Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression

摘要

Purpose: To understand the role of hypoxia in prostate tumor\udprogression and to evaluate the ability of the novel unidirectional\udhypoxia-activated prodrug OCT1002 to enhance the antitumor\udeffect of bicalutamide.\udExperimental Design: The effect of OCT1002 on prostate\udcancer cells (LNCaP, 22Rv1, and PC3) was measured in normoxia\udand hypoxia in vitro. In vivo, tumor growth and lung metastases\udwere measured in mice treated with bicalutamide, OCT1002, or a\udcombination. Dorsal skin fold chambers were used to image\udtumor vasculature in vivo. Longitudinal gene expression changes\udin tumors were analyzed using PCR.\udResults: Reduction of OCT1002 to its active form (OCT1001)\uddecreased prostate cancer cell viability. In LNCaP-luc spheroids,\udOCT1002 caused increased apoptosis and decreased clonogenicity.\udIn vivo, treatment with OCT1002 alone, or with bicalutamide,\udshowed significantly greater tumor growth control and reduced\udlung metastases compared with controls. Reestablishment of the\udtumor microvasculature following bicalutamide-induced vascular\udcollapse is inhibited by OCT1002. Significantly, the upregulation\udof RUNX2 and its targets caused by bicalutamide alone was\udblocked by OCT1002.\udConclusions: OCT1002 selectively targets hypoxic tumor cells\udand enhances the antitumor efficacy of bicalutamide. Furthermore,\udbicalutamide caused changes in gene expression, which\udindicated progression to a more malignant genotype; OCT1002\udblocked these effects, emphasizing that more attention should be\udattached to understanding genetic changes that may occur during\udtreatment. Early targeting of hypoxic cells with OCT1002 can\udprovide a means of inhibiting prostate tumor growth and\udmalignant progression. This is of importance for the design and\udrefinement of existing androgen-deprivation regimens in the\udclinic.