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Studies on Resistance against 5-Fluorouracil^*

III. Selective Value of Resistant, Uridine Kinase-deficient Tumor Cells

( Institute of Medical Chemistry, University of Uppsala, Uppsala; and Department of Tumor Biology, Karolinska Institutet Medical School, Stockholm, Sweden)

With uridine kinase activity used as a marker characteristic, changes were studied in the cellular composition of populations which consisted of resistant and sensitive ELD ascites cells, mixed artificially in various known proportions, and which were either treated or not treated with 5-fluorouracil (FU) in the course of subsequent intraperitoneal passages in mice. The resistant cells had a greatly decreased uridine kinase activity amounting to 5–10 per cent of that of sensitive cells. Mixed cell populations with sensitive cells in excess (10³:1 or 10⁵:1) showed the enzyme activity of sensitive cells in the absence of FU treatment, but displayed the low activity, characteristic of resistant cells, after one or two passages in FU-treated animals, indicating the persistence and the selective advantage of resistant cells. Populations with resistant cells in the majority (3:1 or 10:1) showed intermediate activities which, in the course of subsequent passages in untreated mice, decreased to the uridine kinase pattern of resistant cells, indicating the lack of any adverse selection of resistant cells in the absence of selection pressure.

^* This investigation was supported by grants from the Swedish Cancer Society, the Damon Runyon Memorial Fund for Cancer Research (DRG-470 B), and from the United States Public Health Service (Grant No. Cy 4619-C1).

Received 6/18/62.