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The unidirectional hypoxia-activated prodrug OCT1002 inhibits growth and vascular development in castrate-resistant prostate tumors

Nesbitt, Heather, Worthington, Jenny, Errington, Rachel, Patterson, Laurence H., Smith, Paul J., McKeown, Stephanie R. and McKenna, Declan J. 2017. The unidirectional hypoxia-activated prodrug OCT1002 inhibits growth and vascular development in castrate-resistant prostate tumors. Prostate 77 (15) , pp. 1539-1547. 10.1002/pros.23434

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Abstract

Background OCT1002 is a unidirectional hypoxia-activated prodrug (uHAP) OCT1002 that can target hypoxic tumor cells. Hypoxia is a common feature in prostate tumors and is known to drive disease progression and metastasis. It is, therefore, a rational therapeutic strategy to directly target hypoxic tumor cells in an attempt to improve treatment for this disease. Here we tested OCT1002 alone and in combination with standard-of-care agents in hypoxic models of castrate-resistant prostate cancer (CRPC). Methods The effect of OCT1002 on tumor growth and vasculature was measured using murine PC3 xenograft and dorsal skin fold (DSF) window chamber models. The effects of abiraterone, docetaxel, and cabazitaxel, both singly and in combination with OCT1002, were also compared. Results The hypoxia-targeting ability of OCT1002 effectively controls PC3 tumor growth. The effect was evident for at least 42 days after exposure to a single dose (30 mg/kg) and was comparable to, or better than, drugs currently used in the clinic. In DSF experiments OCT1002 caused vascular collapse in the PC3 tumors and inhibited the revascularization seen in controls. In this model OCT1002 also enhanced the anti-tumor effects of abiraterone, cabazitaxel, and docetaxel; an effect which was accompanied by a more prolonged reduction in tumor vasculature density. Conclusions These studies provide the first evidence that OCT1002 can be an effective agent in treating hypoxic, castrate-resistant prostate tumors, either singly or in combination with established chemotherapeutics for prostate cancer.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley-Blackwell
ISSN: 0270-4137
Date of First Compliant Deposit: 12 February 2018
Date of Acceptance: 9 September 2017
Last Modified: 18 Oct 2019 13:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/109037

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