Silvestrini R, Gornati D, Zaffaroni N, Bearzatto A, De Marco C
Divisione di Oncologia Sperimentale C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Breast Cancer Res Treat. 1997 Jan;42(2):103-12. doi: 10.1023/a:1005725203159.
The ability of lonidamine (LND), an energolytic derivative of indazole-carboxylic acid, to modulate the cytotoxic activity of cisplatin (CDDP) and epidoxorubicin (EPI), singly or in combination, was investigated in two human breast cancer cell lines (MCF7 and T47D). A 72-hr post-incubation with a non-cytotoxic concentration of LND (75 microM) increased the activity of a 1-hr CDDP treatment as well as that of a 1 to 16-hr EPI treatment. A different pattern of interaction among the drugs and modulator was observed as a function of the sequence of drug treatment. Specifically, supra-additive or additive effects of the combination were obtained in the two cell lines according to the different treatment schemes. In particular, the maximum potentiation was observed in MCF7 cells simultaneously exposed to CDDP, EPI and LND for 1 hr and then post-incubated with LND for 72 hr, and in T47 first exposed to EPI and LND, then to CDDP and LND, and finally post-incubated with LND. Flow cytometric analysis of MCF7 cell distribution in the different cycle phases showed that combined treatment with EPI/CDDP/LND was able to stabilize cell cycle perturbations (mainly G2M accumulation) induced by individual agents. The ability of LND to potentiate CDDP and EPI cytotoxicity, and the consideration that LND causes side effects different from those caused by alkylating agents and anthracyclines, make this compound an attractive candidate for multidrug combination therapy in breast cancer.
在两种人乳腺癌细胞系（MCF7和T47D）中，研究了吲唑羧酸的能量分解衍生物氯尼达明（LND）单独或联合调节顺铂（CDDP）和表柔比星（EPI）细胞毒性活性的能力。用非细胞毒性浓度的LND（75 microM）孵育72小时后，增加了1小时CDDP处理以及1至16小时EPI处理的活性。根据药物处理顺序的不同，观察到药物与调节剂之间不同的相互作用模式。具体而言，根据不同的处理方案，在两种细胞系中获得了联合用药的超相加或相加效应。特别是，在MCF7细胞中，同时暴露于CDDP、EPI和LND 1小时，然后用LND孵育72小时，以及在T47细胞中，先暴露于EPI和LND，然后暴露于CDDP和LND，最后用LND孵育，观察到最大增强作用。对MCF7细胞在不同细胞周期阶段分布的流式细胞术分析表明，EPI/CDDP/LND联合处理能够稳定由单个药物诱导的细胞周期扰动（主要是G2M期积累）。LND增强CDDP和EPI细胞毒性的能力，以及LND引起的副作用与烷化剂和蒽环类药物不同的考虑，使该化合物成为乳腺癌多药联合治疗的有吸引力的候选药物。
