RELATIONSHIP BETWEEN TOPOTECAN SYSTEMIC EXPOSURE AND TUMOR-RESPONSE IN HUMAN NEUROBLASTOMA XENOGRAFTS

Background: Topotecan is a topoisomerase I inhibitor with activity aga inst xenografts of childhood solid tumors and established clinical act ivity against neuroblastoma and rhabdomyosarcoma, We have studied the relationship between systemic exposure to and the antitumor activity o f topotecan lactone (the active form of the drug) in the xenograft mod els, Furthermore, we determined whether the responses seen in these mo dels occur at systemic exposure levels that are tolerable in children. Methods: Neuroblastoma xenografts derived from the tumors of six diff erent patients were established subcutaneously in immune-deprived mice , Topotecan was administered by intravenous bolus injection 5 days a w eek for 2 consecutive weeks, repeated every 21 days for three cycles. The minimum daily doses that induced complete responses (CRs) and part ial responses (PRs) were determined, Topotecan lactone pharmacokinetic studies were performed in both tumor-bearing and nontumor-bearing mic e, Results: The minimum doses associated with CRs and PRs in four of t he six neuroblastoma xenografts were 0.61 and 0.36 mg/kg body weight, respectively, The topotecan lactone single-day systemic exposures asso ciated with these doses were 88 and 52 ng.hr/mL, respectively, There w as an approximately sixfold difference in topotecan lactone systemic e xposure (290 ng.hr/mL versus 52 ng.hr/mL) associated with achieving CR s in the least-sensitive and most-sensitive tumors, respectively, Conc lusions: Neuroblastoma xenografts are highly sensitive to topotecan th erapy, and responses in mice are achieved at systemic exposures simila r to those that are clinically effective and tolerable in children, Th ese results support the concept of deriving preclinical data relating systemic exposure to antitumor activity in xenograft models, Such data may be valuable in making informed decisions regarding the clinical d evelopment of new agents.