6-Thioguanine resistance in a human colon carcinoma cell line with unaltered levels of hypoxanthine guanine phosphoribosyltransferase activity

Cell populations resistant to high doses (30 mM) of 6-thioguanine (6-TG, 6-TGr cells) were selected from a human colon carcinoma cell line, LoVo. This cell line, which lacks hMSH2, a component of the human mismatch binding heterodimer hMutSa, is resistant to low doses of 6-TG. The level of activity of hypoxanthine-guanine phosphoribosyltransferase, the enzyme responsible for the phosphoribosylation of the thiopurine, was comparable to that expressed in the parental cells. No significant difference was found in the levels of enzyme activities involved in the conversion of 6-TG or its derivatives into non-toxic compounds. In contrast, a significant difference was found in the uptake kinetics of 6-TG in the 2 cell types. Net uptake of 6-TG ceased after 100-sec incubation in the 6-TGr cells, while it appeared to continue throughout the 10-min incubation in the wild-type cells. As a consequence, after 10-min incubation, the total amount of 6-TG taken up by the parental LoVo cells was approximately 3 times higher than that present in the 6-TGr cells.