Abstract 4377: Metronomic oral prodrug of gemcitabine (LY2334737) causes antitumor effects with concomitant increase in intratumoral blood flow
Authors: Francia Giulio , Shaked Yuval , Hashimoto Kae , Sun John , Xu Ping , Man Shan , Hackl Christina , Stewart Julie , Dantzig Anne H. , Uhlik Mark , Foster Stuart , Kerbel Robert S. 
Published: August 2012

Abstract
Metronomic chemotherapy is the regular administration of chemotherapy drugs at relatively low minimally toxic doses without prolonged break periods; it is currently undergoing phase III trial evaluation. Metronomic chemotherapy is thought to cause anti-tumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow derived cells, including circulating endothelial progenitor cells (CEPs). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 (LY) in non tumor-bearing mice, and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6mg/kg/day) the schedules tested were devoid of toxicity and caused anti-tumor effects; however, a suppressive effect on CEPs was not detected. Human SKOV3-13 ovarian cancer cells were grown as ascites in SCID mice; LY monotherapy (6mg/kg/day), as well as LY in combination with metronomic cyclophosphamide (CTX, 20mg/kg/day), caused a significant increase in survival (n=5 mice per group, p&lt;0.05) compared to controls. Human LM2-4 breast cancer cells, implanted orthotopically into SCID mice, were growth inhibited by LY monotherapy (at 6mg/kg/day as well as at 8mg/kg/day; n=5 mice per group, p&lt;0.05). LM2-4 tumors were also growth inhibited by the combination of LY (6mg/kg/day) plus a bolus of CTX (100mg/kg, single dose) followed immediately by a maintenance regimen of metronomic CTX (20mg/kg/day); this combination did not produce any overt toxicity. Unexpectedly metronomic LY administration caused increased intratumoral blood flow, as measured by ultrasound after 1 week and after 4 weeks of continuous treatment, in luciferase-tagged LM2-4 tumor xenografts; and the increase in blood flow coincided with a relative increase in tumor bioluminescence. Paraffin embedded LM2-4 tumor sections from the therapy experiments were further analyzed by Angiogenesis and by Tumor Health Panel analyses; LY monotherapy did not caused any significant changes in tumor hypoxia, or in intratumoral vessel density, compared to controls. These results highlight the possibility of significant anti-tumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4377. doi:1538-7445.AM2012-4377