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.
OBJECTIVE
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.


METHODS
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.
Zamboni
William C
WC
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA. zamboniwc@msx.upmc.edu
Strychor
Sandra
S
Joseph
Erin
E
Parise
Robert A
RA
Egorin
Merrill J
MJ
Eiseman
Julie L
JL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077143:Docetaxel; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D043823:Taxoids; D000077143:Docetaxel; C079905:rubitecan; D002166:Camptothecin