 2.5 mg/kg/dose, >90% of NB-1643, NB-1691, NB-1382.2, and NB-EB xenografts demonstrated CR, whereas at 1.25 mg/kg/dose, all six tumor lines evaluated demonstrated objective regressions (>/=50% volume reduction), with a high frequency of CRs in four tumor lines. The 10-hydroxy-7-ethyl CPT lactone single-day systemic exposure measured with the minimum dose (2.5 mg/kg) associated with complete response was 198, 257, and 228 ng.h/ml for mice bearing NB-1643, NB-1691, and NB-EB tumors, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by parenteral administration, and that efficacy is schedule dependent.
Thompson
J
J
Departments of Hematology Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Zamboni
W C
WC
Cheshire
P J
PJ
Lutz
L
L
Luo
X
X
Li
Y
Y
Houghton
J A
JA
Stewart
C F
CF
Houghton
P J
PJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D000077146:Irinotecan; D051379:Mice; D008808:Mice, Inbred CBA; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D013934:Thymectomy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin