RESprotect, Fiedlerstr. 34, 01307, Dresden, Germany.
J Cancer Res Clin Oncol. 2011 Sep;137(9):1349-61. doi: 10.1007/s00432-011-1005-1. Epub 2011 Jul 22.
Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer.
Chemistry: Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology: HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004).
Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients.
The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.
有几份报告描述了伴侣蛋白 HSP27（HSPB1）在癌症进展中的重要性，对调节 HSPB1 活性的药物的需求正在迅速增加。我们之前曾报道过，RP101（溴脱氧尿苷，BVDU，Brivudine）可提高胰腺癌化疗的疗效。
化学：通过亲和层析发现 RP101 与 HSPB1 的结合。分子和细胞生物学：HSPB1 体外转录/翻译（TNT），使用 RP101 偶联的磁珠进行下拉，免疫共沉淀，HSP27（HSPB1）的结构建模，通过 PCR 将点突变引入线性表达模板，热休克，肿瘤侵袭。动物实验：在 SD 大鼠中治疗 AH13r 肉瘤。晚期胰腺癌患者的临床研究：初步研究，剂量发现研究，II 期研究（NCT00550004）。
在这里，我们报告 RP101 在体外与热休克蛋白 HSPB1 结合并抑制其与结合伴侣的相互作用。结果，在 RP101 处理的癌细胞中检测到更多激活的 CASP9。我们对 HSPB1 结构进行建模并确定了 RP101 的结合位点。当我们在大鼠模型中测试 RP101 作为抗癌药物时，我们发现它可以改善化疗。在晚期胰腺癌患者的临床研究中，每天 500mg 的剂量是安全有效的，但对于体重较轻的患者，每天 760mg 的剂量过高。
将 RP101 开发为癌症药物代表了一种预防化疗耐药和增强化疗敏感性的真正新方法。
