Gemcitabine: metabolism, mechanisms of action, and self-potentiation.
Gemcitabine: metabolism, mechanisms of action, and self-potentiation.
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DOI：
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发表时间：
1995-08
影响因子：
4
通讯作者：
W. Plunkett;P. Huang;Y. Z. Xu;V. Heinemann;R. Grunewald;V. Gandhi
中科院分区：
文献类型：
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作者：
W. Plunkett;P. Huang;Y. Z. Xu;V. Heinemann;R. Grunewald;V. Gandhi
吉西他滨（Gemcitabine，dFdC）是一种新型的抗癌核苷，是脱氧胞苷的类似物。它是一种前药，一旦转运到细胞中，必须被脱氧胞苷激酶磷酸化为活性形式。二磷酸吉西他滨（dFdCTP）和三磷酸吉西他滨（dFdCTP）均抑制DNA合成所需的过程。dFdCTP掺入DNA很可能是吉西他滨导致细胞死亡的主要机制。在延伸DNA链的末端掺入吉西他滨核苷酸后，再加入一个脱氧核苷酸，此后，DNA聚合酶不能进行。这种作用（“掩蔽终止”）显然将药物锁定在DNA中，因为校对酶无法从该位置去除吉西他滨。此外，吉西他滨代谢产物对细胞调节过程发挥的独特作用有助于增强对细胞生长的总体抑制活性。这种相互作用被称为“自我增强”，并在极少数其他抗癌药物中得到证实。
Gemcitabine (dFdC) is a new anticancer nucleoside that is an analog of deoxycytidine. It is a pro-drug and, once transported into the cell, must be phosphorylated by deoxycytidine kinase to an active form. Both gemcitabine diphosphate (dFdCTP) and gemcitabine triphosphate (dFdCTP) inhibit processes required for DNA synthesis. Incorporation of dFdCTP into DNA is most likely the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added and thereafter, the DNA polymerases are unable to proceed. This action ("masked termination") apparently locks the drug into DNA as the proofreading enzymes are unable to remove gemcitabine from this position. Furthermore, the unique actions that gemcitabine metabolites exert on cellular regulatory processes serve to enhance the overall inhibitory activities on cell growth. This interaction is termed "self-potentiation" and is evidenced in very few other anticancer drugs.