Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies

Abstract

Many solid tumors and hematologic malignancies lack expression of the enzyme methylthioadenosine phosphorylase (MTAP), due either to deletion of the MTAP gene or to methylation of the MTAP promoter. In cells that have MTAP, its natural substrate, methylthioadenosine (MTA), generated during polyamine biosynthesis, is cleaved to adenine and 5-methylthioribose-1-phosphate. The latter compound is further metabolized to methionine. Adenine and methionine are further metabolized and hence salvaged. In MTAP-deficient cells, however, MTA is not cleaved and the salvage pathway for adenine and methionine is absent. As a result, MTAP-deficient cells are more sensitive than MTAP-positive cells to inhibitors of de novo purine synthesis and to methionine deprivation. The challenge has been to take advantage of MTAP deficiency, and the changes in metabolism that follow, to design a strategy for targeted treatment. In this review, the frequency of MTAP-deficiency is presented and past and recent strategies to target such deficient cells are discussed, including one in which MTA is administered, followed by very high doses of a toxic purine or pyrimidine analog. In normal host cells, adenine, generated from MTA, blocks conversion of the analog to its toxic nucleotide. In MTAP-deficient tumor cells, conversion proceeds and the tumor cells are selectively killed. Successful mouse studies using this novel strategy were recently reported.

Figure 1

MTAP metabolic pathway. In normal cells, MTAP cleaves MTA, a by-product of polyamine biosynthesis, into adenine and 5-methylthioribose-1-phosphate (MTR-1-P). Adenine is converted to AMP by the ubiquitous enzyme adenine phosphoribosyltransferase (APRT), with phosphoribosyl-1-pyrophosphate (PRPP) serving as donor of the phosphoribosyl group. MTR-1-P is converted by a series of steps to methionine. AMP is also produced in cells by de novo purine biosynthesis. In addition to APRT, other cellular phosphoribosyltransferases, such as hypoxanthine-guanine phosphoribosyltransferase and orotate phosphoribosyltranferase, convert purines and pyrimidines to nucleotides.

Figure 2

MTA protects host tissues but not MTAP-deficient tumor cells from 6-TG toxicity. (A) NOD-SCID mice (N = 6, per group) were inoculated with one million CCRF-CEM human lymphoblastic leukemia cells and when tumor size was 500 mm³ the mice were treated with either 6-TG, MTA or the combination of the two drugs (MTA followed one hour later by 6-TG) or saline, ♦ control; □, MTA; 100 mg/kg; ▴, 6-TG, 75 mg/kg; X, MTA, 100 mg/kg plus 6-TG, 75 mg/kg. (B) Effect of treatments on body weights. Control and MTA treated mice were sacrificed by day 13 due to large tumors. 6-TG treated mice also died by day 13, due to 6-TG toxicity, while marked tumor regression with minimal toxicity was noted (<10% weight loss) in mice treated with MTA followed one hour later by 6-TG. Vertical bars: SD. (♦, control; □, MTA; 100 mg/kg; ▴, 6-TG, 75 mg/kg; X, MTA, 100 mg/kg plus 6-TG, 75 mg/kg).