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Use of Alanosine as a Methylthioadenosine Phosphorylase-Selective Therapy for T-Cell Acute Lymphoblastic Leukemia in Vitro¹

Departments of Pediatric Hematology/Oncology [A. B., M. B. D., L. J. B., A. L. Y., M. O-M., F. H. K.] and Medicine 92093 [C. J. C.], University of California 92103, The Scripps Research Institute [J. Y.], San Diego, California 92037; Stanford University, Palo Alto, California 94305 [M. D. A.]; and The University of Mississippi, Jackson, Mississippi 39216 [J. P.]

Methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine and methionine and is deficient in a variety of cancers including T-cell acute lymphocytic leukemia (T-ALL). Previously, we reported that the MTAP gene was deleted in over 30% of T-ALL patients at both diagnosis and relapse. We now report that MTAP- primary T-ALL cells are more sensitive to the toxicity of L-alanosine, an inhibitor of de novo AMP synthesis, than are MTAP+ primary T-ALL cells. As measured by [³H]thymidine incorporation, DNA synthesis in all seven MTAP- primary T-ALL cells was inhibited by L-alanosine with a mean IC₅₀ of 4.8 ± 5.3 µM (range, 0.3–11.3 µM). On the other hand, the IC₅₀ for 60% (12 of 20) of MTAP+ primary T-ALL was 19 ± 18 µM (range, 1.7–67 µM;P = 0.02), whereas the remaining 40% (8 of 20) had an IC₅₀ of >80 µM. Furthermore, normal lymphocytes and MTAP+ primary T-ALL cells were rescued from L-alanosine toxicity by the MTAP substrate 5'-deoxyadenosine, but MTAP- T-ALL cells were not. These results indicate that normal cells, which are intrinsically MTAP+, would be 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 salvage 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.

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