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

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-04, Vol.59 (7), p.1492-1497
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adenosine Monophosphate - biosynthesis; Alanine - analogs & derivatives; Alanine - therapeutic use; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Humans; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - metabolism; Medical sciences; Pharmacology. Drug treatments; Polymerase Chain Reaction; Purine-Nucleoside Phosphorylase - deficiency; Purine-Nucleoside Phosphorylase - genetics; Purine-Nucleoside Phosphorylase - metabolism; Thymidine - metabolism
• ISSN: 0008-5472; 1538-7445

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.