Tumor necrosis factor enhances the in vitro and in vivo efficacy of chemotherapeutic drugs targeted at DNA topoisomerase II in the treatment of murine bladder cancer

Recombinant human tumor necrosis factor (rTNF) is a macrophage secretory protein with antitumor activity. The murine bladder tumor cell line MBT-2 was used to evaluate the in vitro and in vivo antitumor effects of rTNF in combination with chemotherapeutic drugs targeted at DNA topoisomerase II. These drugs, such as adriamycin and etoposide (VP 16), are in widespread use in the treatment of human cancer. The rTNF significantly enhanced the cytotoxic efficacy of the topoisomerase-targeted drugs actinomycin D, adriamycin, etoposide (VP 16) and teniposide (VM 26) against MBT-2 cells in vitro. The rTNF alone had no effect upon the cells in the same assay. When examined in vivo using MBT-2 tumor-bearing C3H/HeJ mice, these same antitumor relationships were seen. The addition of rTNF to actinomycin D or VP 16 resulted in a significant reduction in tumor volume at 20 days compared to untreated animals. Actinomycin D, VP 16 or rTNF treatment alone had no significant effect on 20 day tumor volume. The data provide a reasonable basis for the addition of rTNF to experimental protocols for the treatment of human bladder cancer using topoisomerase-targeted drugs such as adriamycin both intravesically and systemically. These observations may also be relevant to other human cancers currently treated with these drugs.