Low-DoseOralMetronomicDosingof theProdrug of Gemcitabine , LY 2334737 , in Human Tumor Xenografts

LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activitywas evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity andwerewell tolerated.Oral gavageof 6mg/kgLY2334737daily for 21daysgave equivalent activity to i.v. 240mg/kg gemcitabine.HCl administered once aweek for 3weeks tomice bearing a patientmesothelioma tumor PXF 1118 or a non–small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus amaximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than eithermonotherapy.During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3was induced inHCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response. Mol Cancer Ther; 12(4); 1–10. 2013 AACR.