Previous preclinical studies with ectopic
tumor models have demonstrated remarkable improvements in the therapeutic profile of
paclitaxel, formulated as a copolymer with poly-
L-glutamic acid, compared with
paclitaxel in the clinical formulation,
Taxol. In this study, we evaluated these formulations in two human ovarian
carcinoma xenograft models, NMP-1 and HEY, in nude mice. i.p. implantation in female nude mice of either cell line gave rise to progressive disease within the peritoneum, in the parenchyma of visceral organs, and eventually at extraperitoneal sites; the resultant, increasing morbidity then required host sacrifice. i.p. administration of multiple-dose
Taxol at its maximum tolerated dose 1 week after
tumor implantation afforded minimal or no increased survival compared with controls in either model. Consistent with the predictions of
drug copolymer behavior,
paclitaxel, as the
poly-L-glutamic acid-paclitaxel copolymer, displayed much less toxicity than
Taxol in these hosts. When evaluated for antitumor efficacy in both the
Taxol-resistant NMP-1 and HEY models, significant improvement in survival, and even some cures, were observed after a single i.p. treatment with this copolymer. The observed antitumor response correlated with histopathological analysis of peritoneal and extraperitoneal
tumor burden in comparing control HEY mice sacrificed near the onset of morbidity with mice receiving
paclitaxel copolymer. We conclude that both the i.p. NMP-1 and HEY models have significant value in establishing the efficacy of candidate agents, which might address
Taxol-resistant human ovarian
carcinoma. Furthermore, the
poly-L-glutamic acid-paclitaxel copolymer has a superior therapeutic profile in these
Taxol-resistant compartmental models.