Differential sensitivity of normal and leukaemic haemopoietic cells to methionine deprivation by L-methioninase.
The in vitro sensitivity of bone marrow cells from patients with leukaemia and from patients with non-malignant diseases to L-methionine removal by L-methioninase (L-methionine-alpha-deamino-gamma-mercaptomethane-lyase, EC 4.4.1.11) was determined using the incorporation of [methyl-3H]thymidine into acid-insoluble material as an index of survival. When compared with controls growing in medium containing 10 micrograms/ml of L-methionine, leukaemic cells showed a lower incorporation of [methyl-3H]thymidine after 24 h in the presence of 0.1 (normal 78 +/- 24%; leukaemic 26 +/- 18%, p less than 0.01) or 0.05 (normal 84 +/- 15%; leukaemic 50 +/- 21%, p less than 0.01) units of L-methioninase per ml. A similar differential sensitivity of leukaemic cells to L-methioninase was seen after 48 h of incubation. There was little effect on [methyl-3H]thymidine incorporation in the presence of boiled enzyme. Attempts to reverse L-methioninase toxicity with D-homocystine did not result in a differential effect on the normal cell population. The effects of L-methionine removal with L-methioninase were similar to those observed in L-methionine-depleted culture medium supplemented with 0.1 mM L-homocysteine. After 24 h in such depleted media leukaemic cells showed a lower incorporation of [methyl-3H]thymidine into acid-insoluble material (normal 88 +/- 17%; leukaemic 35 +/- 14%, p less than 0.01) and there was an elevation of the L-methionine-dependent enzymes: methionine adenosyltransferase, tRNA methyltransferase and S-adenosylmethionine decarboxylase. These results suggest the possibility of trying L-methioninase in the treatment of suitable leukaemias.
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D013437:Carbon-Sulfur Lyases / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D008190:Lyases / Q000494:pharmacology*; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors; D012359:tRNA Methyltransferases / Q000378:metabolism
D006710:Homocysteine; C012439:methylthymidine; D008715:Methionine; D012359:tRNA Methyltransferases; D008716:Methionine Adenosyltransferase; D008190:Lyases; D012437:Adenosylmethionine Decarboxylase; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase; D013936:Thymidine