Vaughan W P, Holm C, Cordel K
University of Nebraska Medical Center, Department of Internal Medicine, Omaha 68105.
Cancer Chemother Pharmacol. 1989;23(1):26-30. doi: 10.1007/BF00258453.
The activities of hydroxyurea (HU), 4'-(9-acridinylamino)methanesulfon-M-anisidide (AMSA) and cyclophosphamide (CY) were examined in the brown Norway rat myelocytic leukemia model in experiments designed to determine the synergy, optimal drug sequencing, and therapeutic index of combinations of these agents. A single dose of CY or four consecutive daily doses of AMSA produced increased survival in leukemic rats, with a positive-slope dose-response curve up to the maximum tolerated dose (MTD). HU at 1/2 MTD produced a minimal antileukemic effect but significantly potentiated the antineoplastic activity of 1/2 MTD of CY or AMSA with no significant toxic death rate. Drug-sequence experiments demonstrated that maximal synergy was achieved when HU was given immediately after CY but immediately before or during AMSA administration. No significant cure rate was seen with any CY/HU or HU/AMSA sequence. The three drugs given in the sequence of CY followed 3 days later by HU and AMSA simultaneously, however, was curative in the majority of rats with advanced leukemia, whereas other sequences were more toxic or less effective. Each of the drugs in these experiments was given at 1/2 of its single-agent MTD. HU significantly potentiates the antineoplastic effect of CY and AMSA in a drug-sequence-dependent manner in this model, apparently with an improved therapeutic index.
在旨在确定羟基脲（HU）、4'-（9-吖啶基氨基）甲磺酰基-M-茴香胺（AMSA）和环磷酰胺（CY）联合用药的协同作用、最佳用药顺序及治疗指数的实验中，对棕色挪威大鼠髓细胞白血病模型进行了这些药物活性的研究。单剂量的CY或连续四天每日给药的AMSA可提高白血病大鼠的生存率，直至最大耐受剂量（MTD），剂量-反应曲线呈正斜率。1/2 MTD的HU产生的抗白血病作用极小，但能显著增强1/2 MTD的CY或AMSA的抗肿瘤活性，且无显著的毒性死亡率。用药顺序实验表明，当CY给药后立即给予HU，但在AMSA给药前或给药期间立即给予HU时，可实现最大协同作用。任何CY/HU或HU/AMSA顺序均未观察到显著的治愈率。然而，按照CY、3天后同时给予HU和AMSA的顺序给药，可治愈大多数晚期白血病大鼠，而其他顺序则毒性更大或效果更差。这些实验中每种药物均按其单药MTD的1/2给药。在该模型中，HU以药物顺序依赖性方式显著增强CY和AMSA的抗肿瘤作用，治疗指数明显提高。
