Novel small molecule has potent antitumor activity in drug-resistant human carcinoma xenograft models

Abstract

We have previously shown that Kevetrin, a novel molecule currently under development, was effective in reducing tumor growth in human multi-drug resistant lung cancer xenograft models while being well tolerated. In this study, we expanded our tests to include other tumor types: colon and breast. Three of the models have been shown to be multi-drug resistant: HCT-15 colon carcinoma have an overexpression of p-glycoprotein that acts as a membrane efflux pump (Iwahashi 1991, Mickley 1989), MDA-MB-435s carcinoma cells have highly active c-Abl and Arg kinases and overexpress Heat Shock Protein 27 which inhibits apoptosis thereby contributing to drug resistance (2006 Srinivasan, 2008 Shi), and A549 lung carcinoma have the K-ras mutation and overexpress STAT3 and Nrf2; mutations associated with resistance to standard chemotherapy (Akudela 2004, Mahaffey 2009, Homma 2009, Kim 2009). To demonstrate a dose response effect, in the multi-drug resistant A549 lung tumor model, nude mice bearing established tumors were treated with either 50, 100, or 200 mg/kg Kevetrin intraperitoneally (IP) every other day for 3 doses or 200 mg/kg every other day for 3 doses followed by a second cycle 10 days later. Kevetrin delayed median tumor growth in a dose dependent manner where 50, 100, and 200 mg/kg produced tumor growth delays (TGDs) of 0%, 6%, and 21%, respectively, relative to controls. When given in 2 cycles at 200 mg/kg, a significantly greater TGD of 35% was achieved. In the HCT-15 multi-drug resistant colon tumor model, nude mice bearing established tumors were treated with either 200 mg/kg Kevetrin IP every other day for 3 doses or 22 mg/kg paclitaxel intravenously (IV) daily for 4 doses. Paclitaxel had no anti-tumor activity, whereas Kevetrin produced a significant TGD of 16 days (43%) relative to controls. In a non drug-resistant colon tumor model, HT-29, Kevetrin produced a similar TGD of 18 days (49%) while 20 mg/kg 5-fluorouracil (5-FU) IP given daily for 5 doses produced a TGD of 9 days (24%). In the MDA-MB-435s drug resistant tumor model, nude mice bearing established tumors were treated as above. Paclitaxel had no significant anti-tumor activity (1% TGD), whereas Kevetrin produced a significant TGD of 20 days (65%). In a non drug-resistant breast tumor model, MDA-MB-231, Kevetrin produced a TGD of 26 days (90%), and paclitaxel produced a significant TGD of 18 days (62%). These results demonstrate that Kevetrin exerted potent anti-tumor activity against three d…