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Synergistic growth inhibiting effect of nitrous oxide and cycloleucine in experimental rat leukaemia
Abstract:
Nitrous oxide (N2O) inactivates the vitamin B12-dependent enzyme methionine synthetase with subsequent impairment of folate metabolism and a reduction of cellular proliferation. Indications exist that this effect is antagonized by S-adenosylmethionine (SAM), and it was investigated whether combination with an inhibitor of SAM synthesis, cycloleucine, would result in increased inhibition of growth in rat leukaemia model (BNML). Leukaemic growth was compared in untreated rats, in rats treated with either nitrous oxide/oxygen (1:1) or cycloleucine (50 mg kg-1 i.p.), and in rats receiving both agents. Combined treatment resulted in the strongest reduction of leukaemic infiltration in spleen and liver, and this reduction often was more than the added effects of single treatments. Peripheral leukocyte counts were also lowest after combined treatment. The deoxyuridine suppression test, measuring folate-dependent de novo synthesis of thymidine, was more severely disturbed with combined treatment. Levels of vitamin B12 in plasma were reduced in rats receiving N2O, but an increase in plasma folate occurred in all treated rats. These results indicate that a reduction of SAM synthesis by cycloleucine can increase the disturbance of folate metabolism that is caused by nitrous oxide, with a potentiation of the effects on leukaemic growth.
Insights
Nitrous oxide impairs folate metabolism by inactivating methionine synthetase. Combining it with cycloleucine, a SAM synthesis inhibitor, potentiated this effect, significantly reducing leukaemic growth in rats.
Area of Science:
- Biochemistry
- Hematology
- Pharmacology
Background:
- Nitrous oxide (N2O) inactivates vitamin B12-dependent methionine synthetase, disrupting folate metabolism and cellular proliferation.
- S-adenosylmethionine (SAM) is known to antagonize the effects of nitrous oxide.
Purpose of the Study:
- To investigate if inhibiting SAM synthesis with cycloleucine enhances the anti-leukaemic effects of nitrous oxide in the Brown Norway rat myeloid leukaemia (BNML) model.
- To evaluate the combined impact of nitrous oxide and cycloleucine on leukaemic growth and folate metabolism.
Main Methods:
- Comparison of leukaemic growth in BNML rats under four conditions: untreated, nitrous oxide/oxygen (1:1), cycloleucine (50 mg kg-1 i.p.), and combined treatment.
- Assessment of leukaemic infiltration in spleen and liver, peripheral leukocyte counts, and the deoxyuridine suppression test.
- Measurement of plasma vitamin B12 and folate levels.
Main Results:
- Combined treatment with nitrous oxide and cycloleucine demonstrated the most significant reduction in leukaemic infiltration in spleen and liver, often exceeding the additive effects of single treatments.
- Peripheral leukocyte counts were lowest in the combined treatment group.
- The deoxyuridine suppression test showed a more severe disturbance of folate-dependent de novo thymidine synthesis with combined treatment.
- Plasma vitamin B12 levels decreased with N2O administration, while plasma folate increased in all treated groups.
Conclusions:
- Inhibition of SAM synthesis by cycloleucine potentiates the folate metabolism disturbance caused by nitrous oxide.
- The combination therapy significantly enhances the anti-leukaemic effects observed in the BNML rat model.
- This suggests a potential therapeutic strategy involving combined nitrous oxide and SAM synthesis inhibition for certain leukaemias.