2015 ACVIM Forum Research Abstract Program

(VCS Award Winner): Platinum compounds, including cisplatin (CDDP), are highly active anticancer agents for use against solid tumors. Like most chemotherapeutics, platinum compounds are toxic to non-tumor tissues and development of unwanted side effects, including neuropathy and nephrotoxicity, often limits treatment dose and duration. Mechanisms of these side effects, particularly neurotoxicity, are undefined. However, accumulation of platinum in spinal cord tissues is associated with development of neuropathy. Remarkably, the clinical and histologic features of CDDPinduced neurotoxicity are similar to those seen in vitamin E (aT) deficiency. Using a preclinical model of epithelial ovarian cancer we tested the hypothesis that adjuvant aT would improve CDDP antitumor efficacy while reducing CDDP-induced oxidative stress and non-tumor toxicity. Tumor-bearing immune competent female rats received one of 4 treatment regimens: (1) saline (2X/ week), (2) aT (2X/week), (3) CDDP (2X/week), or (4) CDDP + aT (2X/week). All regimens were administered for a period of 4.5 weeks. At necropsy, tumor burden was reduced to undetectable levels in 10/16 CDDP + aT treated rats compared to 2/16 rats treated with CDDP alone. CDDP decreased indices of tumor proliferation (measured by Ki-67 immunohistochemistry) by 28% (p < 0.05), while CDDP + aT decreased tumor proliferation by >75% (p < 0.01), compared to saline. Importantly, adjuvant aT decreased accumulation of platinum in spinal cord tissue by >30% (p < 0.05) without altering tumor platinum levels, compared to rats treated with CDDP alone. Interestingly, the presence of tumors in saline treated rats increased plasma F2isoprostane and F2-isoprostane metabolite levels 40%, compared to non-tumor controls; aT (with or without CDDP) returned these levels to those of non-tumor controls. Finally, adjuvant aT prevented CDDP-induced plasma and tissue aT depletion. These data are the first to document the ability of adjuvant aT to (1) improve chemotherapeutic antitumor efficacy, (2) decrease tumor proliferation, and (3) improve antioxidant/oxidative stress status in an immune competent tumor-bearing animal. Further elucidation of the ability of adjuvant aT to improve antitumor efficacy and quality of life outcomes is essential for development of improved treatment regimens for both human and veterinary patients. During the last 20 years, the survival times in dogs with osteosarcoma (OSA) treated with surgery and postoperative adjuvant chemotherapy has not changed. Therefore, new treatment approaches are needed. The antiangiogenic chemotherapy hypothesis proposes that tumors cannot growth more tan a few millimeters without recruiting blood vessels that will supply oxygen and nutrients to the neoplastic cells. One of the major players in the new blood vessel growth is vascular endothelial growth factor (VEGF). Dogs with aggressive tumors, such as OSA, have higher circulating activity of VEGF compared with dogs with benign lesions and it has been proposed that VEGF plays a role in the development of metastasis.