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Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Apr 01; Vol. 23 (7), pp. 1797-1808. Date of Electronic Publication: 2016 Oct 03. - Publication Year :
- 2017
-
Abstract
- Purpose: To understand the role of hypoxia in prostate tumor progression and to evaluate the ability of the novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the antitumor effect of bicalutamide. Experimental Design: The effect of OCT1002 on prostate cancer cells (LNCaP, 22Rv1, and PC3) was measured in normoxia and hypoxia in vitro In vivo , tumor growth and lung metastases were measured in mice treated with bicalutamide, OCT1002, or a combination. Dorsal skin fold chambers were used to image tumor vasculature in vivo Longitudinal gene expression changes in tumors were analyzed using PCR. Results: Reduction of OCT1002 to its active form (OCT1001) decreased prostate cancer cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo , treatment with OCT1002 alone, or with bicalutamide, showed significantly greater tumor growth control and reduced lung metastases compared with controls. Reestablishment of the tumor microvasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the upregulation of RUNX2 and its targets caused by bicalutamide alone was blocked by OCT1002. Conclusions: OCT1002 selectively targets hypoxic tumor cells and enhances the antitumor efficacy of bicalutamide. Furthermore, bicalutamide caused changes in gene expression, which indicated progression to a more malignant genotype; OCT1002 blocked these effects, emphasizing that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumor growth and malignant progression. This is of importance for the design and refinement of existing androgen-deprivation regimens in the clinic. Clin Cancer Res; 23(7); 1797-808. ©2016 AACR .<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Anilides administration & dosage
Animals
Apoptosis drug effects
Cell Hypoxia drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Core Binding Factor Alpha 1 Subunit genetics
Gene Expression Regulation, Neoplastic drug effects
Humans
Male
Mice
Nitriles administration & dosage
Prostatic Neoplasms genetics
Prostatic Neoplasms pathology
Tosyl Compounds administration & dosage
Xenograft Model Antitumor Assays
Anthraquinones administration & dosage
Ethylenediamines administration & dosage
Neoplasm Proteins genetics
Prodrugs administration & dosage
Prostatic Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 23
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 27697998
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-16-1361