CLINICAL TRIALS AND OBSERVATIONS EFA (9- -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-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 26to 41-fold less than that of MTA. In addition, EFA selectively rescued MTAP MOLT-4 cells from L-alanosine toxicity at 25 M with negligible toxicity even at 100 M. As for MTA, significant, albeit incomplete, rescue was achieved at 12.5 M, but higher concentrations were toxic. EFA at 20 M 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. (Blood. 2006;107:898-903)