Relationship between modulation of natural killer cell activity and antitumor activity of bropirimine when used in combination with various types of chemotherapeutic drugs

Bropirimine (ABPP), a pyrimidinone, is currently under clinical trial for its antitumor potential. Bropirimine alone was marginally active against some experimental tumors such as B16 melanoma but was ineffective against others such as P388 or L1210 leukemia. However, it produced statistically significant synergistic activity against P388 leukemia when used in combination with cyclophosphamide (CY). The aim of this investigation was to determine whether the synergism could be achieved with different types of cytotoxic drugs. Actinomycin D (act D), adriamycin, 5-azacytidine, cisplatin, melphalan, mitomycin C, and vincristine were selected. Using an experimental protocol identical to that of CY and bropirimine combination therapy, and using a more or less equally effective dosage of the drug for the initial reduction of tumor burden (i.e., around 100% increase of life span), cisplatin and bropirimine also produced a statistically significant synergism over the treatment with cisplatin alone. The combination of bropirimine with either adriamycin, mitomycin, or vincristine was beneficial but the effect was not as consistent or as striking as that seen with the CY and bropirimine combination. It is clear, however, that the combination of act D and bropirimine was not synergistic under the experimental conditions. Since the antitumor activity of pyrimidinone has been reported to be mediated in part by its stimulation of natural killer cell activity, the effect of these cytotoxic drugs on the immunomodulatory activity of bropirimine was investigated. Like CY, cisplatin did not alter the augmentation of natural killer cell activity by bropirimine. However, adriamycin, mitomycin, or vincristine showed a marked inhibition (25-50%) of the augmentation. Act D completely inhibited the immunomodulating activity of bropirimine 4 days after drug administration and continued to show marked inhibition 18 days later. This may partially explain the reasons for lack of synergism between act D and bropirimine. A prolonged immunosuppressive effect exhibited by act D and the degree of tumor repopulation during this period could render bropirimine ineffective. In addition to the magnitude of initial tumor burden reduction by the chemotherapeutic drugs, the present results indicate that the immunosuppressive property of these drugs may also affect the outcome of chemoimmunotherapy.