Yin M B, Bankusli I, Frank C, Rustum Y M
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263.
Anticancer Res. 1990 Mar-Apr;10(2A):327-32.
Lymphoid cell lines resistant to doxorubicin, P388/R, were characterized by: 1) decreased intracellular acumulatin and retention of DOX; 2) decreased amount of DOX-induced DNA lesions; and 3) rapid repair of DOX-induced DNA lesions. Using the highest noncytotoxic concentrations of three modulators; 2 calcium channel blockers, Verapamil (VEP) and DMDP and a nucleoside transport inhibitor, Dipyridamole (DIP), restoration of Doxorubicin (DOX) sensitivity in vitro against P388/R cells was partial; resistance was reduced from approximately 200 to 10 fold, although DOX accumulation in the resistant cells in the presence of the modulators was completely restored. The DNA single-strand break (SSB) level induced by DOX in P388/S cells (1371 +/- 144 rad equivalents) was significantly higher than in P388/R cells (74 +/- 17 rad equivalents). The effects of VEP, DMDP and DIP on the induction of DNA SSBs by DOX in P388/R were different. DMDP and DIP potentiated the DOX-induced DNA SSBs by 30% each and VEP by 15%. Furthermore, while VEP and DIP had no significant effects on the rapid repair of DOX-induced SSBs, no significant repair of DNA lesion was observed in P388/R treated with DMDP at 1.2 microM, a non-cytotoxic concentration. These data indicate that although these modulators can effectively restore the intracellular accumulation and retention of DOX, these conditions although essential are not sufficient for the complete restoration of DOX sensitivity in this highly resistant cll line. The ability of a calcium antagonist, DMDP, to circumvent DOX resistance might be related not only to the modulation of drug retention, but also to the ability to retard the repair of DOX-induced DNA SSBs.
对阿霉素耐药的淋巴样细胞系P388/R具有以下特征：1）细胞内阿霉素的积累和滞留减少；2）阿霉素诱导的DNA损伤数量减少；3）阿霉素诱导的DNA损伤修复迅速。使用三种调节剂的最高非细胞毒性浓度；两种钙通道阻滞剂维拉帕米（VEP）和DMDP以及一种核苷转运抑制剂双嘧达莫（DIP），体外对P388/R细胞的阿霉素（DOX）敏感性恢复是部分性的；耐药性从约200倍降低到10倍，尽管在存在调节剂的情况下耐药细胞中DOX的积累完全恢复。DOX在P388/S细胞中诱导的DNA单链断裂（SSB）水平（1371±144拉德当量）显著高于P388/R细胞（74±17拉德当量）。VEP、DMDP和DIP对DOX在P388/R中诱导DNA SSB的作用不同。DMDP和DIP使DOX诱导的DNA SSB分别增强30%，VEP增强15%。此外，虽然VEP和DIP对DOX诱导的SSB的快速修复没有显著影响，但在1.2微摩尔（非细胞毒性浓度）的DMDP处理的P388/R中未观察到DNA损伤的显著修复。这些数据表明，尽管这些调节剂可以有效地恢复DOX在细胞内的积累和滞留，但这些条件虽然是必需的，但不足以使这种高度耐药的细胞系中DOX敏感性完全恢复。钙拮抗剂DMDP克服DOX耐药性的能力可能不仅与药物滞留的调节有关，还与延缓DOX诱导的DNA SSB修复的能力有关。
