Evaluation of targeted arterial delivery of the branched chain fatty acid 12-methyltetradecanoic acid as a novel therapy for solid tumors
Kenneth C. Wright, Peiying Yang, Carolyn S. Van Pent, Marshall E. Hicks, Peter Collin, Robert A. Newman
The purpose of this research was to evaluate the effects of targeted arterial delivery of the branched chain fatty acid 12-methyltetradecanoic acid (12-MTA*) on the VX2 squamous cell carcinoma in rabbits. An intramuscular VX2 squamous cell carcinoma was induced at a single site in the right thigh of 39 New Zealand white rabbits. Approximately 10 days after inoculation, a 3-French catheter was introduced into the right common carotid artery and positioned using fluoroscopic guidance in the right deep femoral artery, which was the main, if not exclusive, artery supplying the tumor. Ethiodol alone (targeting agent), Ethiodol containing 12-MTA, or Ethiodol containing myristic acid was then injected through the catheter. Tumor growth and histopathology were evaluated 7-8 days after treatment. Caspase-3 activity was evaluated 2 days after therapy, and tumor tissues were assayed for eicosanoid metabolites 2 and 7 days after treatment to assess the effects of the branched chain fatty acid on the lipoxygenase (LOX) and cyclooxygenase-2 (COX-2) enzyme systems. Targeted arterial delivery of 12-MTA resulted in dosedependent growth inhibition of intramuscular rabbit VX2 tumors while myristic acid, a saturated fatty acid of the same carbon length as 12-MTA, was found to stimulate tumor growth. Two and 7 days following treatment, tumors treated with 12-MTA showed a significant decrease in 5-hydroxyeicosatetraenoic acid (5-HETE) and a concomitant increase in 15-HETE levels while tumors treated with myristic acid exhibited a significant increase in prostaglandin E2 (PGE2) levels. Western blot as well as immunohistochemical analysis showed that 5-LOX and COX-2 proteins were present in the VX2 tumors. No alterations in tumor/tumor cell morphology or caspase-3 activity were evident on microscopic examination following treatment. These studies suggest that targeted arterial delivery of branched chain fatty acids such as 12-MTA may be considered as a potential new therapy for treatment of solid tumors. The exact mechanism(s) responsible for the observed inhibition of VX2 tumor growth by 12-MTA is unclear. Additional in vivo studies are warranted to elucidate 12-MTA’s mechanism of action and further investigate the branched chain fatty acid’s antitumor effects.