Bankusli I, Yin M B, Mazzoni A, Abdellah A J, Rustum Y M
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263.
Anticancer Res. 1989 May-Jun;9(3):567-74.
The effect of DMDP, N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylam ine hydrochloride, on DOX-induced cytotoxicity, drug uptake, DNA damage and repair was investigated in adriamycin sensitive and resistant P388 cell lines. In vitro, the DOX-resistant P388 cells used are about 300-fold more resistant than the sensitive cells. Resistant cells were characterized by lower DOX accumulation, rapid drug efflux, significant decrease of DNA single and double strand breaks and rapid repair of the induced single strand breaks. DMDP, a calcium channel blocker, is an effective modulator of DOX resistance in P388 cells. This modulation was found to be highly dependent of the concentration of the modulators, optimal at the maximally moncytotoxic concentrations of 1-4 microM, and the duration of exposure to the modulator, optimal under conditions of continuous exposure to the modulator. Under the optimal conditions in the presence of the modulator, DMDP, both intracellular concentration and retention of DOX were restored in the resistant P388 cells to the value comparable to those found in DOX sensitive P388 cells. Even though DOX accumulation and retention were at a comparable level in both the sensitive and resistant cells in the presence of DMDP, the amount of DNA single strand breaks achieved in the resistant cells was only about 30% of the amount of damage observed in the sensitive cells. The data indicate that if P388/R cells were only exposed to DOX for about 2 h, the induced DNA single strand breaks were repaired rapidly within 8 h thereafter, while no significant repair was seen in the resistant cells exposed to DOX in combination with DMDP. In contrast, the repair of the extensive DNA single strand breaks induced by DOX in P388/S cells was not effected by DMDP. These data clearly demonstrated that resistance to DOX in P388 cells are multifactorial. Restoration of intracellular accumulation and retention of DOX by DMDP in the resistant cells are although necessary but not sufficient for complete restoration of the sensitivity of the highly resistant cells.
研究了盐酸N-(3,4-二甲氧基苯乙基)-N-甲基-2-(2-萘基)-间二硫杂环戊烷-2-丙胺（DMDP）对阿霉素敏感和耐药的P388细胞系中阿霉素诱导的细胞毒性、药物摄取、DNA损伤和修复的影响。在体外，所使用的阿霉素耐药P388细胞的耐药性比敏感细胞高约300倍。耐药细胞的特征是阿霉素积累较低、药物快速外排、DNA单链和双链断裂显著减少以及诱导的单链断裂快速修复。DMDP是一种钙通道阻滞剂，是P388细胞中阿霉素耐药性的有效调节剂。发现这种调节高度依赖于调节剂的浓度，在最大非细胞毒性浓度1-4 microM时最佳，还依赖于暴露于调节剂的持续时间，在持续暴露于调节剂的条件下最佳。在存在调节剂DMDP的最佳条件下，耐药P388细胞中阿霉素的细胞内浓度和滞留量恢复到与阿霉素敏感P388细胞中相当的值。尽管在存在DMDP的情况下，敏感细胞和耐药细胞中的阿霉素积累和滞留处于相当水平，但耐药细胞中产生的DNA单链断裂量仅为敏感细胞中观察到的损伤量的约30%。数据表明，如果P388/R细胞仅暴露于阿霉素约2小时，此后诱导的DNA单链断裂在8小时内迅速修复，而在与DMDP联合暴露于阿霉素的耐药细胞中未观察到显著修复。相反，DMDP对阿霉素在P388/S细胞中诱导的广泛DNA单链断裂的修复没有影响。这些数据清楚地表明，P388细胞对阿霉素的耐药性是多因素的。DMDP在耐药细胞中恢复阿霉素的细胞内积累和滞留虽然是必要的，但不足以完全恢复高耐药细胞的敏感性。
