Synergy is documented in vitro with low-dose recombinant tumor necrosis factor, cisplatin, and doxorubicin in ovarian cancer cells

Abstract

Ovarian carcinomas have been shown to be sensitive or insensitive to the in vitro exposure of several cytotoxic drugs and cytokines. Because of the potential for cytokines to enhance the efficacy of chemotherapeutic agents and to improve their therapeutic index, the optimal dose and schedule of the combination of these agents have been studied. We examined the cytotoxic effect of a combined modality using a variety of concentrations of recombinant tumor necrosis factor (rTNF) (a cytotoxic cytokine) with Adriamycin (ADR) and cisplatin (CDDP) on human ovarian carcinoma cell lines. Cytotoxicity was determined in a 24-hr 51Cr-release assay and confirmed in a 5-day viability culture assay. Five cell lines were used: PA-1, 222, OVCAR-3, SKOV-3, and OVCAR-8. Doses of rTNF that were minimally cytotoxic resulted in significant cytotoxicity and synergy when used with optimal or suboptimal concentrations of ADR or CDDP. This synergy was observed in four cell lines. Interestingly, the rTNF- and drug resistant SKOV-3 cell line was sensitive to the synergistic effect of Adriamycin and rTNF. The synergistic effect that was obtained was specific to rTNF, while the combined use of ADR and CDDP or recombinant interleukin-2 and cytotoxic drugs had no synergistic effect on tumor cell lysis. Further, the addition of anti-TNF antibody abrogated the synergistic effect seen with rTNF and the cytotoxic drugs. These studies demonstrate clearly that significant synergistic antitumor cytotoxic activity against human ovarian carcinoma cell lines can be achieved with combinations of low doses of rTNF and ADR or CDDP, suggesting their possible adaptation in vivo for cancer therapy. Further, the studies suggest that rTNF and the cytotoxic drugs tested may share a common lytic pathway. Since rTNF used alone has been relatively inactive in clinical trials, its potential activity may be apparent only when combined with conventional cytotoxic chemotherapeutic agents and when administered in relatively low concentration.