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Studies on Resistance against 5-Fluorouracil

I. Enzymes of the Uracil Pathway during Development of Resistance^*

( Department of Chemistry I and Department of Tumor Biology, Karolinska Institute, Stockholm, Sweden)

Four different 5-fluorouracil (FU)-resistant tumor lines were developed by treating a drug-sensitive Ehrlich ascites tumor, ELD, with FU during 25–30 passages. Acetone powder extracts of the tumor lines were assayed for the following enzymes: uridine phosphorylase and kinase, deoxyuridine phosphorylase and kinase.

In all four tumor lines significant decreases in uridine kinase activity occurred during FU treatment, whereas the other enzymes were not affected. The decrease in uridine kinase activity commenced around the tenth tumor passage and showed either a continuous or stepwise character. The enzyme values after twenty passages were between 5 and 15 per cent of the original values. From the available evidence it is proposed that the enzyme changes were caused by a multistep process, probably of genetic origin.

After 25–30 passages the FU-resistant lines were cross-resistant against 5-fluorouridine and 5-fluorodeoxyuridine. Furthermore, two tumor lines, after eight and nine passages, respectively, were resistant against FU before a decrease in uridine kinase activity had occurred. One of these early tumors was also resistant against 5-fluorodeoxyuridine, but not against 5-fluorouridine.

The loss of uridine kinase activity is thus only one biochemical factor which contributes to the resistance of the tumors against fluorouracil, and it is evident that one or several other unknown factors exist which explain the early resistance against the drug.

The resistant tumor lines showed no significant changes in permeability for the drug.

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

Received 9/ 1/61.

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