Anti‐leukemic potential of methyl‐cobalamin inactivation by nitrous oxide

Abstract

Myelo-cytotoxicity of extended nitrous oxide (N2O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti-leukemic effect of N2O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)-suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N2O-oxygen considerably reduced but did not eradicate, BNML-proliferation. Addition of anti-metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co-enzyme dependent methionine synthase step, acted at least synergistically. The anti-leukemic effect of cycloleucine, which reduces S-adenosyl-methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N2O inhalation. Methotrexate, a potent anti-leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di-HF reductase, became highly anti-BNML, even in low dosage when combined with or preceded by N2O. 5-Fluorouracil, which inhibits methylene-THF dependent thymidilate synthase, itself was surprisingly anti-BNML, but also became much more potent with previous or concomitant N2O exposure. Preliminary dU-suppression test results with human acute leukemia cells, exposed to N2O and/or folate antagonists in vitro, correlated well with the in vivo BNML-experiments. Combining the anticobalamin activity of N2O with an anti-folate therefore seems to be a promising chemotherapeutic approach.

Induction of Apoptosis in neoplastic cells by depletion of vitamin B12

“…Indeed, experiments carried out by Lassen and Kristen (1959), Eastwood et al (1963) and Ikeda et al (1989), using nitrous oxide gas to cause a whole body B 12 depletion in patients with leukemias, established that white blood cell counts could be effectively reduced to the point of disease remission. Similar results have been obtained in a mouse ascites tumour model (Parbrook, 1967) and in experimental rat leukemia models (Ermens et al, 1989;Abels et al, 1990). Nitrous oxide oxidizes CoII to CoIII rendering cobalamin inactive (Banks et al, 1968) leading to inhibition of MS activity (Deacon et al, 1980;Kondo et al, 1981), but not methylmalonylCoa mutase activity (Kondo et al, 1981;Chanarin et al, 1985) at least during short-term exposures.…”

Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management

“…Nitrous oxide is potentially toxic to patients with cblC disease because it depletes the body stores of B 12 and inhibits methionine synthase activity (Drummond and Matthews 1994; Abels et al 1990). The death of a child with MTHFR deficiency (Selzer et al 2003) and several cases of acute neurologic deterioration in children with B 12 deficiency (Felmet et al 2000; McNeely et al 2000; Waclawik et al 2003; Schilling 1986; Kinsella and Green 1995) have been reported in association with nitrous oxide.…”

Animal models of acute myelogenous leukaemia – development, application and future perspectives

“…185,186 The BNML rat model has also been evaluated in appraising therapeutic index, optimisation of dose schedules and combinations of anthracyclines, [187][188][189][190][191][192][193] Ara-C, 158,[194][195][196][197][198][199][200][201][202][203][204][205][206][207][208] AMSA 209 and several other therapeutics. [210][211][212][213][214][215][216][217][218][219][220] The concern of relapse following autologous bone marrow transplant (ABMT) in human AML was initially addressed in the BNML rat model, examining antileukemic effects as well as toxicity of various conditioning regimes prior to ABMT, 221,222 including total body irradiation (TBI), 223 marrow ablative chemoradiotherapy, [224][225][226][227][228][229]...…”