Tributyrin: a prodrug of butyric acid for potential clinical application in differentiation therapy.
Tributyrin: a prodrug of butyric acid for potential clinical application in differentiation therapy.
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发表时间：
1994-07
期刊：
影响因子：
11.2
通讯作者：
Zi X. Chen;Theodore Il Breitman
中科院分区：
文献类型：
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作者：
Zi X. Chen;Theodore Il Breitman
丁酸(BA)在体外诱导多种肿瘤细胞分化。BA的代谢速度快，血浆半衰期短，明显难以达到有效浓度，限制了BA的潜在临床应用。在这项研究中，我们讨论了两种可能在体内实现BA有效浓度的方法。一种策略是使用BA衍生物作为前体药物，可以在体内代谢，在持续的一段时间内产生有效的BA浓度。另一种策略是定义与BA具有协同作用的试剂，以便在较低浓度的BA下达到预期的效果。本实验研究了单丁酸甘油酯(MB)和三丁酸甘油酯(TB)对人髓系白血病HL60细胞和小鼠红白血病细胞的体外诱导分化作用。在摩尔基础上，TB诱导HL60细胞分化的能力约为BA或MB的4倍。BA、MB、TB诱导小鼠红白血病细胞向红系分化。在摩尔基础上，TB的效力是BA的3到4倍，而MB的效力远低于BA。全反式维甲酸与BA、MB或TB联合应用可协同诱导HL60细胞向髓系分化。我们看到，为了达到与单一药物相同的效果，每种药物联合使用所需的剂量显著减少。例如，130微米TB、110 nM全反式维甲酸以及13微米TB和13 nM全反式维甲酸的组合都能诱导HL60细胞分化到一半。我们的结果表明，易得的TB可能是BA的一种有效的前体药物，并且可能作为单独药物或与其他药物联合用于人类恶性肿瘤的细胞分化治疗。
Butyric acid (BA) induces cytodifferentiation in vitro of a wide variety of neoplastic cells. The potential clinical utility of BA is limited by the apparent difficulty of achieving effective concentrations because of its rapid metabolism and short plasma half-life. In this study we addressed two approaches that may achieve effective concentrations of BA in vivo. One strategy is to use BA derivatives as prodrugs that can be metabolized to yield effective BA concentrations in vivo over a sustained period of time. Another strategy is to define agents that are synergistic with BA so that the desired effect can be achieved at lower concentrations of BA. In this study monobutyrin (MB) and tributyrin (TB) were studied in vitro for their effects on inducing differentiation of human myeloid leukemia HL60 cells and murine erythroleukemia cells. On a molar basis TB was about 4-fold more potent than either BA or MB for inducing differentiation of HL60 cells. BA, MB, or TB induced erythroid differentiation of murine erythroleukemia cells. On a molar basis TB was 3- to 4-fold more potent than BA, whereas MB was much less potent than BA. Combinations of all-trans-retinoic acid with either BA, MB, or TB induced myeloid differentiation of HL60 cells synergistically. We saw marked reductions in the doses of each agent that were needed in combination to achieve the same effect as single agents. For example, 130 microM TB, 110 nM all-trans-retinoic acid, and a combination of 13 microM TB plus 13 nM all-trans-retinoic acid all induced half-maximal differentiation of HL60 cells. Our results suggest that the readily available TB may be an effective prodrug of BA and may be useful either as a sole agent or in combination with other agents for cytodifferentiation therapy of human malignancies.