Fujioka T, Ishikura K, Hasegawa M, Ogyu K, Matsushita Y, Sato M, Sato F, Aoki H, Kubo T
Department of Urology, Iwate Medical University School of Medicine, Morioka, Japan.
Cancer Chemother Pharmacol. 1995;36(1):7-12. doi: 10.1007/BF00685725.
Bropirimine [2-amino-5-bromo-6-phenyl-4-(3H)-pyrimidinone] is a low-molecular-weight compound that acts as an inducer of interferon in several animal species. Experiments were designed to explore the possibility of using this drug for the treatment of renal-cell carcinoma (RCC). Euthymic BALB/c mice were inoculated with murine RCC (Renca) cells and given graded doses of Bropirimine p.o. for 5 consecutive days beginning on day 1 following tumor inoculation. These mice were killed and tumors were excised on day 21. Bropirimine significantly (P < 0.01) inhibited the tumor growth at a daily dose of 1,000 or 2,000 mg/kg. No adverse effect or toxicity was noted at 1,000 mg/kg, and at 2,000 mg/kg there was only a marginal body-weight reduction without any other appreciable side effect. In addition to the inhibition of tumor growth, there was a small yet significant (P < 0.05) increase in the duration of survival (in days) in the Bropirimine-treated animals. When the treatment was delayed to begin on day 6 following tumor inoculation, Bropirimine did not suppress tumor growth in euthymic mice, pointing to the importance of the timing of the treatment. In athymic nude BALB/c mice lacking T-cells or T-cell function, Bropirimine also inhibited tumor growth (P < 0.01). The antitumor effect of this drug was abolished by pretreatment with anti-asialo GM1 serum, which eliminated natural killer (NK) activity in euthymic mice. In vivo treatment with Bropirimine augmented the cytotoxicity of lymphocytes isolated from the spleens or lungs of the tumor-bearing mice, which were active against Renca and YAC-1 cells in vitro. This activity was NK-cell-dependent as judged on the basis of the results of the in vitro complement-dependent cytotoxicity assay. Since Bropirimine induced interferon (IFN)-alpha/beta production, significantly (P < 0.05) elevating its serum concentration, and since this drug mimics the effects of IFN-alpha/beta, it seemed likely that the Bropirimine-induced NK cell augmentation we found was mediated by IFN-alpha/beta. These results suggest that Bropirimine, a booster of NK activity, may have potential as an adjunct to other therapeutic modalities in the treatment of human RCC.
溴匹立明[2-氨基-5-溴-6-苯基-4-(3H)-嘧啶酮]是一种低分子量化合物，在多种动物物种中可作为干扰素诱导剂。设计实验以探索使用该药物治疗肾细胞癌（RCC）的可能性。将健康的BALB/c小鼠接种鼠RCC（Renca）细胞，并在肿瘤接种后的第1天开始连续5天口服给予不同剂量的溴匹立明。在第21天处死这些小鼠并切除肿瘤。溴匹立明在每日剂量为1000或2000mg/kg时显著（P<0.01）抑制肿瘤生长。在1000mg/kg剂量下未观察到不良反应或毒性，在2000mg/kg时仅体重略有减轻，无任何其他明显副作用。除了抑制肿瘤生长外，溴匹立明治疗的动物的存活时间（以天计）有小幅但显著（P<0.05）的增加。当治疗延迟到肿瘤接种后的第6天开始时，溴匹立明在健康小鼠中并未抑制肿瘤生长，这表明治疗时机的重要性。在缺乏T细胞或T细胞功能的无胸腺裸BALB/c小鼠中，溴匹立明也抑制肿瘤生长（P<0.01）。用抗去唾液酸GM1血清预处理可消除该药物的抗肿瘤作用，抗去唾液酸GM1血清可消除健康小鼠的自然杀伤（NK）活性。用溴匹立明进行体内治疗可增强从荷瘤小鼠脾脏或肺中分离的淋巴细胞的细胞毒性，这些淋巴细胞在体外对Renca和YAC-1细胞具有活性。根据体外补体依赖性细胞毒性试验结果判断，这种活性依赖于NK细胞。由于溴匹立明诱导干扰素（IFN）-α/β产生，显著（P<0.05）提高其血清浓度，且该药物模拟IFN-α/β的作用，我们发现溴匹立明诱导的NK细胞增加似乎是由IFN-α/β介导的。这些结果表明，作为NK活性增强剂的溴匹立明在治疗人类RCC时可能有作为其他治疗方式辅助药物的潜力。
