Evaluation of the "steal" phenomenon on the efficacy of hypoxia activated prodrug TH-302 in pancreatic cancer

• Published in: PloS one Vol. 9; no. 12; p. e113586
• Main Authors: Bailey, Kate M, Cornnell, Heather H, Ibrahim-Hashim, Arig, Wojtkowiak, Jonathan W, Hart, Charles P, Zhang, Xiaomeng, Leos, Rafael, Martinez, Gary V, Baker, Amanda F, Gillies, Robert J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.12.2014; Public Library of Science (PLoS)
• Subjects: Actin; Adenocarcinoma - blood supply; Adenocarcinoma - pathology; Animal models; Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biology and Life Sciences; Blood; Blood Circulation - drug effects; Blood flow; Cancer; Cancer therapies; Cell Hypoxia - drug effects; Cell Line, Tumor; Chemical compounds; Chemotherapy; Coordination; Cytotoxicity; Drug Synergism; Drugs; Female; Hematology; Humans; Hydralazine; Hydralazine - pharmacology; Hydrogen-Ion Concentration; Hypoxia; Immunohistochemistry; Medicine and Health Sciences; Metabolism; Metastasis; Mice; Muscles; Nitroimidazoles - metabolism; Nitroimidazoles - pharmacology; Nuclear medicine; Oncology; Pancreatic cancer; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - pathology; pH effects; Phosphoramide Mustards - metabolism; Phosphoramide Mustards - pharmacology; Physiology; Prodrugs; Prodrugs - metabolism; Prodrugs - pharmacology; Radiation therapy; Reduction; Smooth muscle; Studies; Tumor Microenvironment - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113586

Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the "steal" phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia.