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

Carolyn D. Britten, Elzbieta Izbicka, Susan Hilsenbeck, Richard Lawrence, Karen Davidson, Caeser Cerna, Lionel Gomez, Eric K. Rowinsky, Steven Weitman, Daniel D. Von Hoff

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)105-110
Number of pages6
JournalCancer chemotherapy and pharmacology
Volume44
Issue number2
DOIs
StatePublished - 1999

Keywords

  • Human tumor cloning assay
  • LY231514
  • Multitargeted antifolate

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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