Exploitation of folate and antifolate polyglutamylation to achieve selective anticancer chemotherapy.
Exploitation of folate and antifolate polyglutamylation to achieve selective anticancer chemotherapy.
复制标题
利用叶酸和抗叶酸多聚谷氨酰化实现选择性抗癌化疗。
DOI：
10.1007/bf00194535
复制
发表时间：
1996
影响因子：
3.4
通讯作者：
Galivan,J
中科院分区：
文献类型：
--
作者：
McGuire,JJ;Tsukamoto,T;Hart,BP;Coward,JK;Kalman,TI;Galivan,J
天然叶酸和抗叶酸剂的聚（γ-谷氨酸）代谢物的合成是一个关键过程。叶酰聚谷氨酸对于细胞增殖至关重要。含谷氨酸 (Glu) 的抗叶酸药物的聚谷氨酸盐通常对其细胞毒性作用至关重要，并且与抗叶酸药物耐药性相关。然而，聚谷氨酸合成在选择性中的作用尚不清楚。我们开展了一项研究计划，以进一步明确聚谷氨酸代谢的重要性，并设计利用这种代谢的方法，以在癌症化疗中实现更大的治疗选择性。本文简要回顾了迄今为止测试的几种方法。叶酰聚谷氨酸合成的抑制应导致细胞死亡。目前，含鸟氨酸 (Orn) 的叶酸基抑制剂负责其合成，叶酰聚谷氨酸合成酶 (FPGS) 的运输很差，这显然是由于质子化 δ-胺的干扰。探索了用 4,4-二氟 Orn 代替 Orn，其 δ-胺的 pKa 低得多，因此在生理 pH 下质子化程度较低。由于尚不清楚多谷氨酰化如何有助于选择性，因此我们探索了消除或增强多谷氨酰化的通用方法。数据表明，用一些谷氨酸类似物替代抗叶酸剂中的谷氨酸，其中γ-COOH被改变或取代（例如，γ-四唑-Glu），导致FPGS底物活性和结合力丧失；抗叶酸剂的靶点特异性没有改变，但吸收实际上有所增强。用 3,3-二氟谷氨酸替代 Glu 会增强多谷氨酰化（尽管可能仅针对二谷氨酸），保留靶标特异性，并且至少具有相同的吸收。对含有不同 Glu 替代物（例如 γ-四唑-Glu（无多谷氨酰化）或 3,3-二氟Glu（增强多谷氨酰化））的相同抗叶酸剂的比较研究，将有助于探索多谷氨酰化的作用和意义。
Synthesis of poly(γ-glutamate) metabolites of natural folates and antifolates is a critical process. Folylpolyglutamates are essential for cell proliferation. Polyglutamates of glutamate (Glu)-containing antifolates are often critical for their cytotoxic action and are relevant to antifolate resistance. However, the role of polyglutamate synthesis in selectivity is less clear. We have undertaken a research program to further define the significance of polyglutamate metabolism and to devise ways to exploit this metabolism to achieve greater therapeutic selectivity in cancer chemotherapy. This article briefly reviews several approaches tested thus far.Inhibition of folylpolyglutamate synthesis should lead to cell death. Current ornithine (Orn)-containing folate-based inhibitors of the enzyme responsible for their synthesis, folylpolyglutamate synthetase (FPGS), are poorly transported, apparently because of interference by the protonatedδ-amine. Replacement of Orn with 4,4-difluoroOrn, theδ-amine of which has a much lower pKaand is thus less protonated at physiological pH, was explored.Since it is unclear how polyglutamylation contributes to selectivity, we explored generic means either to eliminate or to enhance polyglutamylation. The data indicate that substitution for Glu in an antifolate by some Glu analogs in which the γ-COOH is either altered or replaced (e.g., γ-tetrazole-Glu) leads to loss of both FPGS substrate activity and binding; antifolate target specificity is unchanged, while uptake is actually enhanced. Substitution of 3,3-difluoroGlu for Glu leads to enhanced polyglutamylation (although probably only to the diglutamate), retention of target specificity, and at least equal uptake. Comparative studies of the same antifolate containing different replacements for Glu, such as γ-tetrazole-Glu (no polyglutamylation) or 3,3-difluoroGlu (enhanced polyglutamylation), will be useful in exploring the role and significance of polyglutamylation.