Relation between 9-aminocamptothecin systemic exposure and tumor response in human solid tumor xenografts.
9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with activity against xenografts from childhood solid tumors; however, clinical trials with this compound have been disappointing, resulting in discontinuation of further development. The objectives of this study were to evaluate the antitumor activity of 9-AC in a panel of pediatric solid tumor xenografts and to relate the 9-AC lactone systemic exposure, defined as area under the concentration time curve (AUC), to the antitumor dose associated with tumor regression in the xenograft model. We evaluated protracted administration of i.v. and oral therapies (daily times 5) for 1, 2, or 3 weeks and for 1 or 3 cycles. The minimum effective dose of 9-AC causing objective regression of advanced tumors was determined for each schedule. 9-AC lactone plasma concentration-time profiles associated with the lowest dose achieving complete and partial responses for each xenograft were then determined for each regimen. Tumors were highly sensitive to 9-AC therapy, but the systemic exposure required for antitumor effect is in excess of that achievable in patients.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
M N
MN
Kirstein
P J
PJ
Houghton
P J
PJ
Cheshire
L B
LB
Richmond
A K
AK
Smith
S K
SK
Hanna
C F
CF
Stewart
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
C402491:9-aminocamptothecin lactone; D000970:Antineoplastic Agents; D007783:Lactones; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin