Use of alanosine as a methylthioadenosine phosphorylase-selective therapy for T-cell acute lymphoblastic leukemia in vitro

Methylthioadenosine phosphorylase (MTAP) is an important enzyme for the sal vage of adenine and methionine and is deficient in a variety of cancers inc luding T-cell acute lymphocytic leukemia (T-ALL). Previously, we reported t hat the MTAP gene was deleted in over 30% of T-ALL patients at both diagnos is and relapse, We now report that MTAP-primary T-ALL cells are more sensit ive to the toxicity of L-alanosine, an inhibitor of de novo AMP synthesis, than are MTAP+ primary T-ALL cells. As measured by [H-3]thymidine incorpora tion, DNA synthesis in all seven MTAP- primary T-ALL cells was inhibited by L-alanosine with a mean IC50 of 4.8 +/- 5.3 mu M (range, 0.3-11.3 mu M). O n the other hand, the IC50 for 60% (12 of 20) of MTAP+ primary T-ALL was 19 +/- 18 mu M (range, 1.7-67 mu M; P = 0.02), whereas the remaining 40% (8 o f 20) had an IC50 of >80 mu M. Furthermore, normal lymphocytes and MTAP pri mary T-ALL cells were rescued from L-alanosine toxicity by the MTAP substra te 5'-deoxyadenosine, but MTAP- T-ALL cells were not. These results indicat e that normal cells, which are intrinsically MTAP+, would he protected from L-alanosine toxicity, whereas MTAP- tumor cells would be killed, Thus, our results support the use of L-alanosine alone or in combination with a salv age agent as a MTAP-selective therapy and therefore lay the foundation for the initiation of clinical trials for the treatment of T-ALL and other MTAP -deficient malignancies with L-alanosine.