EFA (9-beta-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine.
The deficiency of methylthioadenosine phosphorylase (MTAP) in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers, while constitutively expressed in normal cells, allows for selective therapy using L-alanosine, an inhibitor of de novo AMP synthesis. We demonstrate that MTAP- T-ALL cells obtained at relapse are as sensitive to L-alanosine toxicity as diagnosis samples. The therapeutic index of L-alanosine can be increased by the use of a MTAP substrate, which protects MTAP+ normal cells. Since MTAP substrates MTA and 5'deoxyadenosine are prone to toxicities associated with adenosine, we synthesized and evaluated a potentially nontoxic MTAP substrate, 9-beta-D-erythrofuranosyladenine (EFA). The cytotoxicity of EFA to hematopoietic progenitors erythroid burst-forming units (BFU-Es) and granulocyte-macrophage colony-forming units (CFU-GMs) was at least 26- to 41-fold less than that of MTA. In addition, EFA selectively rescued MTAP+ MOLT-4 cells from L-alanosine toxicity at 25 microM with negligible toxicity even at 100 microM. As for MTA, significant, albeit incomplete, rescue was achieved at 12.5 microM, but higher concentrations were toxic. EFA at 20 microM or less rescued primary MTAP+ T-ALL cells and normal lymphocytes from L-alanosine toxicity. Collectively, these data indicate that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to MTA due to lower cytotoxicity.
Batova
Ayse
A
Department of Pediatrics/Hematology-Oncology, University of California San Diego, San Diego, CA 92103-8447, USA.
Cottam
Howard
H
Yu
John
J
Diccianni
Mitchell B
MB
Carrera
Carlos J
CJ
Yu
Alice L
AL
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015672:Erythroid Precursor Cells / Q000201:enzymology / Q000473:pathology; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D042381:Granulocyte Precursor Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000172:deficiency; D016879:Salvage Therapy; D013872:Thionucleosides / Q000494:pharmacology / Q000627:therapeutic use
C508192:9-beta-D-erythrofuranosyladenine; D000903:Antibiotics, Antineoplastic; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D005663:Furans; D013872:Thionucleosides; C000082:alanosine; C008500:5'-methylthioadenosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000225:Adenine; D000409:Alanine