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Amethopterin Resistance in Clonal Lines of L1210 Mouse Leukemia: Some Associated Biologic and Biochemical Alterations¹

Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, and Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University Medical College, New York, New York

The early stages of the development of amethopterin (A)⁴ resistance in 6 sublines derived from 2 karyotypically different cell types have been studied. In vivo resistance of greater than 16-fold was observed after 3–4 transfer generations. With only 1 resistant subline, L26/A₃, was there a correlation between maximum in vivo resistance and maximum dihydrofolate reductase activity. In the other sublines 1–5 additional treated transfer generations were required for the elevation of the reductase activity to its maximum level. Subline L27/A₃ showed maximum resistance at generation 3 with no increase in reductase activity, yet after 2 additional treated transfer generations there was a 9-fold increase in enzyme activity. After 20–28 transfers in the absence of amethopterin the dihydrofolate reductase activity of L27/A₁ and L26/A₁ gradually decreased to that of L27 and L26, respectively. However, both sublines remained resistant to amethopterin.

Amethopterin treatment caused chromosomal alterations in some proportions of the cells in all 6 resistant sublines. The quantitative differences in responses of the amethopterin-resistant sublines to a spectrum of chemotherapeutic drugs indicated that each has its own unique characteristics which result from inherent differences in the amethopterin-resistant cells of the population.

¹ This work was supported in part by Grants CA 03192-08 and 5T4 CA 5015 from the National Cancer Institute, NIH, Bethesda, Maryland, and by Grant T-107 from the American Cancer Society.

⁴ The abbreviations used are: A, amethopterin; 6-MP, 6-mercaptopurine; 5-FU, 5-flourouracil; VLB, vinblastine sulfate; MGGH, methylglyoxal-bis-guanylhydrazone; HU, hydroxyurea; FUDR, 5-fluorodeoxyuridine; AST, average survival time; SM, submetacentric chromosome; ST, subtelocentric chromosome; 1m, minute chromosome; m, small minute chromosome; M, metacentric chromosome.

² Present address: Aichi Cancer Center, Nagoya, Japan.

³ USPHS Research Career Development Awardee Grant 1-K3-CA-5275-02.

Received 8/ 9/65. Revised 12/ 2/65.