Potentiation of antitumor efficacy of paclitaxel by recombinant tumor necrosis factor-alpha.

Abstract

We studied the combination of tumor necrosis factor (TNF) and paclitaxel. Our aim was to determine whether TNF increases the antitumor efficacy of paclitaxel and if so whether the increase is mediated through the enhancement of apoptosis induction by paclitaxel. Mice bearing 6 mm MCa-K or MCa-4 mammary carcinomas, OCa-I ovarian carcinomas, or HCa-I hepatocarcinomas in their legs were treated with TNF, paclitaxel of their combination. TNF was administered i.p. daily at a dose of 10 micrograms per mouse for 7 days; paclitaxel at a dose of 40 mg/kg per mouse was given as a single i.v. injection 1 h before the second dose of TNF. Tumor growth delay was used as the endpoint of tumor response to the treatments. The results showed that the combination was either additive or supraadditive; supraadditive action occurred in three of the four tumors tested. The enhancement factors (EFs) were 1.24 for MCa-K, 1.53 for MCa-4, 1.0 for OCa-I and 2.17 for HCa-I. Histological analysis of treated MCa-K tumors revealed that TNF alone did not induce apoptosis of tumor cells, but in the combination it enhanced the apoptotic response to paclitaxel. Thus, TNF increased the antitumor efficacy of paclitaxel by enhancing cellular sensitivity to paclitaxel's induction of apoptosis. The results imply that the combination of TNF and paclitaxel has potential as a treatment for cancer.