Evidence for persistence of mitoxantrone within the peritoneal cavity following intraperitoneal delivery

In clinical trials examining the intraperitoneal (ip) administration of mitoxantrone as therapy of platinum-refractory small-volume residual ovarian cancer, the characteristic "blue color" of the agent has been demonstrated to stain the surface of the peritoneal cavity and to persist for > or = 1 month following the last course of therapy. To determine if this blue staining material contains potentially cytotoxic concentrations of mitoxantrone, we analyzed tissue obtained at exploratory laparotomy in six women who had last received the agent administered ip from 6-22 weeks prior to surgery. Concentrations of mitoxantrone ranged from < 0.1 to 13.8 micrograms/g of tissue examined. Since any mitoxantrone present on the peritoneal surface will be highly protein bound, any residual drug may not have cytotoxic potential. The dose-response curves of mitoxantrone in a human clonogenic cytotoxicity assay against the RPMI 2780/S human ovarian cell line were virtually identical when the cells were incubated in either 5 or 50% fetal bovine serum, suggesting that protein binding will not significantly impair mitoxantrone-induced tumor cell killing. We conclude that the ip administration of mitoxantrone may lead to prolonged exposure of surface tumor to the high local concentrations of the active cytotoxic agent. This effect may contribute significantly to the antineoplastic potential of ip mitoxantrone in patients with small-volume residual ovarian cancer.