RESISTANCE TO PURINE RIBONUCLEOSIDE ANALOGUES IN AN ASCITES TUMOR

Abstract

A tumor subline (EAC-R2) which is resistant to the growth-inhibitory effects of 6-(methylmercapto)purine ribonucleoside (Me6MPR) and formycin has been selected from the Ehrlich ascites carcinoma (EAC) by repeated administration of Me6MPR during the propagation of the tumor. Some biochemical characteristics of the two tumor lines have been compared.Cells of the EAC-R2 tumor could not form phosphorylated derivatives of Me6MPR and formycin, whereas these metabolites were readily formed by EAC cells. Extracts of the resistant cells could not convert Me6MPR to the 5′-phosphate, indicating that they were deficient in purine ribonucleoside kinase activity.Me6MPR, formycin, and several other purine nucleoside analogues produced much less inhibition of purine synthesis de novo in EAC-R2 cells than in the parent line of cells. However, adenine produced a similar degree of inhibition in both tumor lines, indicating that this pathway in the resistant variant is susceptible to feedback inhibition.It is proposed that a deficiency of purine ribonucleoside kinase(s) may be responsible for the inability of Me6MPR and formycin to inhibit the growth of the EAC-R2 tumor.