S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine.
A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.
D000208:Acute Disease; D000241:Adenosine / Q000097:blood / Q000652:urine; D000328:Adult; D003070:Coformycin / Q000008:administration & dosage* / Q000031:analogs & derivatives; D003839:Deoxyadenosines / Q000097:blood / Q000652:urine; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000032:analysis; D006710:Homocysteine / Q000031:analogs & derivatives*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D008214:Lymphocytes / Q000032:analysis / Q000201:enzymology; D008297:Male; D015649:Pentostatin; D012263:Ribonucleosides / Q000008:administration & dosage*; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D013997:Time Factors; D014740:Vidarabine / Q000008:administration & dosage* / Q000097:blood / Q000652:urine
D003839:Deoxyadenosines; D012263:Ribonucleosides; D006710:Homocysteine; D003070:Coformycin; D015649:Pentostatin; D012435:S-Adenosylhomocysteine; D014740:Vidarabine; D000241:Adenosine