Tumor, tissue, and plasma pharmacokinetic studies and antitumor response studies of docetaxel in combination with 9-nitrocamptothecin in mice bearing SKOV-3 human ovarian xenografts.

PURPOSE: We evaluated the antitumor activity of two different schedules of docetaxel and 9-nitrocamptothecin (9NC) in mice bearing human SKOV-3 ovarian carcinoma xenografts and evaluated the plasma, tissue, and tumor disposition of each agent alone and in combination. EXPERIMENTAL DESIGN: The following treatment groups were evaluated: (1) docetaxel 10 mg/kg IV on days 0 and 7; (2) 9NC 0.67 mg/kg PO qdx5dx2wk; (3) 9NC 0.67 mg/kg PO qdx5dx2wk in combination with docetaxel 10 mg/kg IV on days 0 and 7; and (4) 9NC 0.67 mg/kg PO qdx5dx2wk in combination with docetaxel 10 mg/kg IV on days 4 and 11; (5) vehicle controls for each agent; and (6) no treatment controls. RESULTS: All treatment regimens produced significant antitumor activity as compared with control groups (P < 0.05). Docetaxel administered on days 0 and 7 or on days 4 and 11 in combination with 9NC resulted in similar antitumor activity (P > 0.05). High docetaxel concentrations in tumor were maintained at late time points as compared with plasma and tissues with the retention of docetaxel at 24 h being 132-fold and 15-fold higher in tumor than in plasma and liver, respectively. After administration of 9NC alone, the ratio of the 9-aminocamptothecin (9AC) area under the concentration versus time curve (AUC) to 9NC AUC in plasma and tumor was 0.15 and 1.34, respectively. CONCLUSIONS: The combination of docetaxel and 9NC was effective against SKOV-3 xenografts. The lack of a difference in sequence-dependent antitumor activity may reflect the sensitivity of the SKOV-3 xenograft to 9NC. The factors associated with tumor-specific retention of docetaxel and the ratio of 9NC to 9AC in tumors is unknown.