Ex vivo assays to predict enhanced chemosensitization by hyperthermia in urothelial cancer of the bladder

Nathalie van den Tempel, Kishan A. T. Naipal, Anja Reams, Dik C. van Gent, Martine Franckena, Joost L. Boormans, Roland Kanaar

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    Abstract

    Introduction

    Bladder cancer (urothelial carcinoma) is a common malignancy characterized by high recurrence rates and intense clinical follow-up, indicating the necessity for more effective therapies. Current treatment regimens include intra-vesical administration of mitomycin C (MMC) for non-muscle invasive disease and systemic cisplatin for muscle-invasive or metastatic disease. Hyperthermia, heating a tumor to 40-44 degrees C, enhances the efficacy of these chemotherapeutics by various modes of action, one of which is inhibition of DNA repair via homologous recombination. Here, we explore whether ex vivo assays on freshly obtained bladder tumors can be applied to predict the response towards hyperthermia.

    Material and methods

    The cytochrome C release assay (apoptosis) and the RAD51 focus formation assay (DNA repair) were first established in the bladder cancer cell lines RT112 and T24 as measurements for hyperthermia efficiency, and subsequently tested in freshly obtained bladder tumors (n = 59).

    Results

    Hyperthermia significantly increased the fraction of apoptotic cells after cisplatin or MMC treatment in both RT112 and T24 cells and in most of the bladder tumors (8/10). The RAD51 focus formation assay detected both morphological and numerical changes of RAD51 foci upon hyperthermia in the RT112 and T24 cell lines. In 64% of 37 analyzed primary bladder tumor samples, hyperthermia induced similar morphological changes in RAD51 foci.

    Conclusion

    The cytochrome C assay and the RAD51 focus formation assay are both feasible on freshly obtained bladder tumors, and could serve to predict the efficacy of hyperthermia together with cytotoxic agents, such as MMC or cisplatin.

    Original languageEnglish
    Article number0209101
    Number of pages16
    JournalPLoS ONE
    Volume13
    Issue number12
    DOIs
    Publication statusPublished - 14-Dec-2018

    Keywords

    • HOMOLOGOUS RECOMBINATION
    • MITOMYCIN-C
    • CROSS-LINKS
    • CELL-LINES
    • REPAIR
    • CHEMOTHERAPY
    • CARCINOMA
    • CISPLATIN
    • THERAPY
    • FUTURE

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