Nitrous oxide reduces growth of experimental rat leukemia

Kroes, A. C. M.; Lindemans, Jan; Hagenbeek, Anton; Abels, J.

doi:10.1016/0145-2126(84)90085-7

Cited by 17 publications

(4 citation statements)

References 21 publications

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“…The dU-suppression test on leukemic spleen cells from N,O treated rats showed decrease of "de novo" thymidine synthesis in comparison with non-treated rats, compatible with methylcobalamin inactivation [34]. The overall results in BNML rats indicate that continuous breathing of N,O retards leukemic growth but does not eradicate the leukemic process [23,28]. Possible synergism of N,O with other folate antagonists, known to interfere with specific enzymatic steps in the folate metabolism (Fig.…”

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confidence: 79%

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

et al. 1990

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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.

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confidence: 79%

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

et al. 1990

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“…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]...…”

Section: Transplantable Modelsmentioning

confidence: 99%

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

2005

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From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.

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“…Moreover, there have been several studies on the restriction of diet containing amino acids related to folate metabolism or the suppression of growth of cancer cells by administration of nitrous oxide [1, 18,19]. The administration of nitrous oxide is based on the fact that nitrous oxide impairs DNA synthesis and suppress cell growth by inactivation of methionine synthase through the irreversible oxidation of cobalt atoms in vitamin B 12 [8,9, 20] (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

“…However, several side effects were reported when nitrous oxide was used in combination with inhalation anesthetics: impairment of hematopoiesis after ≥6 hours of anesthesia, megaloblastic pancytopenia after ≥24 hours of anesthesia and neurodegeneration and myelinopathy after long-term use [7]. It has been demonstrated that such side effects are attributed to the inhibition of DNA synthesis that results from the inactivation of methionine synthase by nitrous oxide [8, 9]. In addition, it has been suggested that hyperbaric nitrous oxide and methotrexate suppress the growth of leukemic cells [10].…”

Section: Introductionmentioning

confidence: 99%

Growth suppression of four cancer cells by hyperbaric nitrous oxide and methotrexate

Jung

Sim

Ahn

2010

Korean J Anesthesiol

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BackgroundNitrous oxide concentration is easily controlled by respiratory ventilation. It suppresses bone marrow via the inhibition of thymidylate synthesis. The aim of this work was to determine the optimal pressure and exposure duration of nitrous oxide, as well as methotrexate concentration that maximizes the suppression of 4 cancer cells: CCRF-CEM, K562, A549 and MDA-MB-231.MethodsEach cancer cell was cultured in a hyperbaric chamber at 1, 2 and 3 atmosphere of 74% nitrous oxide for 24, 48, and 72 hours at 0, 0.3, 0.7, 1, 2, 5 and 10 µM methotrexate (MTX), respectively. The results were expressed in the ratio of the number of cancer cells cultured under specific conditions (S cells) to that under normal conditions (N cells).ResultsThe S/N ratio of CCRF-CEM cells was 87.4% in 24-hour culture, 95.0% in 48-hour culture and 115.9% in 72-hour culture (P < 0.05). The S/N ratio of K562 cells was 103.6% at 1 atm, 102.4% at 2 atm and 115.6% at 3 atm (P < 0.05). The S/N ratio of A549 cells was 94.3% at 1 atm, 94.1% at 2 atm, 99.3% at 3 atm, 96.2% in 24-hour culture, 99.2% in 48-hour culture and 99.3% in 72-hour culture (P > 0.05). However, the S/N ratio of MDA-MB 231 cells was 66.9% in 24-hour culture, 83.1% in 48 hour culture and 87.8% in 72-hour culture (P < 0.05).ConclusionsOnly the growth of the MDA-MB-231 cells was significantly reduced after a longer exposure time to nitrous oxide, but those of the other cells were not.

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Nitrous oxide reduces growth of experimental rat leukemia

Cited by 17 publications

References 21 publications

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

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

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

Growth suppression of four cancer cells by hyperbaric nitrous oxide and methotrexate

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