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Inability of Leucovorin to Rescue a Naturally Methotrexate-resistant Human Soft Tissue Sarcoma Cell Line from Trimetrexate Cytotoxicity¹

Laboratory of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

² To whom requests for reprints should be addressed.

A human lymphoblastoid line (RPMI-1788), a methotrexate-sensitive human fibrosarcoma cell line (HT-1080), and a naturally resistant mixed mesodermal human sarcoma cell line with impaired methotrexate polyglutamylation (HS-42), recently established in our laboratory, were used to compare the ability of leucovorin to prevent trimetrexate cytotoxicity. Growth inhibition and an in situ thymidylate synthesis activity assay showed that inhibitory effects of trimetrexate (1 to 10 µM), 24-h exposure, were prevented by 10 µM leucovorin in the RPMI-1788 and HT-1080 cell lines but not in the HS-42 cell line. Total intracellular reduced folates increased about 2-fold in the three cell lines after exposure to leucovorin (10 µM) for 4 h, and after a 6-hour efflux remained elevated (1.5- and 1.3-fold of control levels) in RPMI-1788 and HT-1080 cells but decreased to 80% of control levels in HS-42 cells. Although uptake of leucovorin and levels of N⁵,N¹⁰-methylenetetrahy-drofolate achieved after leucovorin administration were similar in RP-MI-1788 and HS-42 cells, polyglutamylate forms of this coenzyme were less in the HS-42 cells as compared to RPMI-1788 cells. Based on these studies, the combination of trimetrexate with leucovorin should be further investigated as a way to increase the therapeutic index in some patients with soft tissue sarcomas.

¹ Supported by CA-47179. J. R. B. is American Cancer Society Professor of Medicine and Pharmacology.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/15/92. Accepted 10/ 7/92.

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