Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay |
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Authors: | Carolyn D. Britten Elzbieta Izbicka Susan Hilsenbeck Richard Lawrence Karen Davidson Caeser Cerna Lionel Gomez Eric K. Rowinsky Steven Weitman Daniel D. Von Hoff |
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Affiliation: | (1) University of Texas at San Antonio and Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr., Suite 700, San Antonio, Texas 78229, USA, US;(2) Institute for Drug Development, Cancer Therapy and Research Center, Grossman Cancer Center, Rm. 337, 7979 Wurzbach, San Antonio, TX 78229, USA Tel.: +1-210-616-5892; Fax: +1-210-616-5962, US |
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Abstract: | Purpose: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. Materials and methods: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 μg/ml in 1-h exposure studies. The responses of a limited number of specimens were 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 observed in 3% of specimens (4/144) at 0.1 μg/ml, 11% (17/148) at 1.0 μg/ml, and 23% (33/141) at 10 μg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 μg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. Conclusions: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant. Received: 18 September 1998 / Accepted: 21 December 1998 |
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Keywords: | Human tumor cloning assay LY231514 Multitargeted antifolate |
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