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

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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.