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.