Synergistic growth inhibiting effect of nitrous oxide and cycloleucine in experimental rat leukaemia

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

doi:10.1038/bjc.1984.258

Cited by 14 publications

(5 citation statements)

References 24 publications

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“…Further, it has been shown that exposure to N 2 O leads to a rapid decrease in the level of methionine synthase activity (19). More recent therapeutic studies in rats have combined the effects of depletion of cobalamin with the commonly used antineoplastic agents, 5-fluorouracil (21), cycloleucine (22), and methotrexate (23,24).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Cobalamin−Biotin Conjugates That Vary in the Position of Cobalamin Coupling. Evaluation of Cobalamin Derivative Binding to Transcobalamin II

et al. 1996

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Six cobalamin-biotin conjugates have been prepared. The cobalamin-biotin conjugates were prepared to evaluate the effect that the location of attachment had on the binding with transcobalamin II (TCII), the cobalamin binding protein in plasma, and to evaluate their potential use for in vitro and in vivo applications. This study focused only on the effect of binding with TCII. To decrease the possibility of steric problems in binding of the cobalamin conjugates with TCII, and biotin's binding with streptavidin or avidin, moieties of 11-18 atoms in length were used as linkers. Four biotin conjugates were prepared which were attached to the corrin ring of the cobalamin molecule (on b-, c-, d-, and e-side chains). One conjugate was attached to the 5'-OH of the ribose moiety, and another conjugate was attached at the cobalt metal (in place of the cyanide moiety of cyanocobalamin). Competitive binding studies were conducted where various amounts of the cobalamin-biotin conjugates and their precursor cobalamin derivatives competed with [57Co]cyanocobalamin for binding of recombinant human TCII (rhTCII). Evaluation of cobalamin derivatives which were conjugated at the 5'-OH of ribose or the cobalt metal center indicated that conjugation at either of these positions had little effect on binding with rhTCII. However, conjugates where the attachment was made on the corrin ring substituents had a large variation in binding with rhTCII. Conjugates on the e-propionamide side chain had little effect (relative affinity was equal to or decreased less than a factor of 3) on binding with rhTCII, conjugates of the b-isomer had decreased binding (relative affinity decreased less than a factor of 10), conjugates of the d-propionamide had further decreased binding (relative affinity decreased between 44 and 69 times), and conjugates on the c-acetamide group had poor binding to rhTCII (relative affinity decreased between 295 and 1160 times). The significance of the side chains on the corrin ring in providing specificity and high-affinity binding with rhTCII is discussed.

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Section: Introductionmentioning

confidence: 99%

Synthesis of Cobalamin−Biotin Conjugates That Vary in the Position of Cobalamin Coupling. Evaluation of Cobalamin Derivative Binding to Transcobalamin II

et al. 1996

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“…It made no difference if cycloleucine was injected or added in vitro to spleen cells from N,Otreated leukemic rats [24].…”

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confidence: 99%

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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“…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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Synergistic growth inhibiting effect of nitrous oxide and cycloleucine in experimental rat leukaemia

Cited by 14 publications

References 24 publications

Synthesis of Cobalamin−Biotin Conjugates That Vary in the Position of Cobalamin Coupling. Evaluation of Cobalamin Derivative Binding to Transcobalamin II

Synthesis of Cobalamin−Biotin Conjugates That Vary in the Position of Cobalamin Coupling. Evaluation of Cobalamin Derivative Binding to Transcobalamin II

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

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

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