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 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.
Batova
A
A
Department of Pediatric Hematology/Oncology, University of California, San Diego 92103-8447, USA.
Diccianni
M B
MB
Omura-Minamisawa
M
M
Yu
J
J
Carrera
C J
CJ
Bridgeman
L J
LJ
Kung
F H
FH
Pullen
J
J
Amylon
M D
MD
Yu
A L
AL
D000249:Adenosine Monophosphate / Q000096:biosynthesis; D000409:Alanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C000082:alanosine; D000249:Adenosine Monophosphate; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000409:Alanine; D013936:Thymidine