The Uptake of Guanine, Uracil, Lysine and Glycine by Ascites Cells

Synthetic purine and pyrimidine analogues have been widely studied as inhibitors ofbacterial growth and as cancer chemotherapeutic agents. A number of these compounds, e.g. fluorouracil (Chaudhuri, Montag & Heidelberger, 1958) and 8-azaguanine (Mandel, Carlo & Smith, 1954), are incorporated to a greater or less extent into cellular RNA. Others, e.g. bromoand iodo-deoxyuridine, have been shown to be incorporated into DNA (Hakala, 1959; Prusoff, 1959), and in small amounts 6-mercaptopurine appeared to be incorporated into both RNA and DNA (Bieber, Dietrich, Elion, Hitchings & Martin, 1961). In addition to their ability to become incorporated into nucleic acids, such substances may interfere with specific steps in nucleic acid synthesis. Thus iododeoxyuridine inhibits the incorporation of either [14C]formate or [14C]orotate into DNA thymine (Prusoff, 1960). Fluorodeoxyuridine, which is interconvertible with fluorouracil, acted as a powerful inhibitor of thymidylate synthetase in addition to being incorporated (as fluorouracil) into RNA (Cohen, Flaks, Barner, Loeb & Lichenstein, 1958; Habers, Chaudhuri & Heidelberger, 1959). Many similar examples appear in the literature. There have also been many suggestions that RNA containing abnormal bases has a diminished capacity for the synthesis of specific proteins or produces proteins with altered amino acid sequences (Creaser, 1956; Chantrenne, 1958; Mandel & Markham, 1958; Chantrenne & Devreux, 1960; Kvam & Parks, 1960; Mandel & Altman, 1960; Naono & Gros, 1960; Aaronson, 1961). So far, however, no studies appear to have been made on the metabolism of cells that have incorporated 6-thioguanine. 6-Thioguanine has a pronounced inhibitory effect on many tumours, and a combination of thioguanine with pretreatment with azaserine increased both the 6-thioguanine incorporation andtumour inhibition (Sartorelli & LePage, 1958b). According to LePage (1960) the incorporation of 6-thioguanine into DNA was the only property that correlated with its tumour-inhibitory action. However, since incorporation into DNA