Michael Amylon

Publication Details

  • Use of alanosine as a methylthioadenosine phosphorylase-selective therapy for T-cell acute lymphoblastic leukemia in vitro CANCER RESEARCH Batova, A., Diccianni, M. B., Omura-Minamisawa, M., Yu, J., Carrera, C. J., Bridgeman, L. J., Kung, F. H., Pullen, J., Amylon, M. D., Yu, A. L. 1999; 59 (7): 1492-1497

    Abstract:

    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 ILM (range, 0.3-11.3 microM). On the other hand, the IC50 for 60% (12 of 20) of MTAP+ primary T-ALL was 19+/-18 microM (range, 1.7-67 microM; P = 0.02), whereas the remaining 40% (8 of 20) had an IC50 of >80 microM4. 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.

    View details for Web of Science ID 000079527800021

    View details for PubMedID 10197619

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