Li L H, DeKoning T F, Wallace T L
Cancer and Viral Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Cancer Res. 1987 Nov 15;47(22):5894-900.
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.
溴匹立明（ABPP），一种嘧啶酮，目前正在进行临床试验以评估其抗肿瘤潜力。单独使用溴匹立明对某些实验性肿瘤如B16黑色素瘤有微弱活性，但对其他肿瘤如P388或L1210白血病无效。然而，当与环磷酰胺（CY）联合使用时，它对P388白血病产生了具有统计学意义的协同活性。本研究的目的是确定与不同类型的细胞毒性药物联合使用时是否能实现协同作用。选择了放线菌素D（act D）、阿霉素、5-氮杂胞苷、顺铂、美法仑、丝裂霉素C和长春新碱。采用与CY和溴匹立明联合治疗相同的实验方案，并使用大致等效剂量的药物来初步减轻肿瘤负荷（即寿命延长约100%），顺铂和溴匹立明联合使用也比单独使用顺铂治疗产生了具有统计学意义的协同作用。溴匹立明与阿霉素、丝裂霉素或长春新碱联合使用是有益的，但效果不如CY和溴匹立明联合使用那样一致或显著。然而，很明显，在实验条件下act D和溴匹立明联合使用没有协同作用。由于据报道嘧啶酮的抗肿瘤活性部分是通过其对自然杀伤细胞活性的刺激介导的，因此研究了这些细胞毒性药物对溴匹立明免疫调节活性的影响。与CY一样，顺铂不会改变溴匹立明对自然杀伤细胞活性的增强作用。然而，阿霉素、丝裂霉素或长春新碱显示出明显的抑制作用（25%-50%）。给药4天后，act D完全抑制了溴匹立明的免疫调节活性，18天后仍显示出明显的抑制作用。这可能部分解释了act D和溴匹立明之间缺乏协同作用的原因。act D表现出的长期免疫抑制作用以及在此期间肿瘤的再增殖程度可能使溴匹立明无效。除了化疗药物最初减轻肿瘤负荷的程度外，目前的结果表明这些药物的免疫抑制特性也可能影响化疗免疫治疗的结果。
