Lopes de Menezes D E, Hudon N, McIntosh N, Mayer L D
Department of Advanced Therapeutics, British Columbia Cancer Research Centre, Vancouver, Canada.
Clin Cancer Res. 2000 Jul;6(7):2891-902.
Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresistance for a variety of malignancies by blocking programmed cell death. This study investigated the activity of the Bcl-2 antisense oligodeoxynucleotide (AS ODN) G3139 combined with free doxorubicin (F-DOX) or sterically stabilized liposomal doxorubicin (SL-DOX) to determine the role that drug pharmacodistribution properties may have on antitumor activity using a Bcl-2-expressing human breast solid tumor xenograft model. Administration of G3139 was able to delay the growth of MDA435/LCC6 cells compared with control ODN-treated animals; however, in all of the cases, tumors reestablished after AS ODN treatment. Western blot analyses of Bcl-2 levels of solid tumors showed a sequence-specific down-regulation of the Bcl-2 protein after four daily doses of G3139, which correlated with histological evidence of tumor cell death. Interestingly, the expression of Bcl-2 returned to pretreatment levels during the course of subsequent ODN administration, which suggested the development of resistance to continued Bcl-2 ODN treatment. The antitumor activity of ODN given in conjunction with either F-DOX or SL-DOX was also examined. The combination of G3139 and F-DOX was able to suppress the growth of MDA435/LCC6 cells beyond that obtained with either of the treatments given alone, indicative of synergistic action. Examination of the pharmacokinetics of F-DOX with systemic G3139 administration revealed that elevated tumor drug DOX levels were obtained compared with DOX treatment in the absence of G3139. This effect was sequence-specific and plasma DOX levels were unaffected by G3139 treatment, which indicated possible positive ODN-drug interactions at the tumor site. Combining G3139 with SL-DOX further increased the degree of antitumor activity. The improved efficacy of this combination was attributed to increased tumor drug levels that arise from the ability of SL-DOX to passively accumulate in solid tumors. These results suggest that additional benefits of Bcl-2 antisense ODN may be obtained when it is combined with liposomal formulations of anticancer drugs such as DOX.
Bcl-2是一种关键的凋亡调节蛋白，通过阻断程序性细胞死亡参与多种恶性肿瘤的化疗耐药机制。本研究利用表达Bcl-2的人乳腺实体瘤异种移植模型，研究了Bcl-2反义寡脱氧核苷酸（AS ODN）G3139与游离阿霉素（F-DOX）或空间稳定脂质体阿霉素（SL-DOX）联合使用的活性，以确定药物药代分布特性在抗肿瘤活性中可能发挥的作用。与对照ODN处理的动物相比，给予G3139能够延缓MDA435/LCC6细胞的生长；然而，在所有情况下，AS ODN治疗后肿瘤会重新生长。对实体瘤Bcl-2水平的蛋白质印迹分析显示，每日4次给予G3139后，Bcl-2蛋白出现序列特异性下调，这与肿瘤细胞死亡的组织学证据相关。有趣的是，在随后的ODN给药过程中，Bcl-2的表达恢复到预处理水平，这表明对持续的Bcl-2 ODN治疗产生了耐药性。还研究了ODN与F-DOX或SL-DOX联合使用时的抗肿瘤活性。G3139和F-DOX联合使用能够比单独使用任何一种治疗更有效地抑制MDA435/LCC6细胞的生长，表明具有协同作用。对全身给予G3139时F-DOX的药代动力学研究表明，与未使用G3139的DOX治疗相比，肿瘤药物DOX水平升高。这种作用具有序列特异性，血浆DOX水平不受G3139治疗的影响，这表明在肿瘤部位可能存在ODN与药物的积极相互作用。将G3139与SL-DOX联合使用进一步提高了抗肿瘤活性的程度。这种联合用药疗效的提高归因于SL-DOX在实体瘤中被动蓄积导致肿瘤药物水平升高。这些结果表明，当Bcl-2反义ODN与阿霉素等抗癌药物的脂质体制剂联合使用时，可能会获得额外的益处。
