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Comparative Effects of Amethopterin and 3',5'-Dichloroamethopterin in Sensitive and Resistant Sublines of the Ehrlich Carcinoma

( Biomedical Division of The Samuel Roberts Noble Foundation, Inc., Ardmore, Oklahoma)

The inhibitory effects of amethopterin and 3',5'-dichloroamethopterin were compared in antifolic-sensitive and -resistant sublines of the Ehrlich ascites carcinoma. Molar equivalent doses of amethopterin and 3',5'-dichloroamethopterin caused similar retardation of glycine-2-C¹⁴ incorporation into polynucleotide purines, DNA thymine, lipide, and protein of the Ehrlich carcinoma. In general, the duration of inhibition of the various metabolic processes was comparable; however, the duration of inhibition of purine nucleotide biosynthesis de novo by 3',5'-dichloroamethopterin was slightly more transient than that of amethopterin. This may be responsible for the fact that equimolar doses of dichloroamethopterin are less effective than amethopterin as inhibitors of the growth of this neoplasm. The inhibition of sodium formate-C¹⁴ incorporation into DNA thymine of sensitive Ehrlich cells by both antifolics appeared to persist for a longer period than did the inhibition of purine synthesis. The results of these studies suggest that multiple factors are involved in the biochemical basis for resistance. At the dose levels employed, dichloroamethopterin caused inhibition of the measured metabolic reactions which was equal to or greater than that produced by amethopterin in the resistant neoplasm. A difference in the response of the variant cells to the two drugs was observed in that a degree of dependency to amethopterin was exhibited at all the dose levels tested, whereas a comparable effect by 3',5'-dichloroamethopterin was obtained only at the highest dose employed. The resistant tumor exhibited a pronounced increase in sensitivity to 5-fluorouracil and 5-fluoro-2'-deoxyuridine, whereas sensitivity to 6-azauracil, 6-azauridine, 5-iodo-2'-deoxyuridine, and to inhibitors of purine biosynthesis was not increased.

^* Present address: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.

Received 8/11/61.