Combined activity of the cancer metabolism inhibitor MPC-8640 and 5-fluorouracil in xenograft models
| Autor: | Orvelin Roman, Lori Fotheringham, Robert O. Carlson, Brita Brown, J. Scott Patton, Thomas B. Douce, Lynn DeMie, Vijay Baichwal, Chad Bradford, Leslie Reeves |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 30:e13581-e13581 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2012.30.15_suppl.e13581 |
| Popis: | e13581 Background: Nicotinamide (Nam) phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in NAD biosynthesis from Nam. Nampt inhibition causes NAD depletion, inhibition of ATP synthesis and cell death. MPI-0487316 is a selective Nampt inhibitor with potent tumoricidal activity against cancer cell lines of diverse origin. MPC-8640, an orally bioavailable prodrug of MPI-0487316, induces regressions in xenograft models. Combining Nampt inhibitors with 5-fluorouracil (5-FU) results in synergistic tumoricidal activity in cells. We have explored the combination of MPC-8640 with 5-FU in a colon carcinoma xenograft model. Methods: In vitro studies were done in HCT-116 human colon carcinoma cells. Cell viability was measured by determining ATP levels. Xenograft studies were done with cells implanted subcutaneously into athymic mice (nu/nu). MPC-8640 was dosed orally at 12 to 48 mg/kg daily on Days 1-7 and 15-21. 5-FU was dosed intraperitoneally, weekly at 100 mg/kg. Results: MPI-0487316 showed synergistic tumoricidal activity in vitro with 5-FU. In xenograft studies, the prodrug MPC-8640, at 12, 24 and 36 mg/kg, resulted in tumor growth inhibition (TGI) of 64%, 98% and 91%, respectively, at the end of dosing on Day 22 and tumor regression of 5%, when dosed at 48 mg/kg. In the 36 and 48 mg/kg group, 20% and 10% of the mice, respectively, had no detectable tumors by the end of the study on Day 42. In another study, mice were given 5-FU or MPC-8640 as single agents or in combination. Combining 5-FU with MPC-8640 at 24 mg/kg resulted in 45% tumor regression on Day 21 compared to TGI of 88% and 78% for MPC-8640 or 5-FU, respectively, dosed as single agents. Similarly, combining 5-FU and MPC-8640 at 32 mg/kg resulted in 83% tumor regression on Day 21 compared to TGI of 86% and 78% for MPC-8640 and 5-FU, respectively, dosed as single agents. The combinations of 5-FU and MPC-8640 were well-tolerated with |
| Databáze: | OpenAIRE |
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