ABSTRACT
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.
