Resistance to multiple adenine nucleoside and methionine analogues in mutant murine lymphoma cells with enlarged S-adenosylmethionine pools.
Adenosine and many adenosine analogues exert toxicity to mammalian cells at the nucleoside level. The mechanism of action of these agents is controversial. Previous experiments suggested that adenosine toxicity could be mediated by the accumulation of S-adenosylhomocysteine (AdoHcy), a potent inhibitor of S-adenosylmethionine (AdoMet) dependent methylation reactions. To analyze this question genetically, adenosine resistant, adenosine kinase deficient mutant clones of a murine T-lymphoma cell line (R1.1) have been selected and analyzed. Compared to parental lymphoma cells, the adenosine resistant mutants had severalfold elevated levels of AdoMet and an increased AdoMet:AdoHcy ratio. The activity of methionine adenosyltransferase was also raised in the mutants. The mutant cells were cross-resistant to agents postulated to cause accretion of AdoHcy, formation of AdoHcy analogues, impairment of AdoMet synthesis, or direct interference with AdoMet dependent reactions. These included 3-deazaadenosine, carbocyclic adenosine, carbocyclic 3-deazaadenosine, formycin A, 8-azaadenosine, 5'-deoxy-5'-methylthiotubercidin, 5'-deoxy-5'-methylthioadenosine, 5'-deoxy-5'-S-isobutylthioadenosine, adenine, cycloleucine, L-ethionine, seleno-DL-ethionine, and (+/-)-2-aminobicyclo[2.1.1]hexane-2-carboxylic acid. These results suggest that diverse purine nucleoside and methionine analogues may block the growth of adenosine kinase deficient cells by interference with AdoMet synthesis and degradation. An increase in AdoMet pools can render mammalian cells cross-resistant to multiple drugs affecting this essential metabolic pathway.
Kajander
E O
EO
Kubota
M
M
Carrera
C J
CJ
Montgomery
J A
JA
Carson
D A
DA
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004351:Drug Resistance; D006710:Homocysteine / Q000494:pharmacology; D007700:Kinetics; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology*; D008716:Methionine Adenosyltransferase / Q000032:analysis; D051379:Mice; D009154:Mutation; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism*
D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D008716:Methionine Adenosyltransferase; D000241:Adenosine