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 aga inst xenografts from childhood solid tumors; however, clinical trials with this compound have been disappointing, resulting in discontinuation of furt her development. The objectives of this study were to evaluate the antitumo r activity of 9-AC in a panel of pediatric solid tumor xenografts and to re late the 9-AC lactone systemic exposure, defined as area under the concentr ation time curve (AUC), to the antitumor dose associated with tumor regress ion 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 cycl es. The minimum effective dose of 9-AC causing objective regression of adva nced tumors was determined for each schedule. 9-AC lactone plasma concentra tion-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 re quired for antitumor effect is in excess of that achievable in patients.