Abstract 324: Pantethine, a new therapeutic approach against ovarian cancer.

Abstract

Abstract Ovarian cancer is the leading cause of death from gynecologic malignancy among women in developed countries with an estimated incidence of 205,000 cases worldwide per year, resulting in 125,000 deaths. Although the prognosis in cases detected at early stage is quite favorable, the vast majority of cases are diagnosed at an advanced stage, when five-year survival rates are only 30-40%. The poor prognosis of ovarian cancer is due to a combination of the aggressive characteristics of the disease and a lack of effective therapy, further compounded by late detection of the disease and resistance of most tumors to current treatments. Metastases and malignant ascites, a devastating condition that significantly contributes to poor quality of life and mortality, are complications frequently observed in terminal ovarian cancer. New therapeutic strategies exploiting novel targets are urgently needed to minimize morbidity and improve survival rates for ovarian cancer patients. In the present study, we applied non-invasive MRI to determine the use of pantethine as a therapeutic agent in an orthotopic model of ovarian cancer. Pantethine is the stable disulfide form of pantetheine, a derivative of vitamin B5; it is the precursor of coenzyme A. In a mouse model, pantethine has been shown to prevent the perivascular inflammation associated with cerebral malaria (1) and to inhibit cell transendothelial migration (Gharib B, unpublished data). To detect the effect of pantethine on ovarian cancer progression, metastases, and ascites build-up, we used an orthotopic model in which the relevant tumor physiological environment is maintained, and that frequently result in metastases and malignant ascites. OVCAR3 human epithelial ovary adenocarcinoma cells were used in the present study. The orthotopic implantation was performed by surgically transplanting a piece of OVCAR3 tumor tissue on the ovary of severe combined immunodeficient female mice. We started the treatment 4 weeks post-implantation, when the tumors were approximately 100 mm3 with a daily i.p. injection of pantethine at a dose of 750 mg/kg. Under these conditions, no side effects were observed. A control group was injected daily with saline. Tumor growth was followed weekly non-invasively by MRI on a 4.7T spectrometer. Slower tumor growth was observed in the treated group. Interestingly, when we sacrificed the mice after 4 weeks of treatment, we observed liver metastases in 6 out of 7 control mice, but only in 3 out of 7 treated mice, lungs metastases in 2 out of 7 control mice, and 0 out of 7 treated mice and finally, ascites in 6 out of 7 control mice, and 2 out of 7 treated mice. Our study identifies pantethine as a new promising drug against ovarian cancer, showing effects on tumor progression, metastases occurrence, and ascites formation. (1) Penet MF et al. PNAS 105:1321-6, 2008. This work was supported by a Career Award to M-FP from NIH P50CA103175, The HERA Foundation, and The Honorable Tina Brozman Foundation. Citation Format: Marie-France Penet, Silvana Canevari, Franca Podo, Max de Reggi, Bouchra Gharib, Zaver M. Bhujwalla. Pantethine, a new therapeutic approach against ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 324. doi:10.1158/1538-7445.AM2013-324