Inutsuka S, Baba H, Maehara Y, Sugimachi K
Cancer Center of Kyushu University Hospital, Fukuoka, Japan.
Cancer Chemother Pharmacol. 1998;42(3):194-200. doi: 10.1007/s002800050805.
MST-16, a derivative of bis(2,6-dioxopiperazine), is a newly developed anticancer agent that is potentially effective in combination with anthracyclines. It has a structural similarity to ICRF-187. The effects of MST-16 and its active form, ICRF-154, on the cytotoxic activities of six anthracyclines were investigated both in vitro and in vivo. Adriamycin (ADM), therarubicin (THP) and ME2303 (ME) showed synergistic cytotoxicity against colon 26 cells, when combined with MST-16. Epirubicin (EPI) and menogaril (TUT-7) and daunomycin (DM) all had a combination index of less than 1.0 only in the lower fraction affected range and, so there were probably no synergistic interactions between these drugs and MST-16. In colon 26 tumor-bearing mice, a significant delay in tumor growth was noted in the mice treated with ADM (7.5 mg/kg) and MST-16 (750 mg/kg) compared with mice given either drug alone. Similarly, tumor growth in mice treated with THP (10 mg/kg) or ME (10 mg/kg) with MST-16 (750 mg/kg) was significantly delayed. To elucidate the mechanism of synergy between these anthracyclines and MST-16, the concentration of anthracyclines in the treated cells was measured by flow cytometry. No increased intracellular accumulation of ADM. THP or ME was evident even when combined with MST-16. Cell cycle analysis revealed that MST-16 enhanced the accumulation of cells in G2M induced by ADM, THP and ME 1.6, 1.4, and 1.5 times, respectively. We thus conclude that the administration of ADM, THP and ME combined with MST-16 is synergistic and that the mechanism may not include an increase in the intracellular drug uptake but rather an increase in G2M accumulation.
MST - 16是双（2,6 - 二氧代哌嗪）的衍生物，是一种新开发的抗癌药物，与蒽环类药物联合使用可能有效。它与ICRF - 187结构相似。研究了MST - 16及其活性形式ICRF - 154对六种蒽环类药物细胞毒性活性的体内外作用。阿霉素（ADM）、吡柔比星（THP）和ME2303（ME）与MST - 16联合使用时，对结肠26细胞表现出协同细胞毒性。表柔比星（EPI）、美诺加明（TUT - 7）和柔红霉素（DM）仅在较低受影响分数范围内联合指数小于1.0，因此这些药物与MST - 16之间可能不存在协同相互作用。在荷结肠26肿瘤的小鼠中，与单独给予任一药物的小鼠相比，用ADM（7.5 mg/kg）和MST - 16（750 mg/kg）治疗的小鼠肿瘤生长明显延迟。同样，用THP（10 mg/kg）或ME（10 mg/kg）与MST - 16（750 mg/kg）治疗的小鼠肿瘤生长也明显延迟。为了阐明这些蒽环类药物与MST - 16之间协同作用的机制，通过流式细胞术测量处理细胞中蒽环类药物的浓度。即使与MST - 16联合使用，ADM、THP或ME的细胞内积累也没有明显增加。细胞周期分析显示，MST - 16分别将ADM、THP和ME诱导的G2M期细胞积累增强了1.6倍、1.4倍和1.5倍。因此，我们得出结论，ADM、THP和ME与MST - 16联合给药具有协同作用，其机制可能不包括细胞内药物摄取增加，而是G2M期积累增加。
