Relation between 9-aminocamptothecin systemic exposure and tumor response in human solid tumor xenografts
2001
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.
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