Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay

Purpose: This study was performed to evaluate the activity of the multitarg eted antifolate (RITA or LY231514) against a broad range of human tumors ta ken directly from patients. Materials and Methods: Human tumor colony-formi ng units were treated with MTA at concentrations of 0.1, 1.0, and 10 mu g/m l in 1-h exposure studies. The responses of a limited number of specimens w ere also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil , irinotecan, and/or paclitaxel. Results: Of 358 specimens plated in the 1- h exposure studies, 148 (41%) were evaluable. Overall, responses were obser ved in 3% of specimens (4/144) at 0.1 mu g/ml, 11% (17/148) at 1.0 mu g/ml, and 23% (33/141) at 10 mu g/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. A t 10 mu g/ml in the 1-h exposure studies, the response rate in colorectal c ancer specimens was 32% (9/28), and the response rate in non-small-cell lun g cancer was 25% (6/24). Responses were also observed in several chemoresis tant tumors, including renal cell carcinoma, hepatocellular carcinoma, meso thelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and pacli taxel. Conclusions: MTA demonstrated in vitro activity against a spectrum o f tumors, including several tumors generally considered chemoresistant.