Preclinical studies and clinical correlation of the effect of alkylating dose.
Preclinical studies and clinical correlation of the effect of alkylating dose.
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发表时间：
1988-11
期刊：
影响因子：
11.2
通讯作者：
E. Frei;B. Teicher;S. Holden;K. Cathcart;Yenyun Wang
中科院分区：
文献类型：
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作者：
E. Frei;B. Teicher;S. Holden;K. Cathcart;Yenyun Wang
在MCF-7人乳腺癌细胞系和EMT 6和FSaIIC小鼠肿瘤系中，使用烷化剂[氮芥、N，N '-双（2-氯乙基）-N-亚硝基脲、美法仑、顺铂（CDDP）、4-氢过氧环磷酰胺（4-HC）和三亚甲基亚胺硫代磷酰胺]进行剂量反应研究。增加选择压力与烷化剂CDDP，美法仑，4-HC在体外产生低水平（6.5至9倍）的耐药性，尽管密集和长期的治疗计划。对CDDP和4-HC具有耐药性的MCF-7亚系对其他烷基化剂没有表现出交叉耐药性;然而，对美法仑具有耐药性的MCF-7亚系对氮芥、4-HC和CDDP具有部分交叉耐药性。对数线性关系保持MCF-7细胞的存活分数与烷化剂的药物浓度之间的文化，而非烷化剂的生存曲线趋于平台在高浓度的药物。对数线性的肿瘤细胞杀伤也获得了广泛的剂量范围内与几个烷化剂在小鼠肿瘤治疗的体内。通过集落形成进行的肿瘤细胞存活试验表明，即使在高水平的肿瘤细胞杀伤下，剂量在药物作用中也具有持续的重要性。对于某些药物，体内肿瘤细胞杀伤曲线的斜率与体外相比存在差异。环磷酰胺在体外（4-HC）的效力远高于体内（环磷酰胺）。三亚甲基亚胺硫代磷酰胺和N，N '-双（2-氯乙基）-N-亚硝基脲在体内比体外更有效。这些差异可以通过这些药物的不同代谢模式来解释。烷化剂的剂量显然是一个关键的变量，特别是在多对数肿瘤细胞杀伤是目标的情况下，并且在这方面，药物剂量对烷化剂的杀肿瘤作用的影响显著大于非烷化剂。
Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents.