This thesis deals with several aspects of the effects of cobalamin inactivation by
nitrous oxide on cellular folate metabolism and the consequences on normal and malignant hematopoiesis. Kroes et al. demonstrated the antileukemic effects of
nitrous oxide either or not in combination with other drugs interfering with the folate
metabolism (132-136). Especially the potentiation of methotrexate activity in the
employed rat model for myeloid leukemia (BNML) after preexposure to nitrous oxide
was striking (134).
Based on those findings part of the work presented in this thesis focuses on the in
vivo interaction between nitrous oxide and methotrexate. In order to establish the
cytotoxicity of the nitrous oxide-methotrexate combination for normal cells, we
conducted an extensive toxicological study in healthy rats in which we concentrated on
the effects on the rapidly dividing cells of bone marrow and gut mucosa (Chapter 3).
Moreover, effects of nitrous oxide and/ or methotrexate on folate metabolism and
folate-depedent dTMP synthesis of fresh human leukemic cells were studied in order
to clarify the actual working mechanism (Chapter 4,5)
