Teicher B A, Herman T S, Tanaka J, Eder J P, Holden S A, Bubley G, Coleman C N, Frei E
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Cancer Res. 1991 Feb 15;51(4):1086-91.
Tumor cell survival assay in the FSaIIC murine fibrosarcoma demonstrated that when the modulator Fluosol-DA (0.3 ml; 12 ml/kg i.v.) was administered just prior to an alkylating agent plus carbogen breathing for 6 h or the modulator etanidazole (1 g/kg i.p.) was administered just prior to an alkylating agent, the combination treatment produced significantly more tumor cell killing across the dosage range of each alkylating agent tested compared with the alkylating agent alone. Each alkylating agent produced a dose-dependent log-linear tumor cell survival curve. There was an increase in tumor cell killing of 5-10-fold when either Fluosol-DA/carbogen or etanidazole was added to treatment with the alkylating agent. For cis-diamminedichloroplatinum(II) (CDDP) and N,N',N''-triethylenethiophosphoramide, the modulators used in combination increased tumor cell killing by only 2-3-fold over that obtained with a single modulator, but for the other alkylating agents, tumor cell killing was increased by 10-50-fold when the combination of modulators was used. Bone marrow granulocyte-macrophage colony-forming unit survival assays showed that the combination of modulators with the alkylating agents resulted in only small increases in bone marrow toxicity of the alkylating agents except for N,N',N''-triethylenethiophosphoramide and L-phenylalanine mustard (L-PAM), for which the toxicity to the bone marrow granulocyte-macrophage colony-forming unit was increased by 5-10-fold compared with the alkylating agents alone. The Hoechst 33342 dye diffusion defined tumor cell subpopulation assay, also in the FSaIIC tumor, demonstrated that the combination of modulators increased the toxicity of CDDP, cyclophosphamide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea by 9-55-fold compared with the alkylating agent alone in both the bright (euxoic-enriched) and dim (hypoxic-enriched) cells. For each alkylating agent except 1,3-bis(2-chloroethyl)-1-nitrosourea, the increase in tumor cell killing was greater in the dim cells than in the bright cells. Finally, tumor growth delay studies in both the FSaIIC tumor and the EMT-6 murine mammary adenocarcinoma confirmed that the combination of modulators significantly increased the tumor growth delay caused by CDDP, carboplatin, cyclophosphamide, N,N'N"-triethylenethiophosphoramide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea. The greatest increases (4-5-fold) were observed for carboplatin and L-PAM in the FSaIIC tumor and CDDP and cyclophosphamide in the EMT-6 tumor. These results suggest that Fluosol-DA/carbogen together with etanidazole may be an effective modulator combination of alkylating agents in the clinic.
在FSaIIC小鼠纤维肉瘤中进行的肿瘤细胞存活试验表明，当在给予烷化剂并同时吸入含95%氧和5%二氧化碳的混合气6小时之前静脉注射调节剂全氟三丙胺（0.3毫升；12毫升/千克），或者在给予烷化剂之前腹腔注射调节剂乙硝唑（1克/千克）时，与单独使用烷化剂相比，联合治疗在每种测试烷化剂的剂量范围内均能显著提高肿瘤细胞杀伤率。每种烷化剂均产生剂量依赖性的对数线性肿瘤细胞存活曲线。当将全氟三丙胺/含95%氧和5%二氧化碳的混合气或乙硝唑添加到烷化剂治疗中时，肿瘤细胞杀伤率提高了5至10倍。对于顺二氯二氨铂（II）（CDDP）和氮芥，联合使用的调节剂使肿瘤细胞杀伤率仅比单一调节剂提高了2至3倍，但对于其他烷化剂，联合使用调节剂时肿瘤细胞杀伤率提高了10至50倍。骨髓粒细胞 - 巨噬细胞集落形成单位存活试验表明，除了氮芥和左旋苯丙氨酸氮芥（L - PAM）外，调节剂与烷化剂联合使用只会使烷化剂的骨髓毒性略有增加，对于氮芥和左旋苯丙氨酸氮芥，与单独使用烷化剂相比，对骨髓粒细胞 - 巨噬细胞集落形成单位的毒性增加了5至10倍。在FSaIIC肿瘤中进行的Hoechst 33342染料扩散定义肿瘤细胞亚群试验表明，与单独使用烷化剂相比，调节剂联合使用使CDDP、环磷酰胺、L - PAM和1,3 - 双（2 - 氯乙基） - 1 - 亚硝基脲在明亮（富氧）和暗淡（缺氧）细胞中的毒性提高了9至55倍。对于除1,3 - 双（2 - 氯乙基） - 1 - 亚硝基脲之外的每种烷化剂，暗淡细胞中的肿瘤细胞杀伤率增加幅度大于明亮细胞。最后，在FSaIIC肿瘤和EMT - 6小鼠乳腺腺癌中进行的肿瘤生长延迟研究证实，调节剂联合使用显著增加了CDDP、卡铂、环磷酰胺、氮芥、L - PAM和1,3 - 双（2 - 氯乙基） - 1 - 亚硝基脲引起的肿瘤生长延迟。在FSaIIC肿瘤中观察到卡铂和L - PAM以及在EMT - 6肿瘤中观察到CDDP和环磷酰胺的增加幅度最大（4至5倍）。这些结果表明，全氟三丙胺/含95%氧和5%二氧化碳的混合气与乙硝唑联合使用可能是临床上烷化剂的一种有效调节剂组合。
