ANTILEUKEMIC POTENTIAL OF METHYL-COBALAMIN INACTIVATION BY NITROUS-OXIDE
ANTILEUKEMIC POTENTIAL OF METHYL-COBALAMIN INACTIVATION BY NITROUS-OXIDE
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DOI：
10.1002/ajh.2830340209
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发表时间：
1990-06-01
影响因子：
12.8
通讯作者：
LINDEMANS, J
中科院分区：
文献类型：
--
作者：
ABELS, J;KROES, ACM;LINDEMANS, J
广泛吸入氧化亚氮（N2O）的骨髓细胞毒性大约在四十年前被描述，然后偶然应用于抑制白血病已经取得了暂时的成功。1948年，伴随的巨幼细胞成熟停滞被解释为甲基钴胺辅酶失活和随后的叶酸缺乏。我们研究了N2O对B（褐色）N（orway）大鼠可移植急性白血病的抗白血病作用。这种B，N，M（黄血细胞）L（白血病）的进展通过脾脏和肝脏的重量和白血病血细胞计数来测量。脱氧尿苷（dU）抑制试验提供了白血病细胞功能性叶酸活性的体外指示。吸入n2o -氧可显著减少但不能根除bnml的增殖。添加抗代谢物，干扰叶酸代谢中的一些酶，超过甲基钴胺辅酶依赖的蛋氨酸合成酶步骤，至少起协同作用。环亮氨酸通过使蛋氨酸腺苷转移酶失活而减少s -腺苷蛋氨酸的合成，其抗白血病作用一般，但吸入N2O后其抗白血病作用增强。甲氨蝶呤是一种有效的抗白血病药物，通过抑制二氢氟化物还原酶的失活来抑制四氢叶酸（THF）的产生，即使在低剂量下与N2O联合或先用N2O，也能成为高度抗bnml的药物。5-氟尿嘧啶抑制亚甲基四氢呋喃依赖性胸苷合成酶，其本身具有令人惊讶的抗bnml作用，但在先前或伴随的N2O暴露中也变得更有效。在体外暴露于N2O和/或叶酸拮抗剂的人急性白血病细胞中，初步的du抑制实验结果与体内bnml实验结果吻合良好。因此，将N2O的抗钴胺素活性与抗叶酸结合似乎是一种很有前途的化疗方法。
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.