In vitro evaluation of anticancer drugs against ovarian cancer at concentrations achievable by intraperitoneal administration

Abstract

High-dose intraperitoneal chemotherapy is a current developmental approach in the treatment of advanced ovarian cancer. Considerable pharmacologic data have been obtained on the intraperitoneal X time product for a number of agents administered by this route. We used the human tumor cloning assay (HTCA) to compare the activities of both standard and experimental agents used for intraperitoneal treatment. In vitro dose-survival curves were constructed for each drug over a two-log range of concentrations using fresh ovarian cancers from more than 50 patients. The mean concentration X time product (CXT) achievable in the intraperitoneal space after high-dose intraperitoneal drug administration was divided by the corresponding ID50 value (concentration of drug in vitro associated with 50% survival of tumor colonies) for each agent to calculate in vivo CXT: in vitro ID50 ratios. Using this approach, the standard agents, melphalan, cisplatin, and 5-FU were predicted to have similar efficacies by intraperitoneal administration, but doxorubicin and mitomycin were significantly inferior. Of the drugs tested, the new agent mitoxantrone was associated with the most favorable CXT to ID50 ratio and is, therefore, predicted to be particularly promising for intraperitoneal administration.