Abstract 1686: Low dose metronomic gemcitabine has high antimetastatic efficacy in an orthotopic mouse model of pancreatic cancer

Abstract

Abstract Therapies for metastasis of pancreatic cancer (PC) are ineffective. We report here the efficacy of metronomic gemcitabine with and without the tyrosine kinase inhibitor sunitinib (SU) on metastasis in an orthotopic model of PC. Mice with highly metastatic, orthotopic PC expressing red fluorescent protein (RFP) were treated with intraperitoneal gemcitabine on a metronomic (1 mg/kg daily, MET) or with maximum tolerated dose (150 mg/kg twice weekly, MTD) schedule with or without oral SU. Primary tumor growth, metastasis, and survival were evaluated. Primary tumor growth and metastasis were quantified by fluorescence imaging. Control mice with orthotopically-implanted MIA-PaCa-2-RFP died of local and widespread metastatic disease within 4 weeks. Gemcitabine at daily doses of 2 mg or greater led to toxicity and death within 1 month in mice without tumors but MET at 1 mg/kg daily was well tolerated. Treatment of mice with orthotopic MIA-PaCa-2-RFP with MET at 1 mg/kg daily for 2 weeks dramatically suppressed metastasis at multiple sites_an effect enhanced by SU (p<0.05). Although primary tumor growth was inhibited by MET+SU (p<0.05), it was not inhibited by either MET or SU alone. Both MET and SU had a modest effect on survival compared to control but survival was limited by extensive primary tumor growth. MET+SU had a more pronounced effect on survival (p<0.05). MTD with or without SU had the most pronounced effects on primary tumor growth and survival but its antimetastatic effect was similar to that of MET+SU (p<0.05). Antimetastatic activity approaching that of standard MTD gemcitabine was achieved with a gemcitabine dose reduced 42 times from MTD using MET and was further enhanced by sunitinib. Our results suggest the clinical potential of this well-tolerated regimen of MET against PC in the adjuvant and maintenance settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1686.