Pyrrole-imidazole polyamides for suppression of hypoxia inducible factors in chemotherapy-resistant urogenital cancers

我们已经开发了一种新的方法，抑制血管内皮生长因子的组合使用四个吡咯-咪唑发夹聚酰胺。研究结果发表在Acta Oncologica杂志上。在此基础上，我们合成了直接靶向缺氧诱导因子1 α（HIF 1 α）编码区的吡咯-咪唑聚酰胺。聚酰胺被设计为与HIF 1 α基因外显子1中的序列相互作用。我们通过RT-PCR和Western blot评估了这些聚酰胺对人肾细胞癌细胞系中HIF 1 α和VEGF转录和翻译的影响。不幸的是，这些分子的抑制并不显著。分子畸变可能是负结果的原因，因为每个聚酰胺被设计成识别长达20个碱基对的序列以获得最大的特异性。然后，我们将重点放在与HIF 1 α分子稳定性密切相关的热休克蛋白上。我们用免疫组化方法检测了HSP 27、HSP 60、HSP 70和HSP 90在膀胱癌组织中的表达.我们发现HSP 60的表达水平可能预示着对肌层浸润性膀胱癌放化疗的良好反应。研究结果发表在《日本临床肿瘤学杂志》上。

We have developed a novel method of suppressing VEGF using a combination of four pyrrole -midazole hairpin polyamides. The results were published in the journal, Acta Oncologica. Based on this successful work, we synthesized pyrrole-imidazole polyamides directly targeting coding regions of hypoxia inducible factor 1 alpha (HIF 1 alpha). The polyamides were designed to interact with sequences in exon 1 of the HIF 1 alpha gene. We evaluated effects of these polyamides on transcription and translation of HIF 1 alpha as well as VEGF in a human renal cell carcinoma cell line by RT-PCR and Western blot Unfortunately suppression of these molecules was not significant. Molecular distortion may be responsible for the negative results because each polyamide were designed to recognize sequences as long as 20 base pairs to obtain maximum specificity Then, we focused on the heat shock proteins closely related to stability of HIF 1 alpha molecule. We assessed expression of HSP 27, HSP 60, HSP 70, and HSP 90 in bladder cancer tissues by immunohistochemistry. We found that expression level of HSP 60 may predict good response to chemoradiotherapy in muscle invasive bladder cancer. The results were published in Japanese Journal of Clinical Oncology.