Shewach D S, Lawrence T S
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor 48109-0504, USA.
Invest New Drugs. 1996;14(3):257-63. doi: 10.1007/BF00194528.
Gemcitabine is a nucleoside analogue with excellent clinical activity against solid tumors. Within the cell, gemcitabine is rapidly phosphorylated to its active di- and triphosphate metabolites. Cytotoxicity with gemcitabine appears to be related to multiple effects on DNA replication, where gemcitabine triphosphate can serve as both an inhibitor and substrate for DNA synthesis. Gemcitabine diphosphate inhibits ribonucleotide reductase, producing decreases in cellular dNTP pool levels in a cell-specific manner. These two major characteristics of gemcitabine, reduction in cellular dNTP pools and incorporation into DNA, are features of other antimetabolites antitumor agents which also exhibit radiosensitizing properties. Based on these favorable metabolic characteristics and the clinical activity of gemcitabine in tumor types which are commonly treated with radiation, the ability of gemcitabine to enhance X-radiation induced cytotoxicity was evaluated. Gemcitabine has been shown to be a potent radiosensitizer in a variety of tumor cell lines, including HT-29 colorectal carcinoma, pancreatic cancer, breast, non-small cell lung and head and neck cancer cell lines. Gemcitabine was most effective as a radiosensitizer when administered at least 2 hours prior to irradiation. For most cell lines, radiosensitization was evident at non-cytotoxic concentrations. The extent of radiosensitization increased with both increasing gemcitabine concentration and duration of exposure. Radiosensitization did not require redistribution of cells into a more radiosensitive phase of the cell cycle. The major metabolic effects observed under radiosensitizing conditions were the accumulation of high levels of gemcitabine triphosphate, and a selective decrease in the cellular dATP pool. The pattern of dATP decrease paralleled the increase in radiosensitization, whereas the level of gemcitabine triphosphate was not associated with the enhanced sensitivity to radiation. Compared to other radiosensitizers, the advantage of gemcitabine is that is can induce radiosensitization at concentrations that are 1000 times lower than typical plasma levels obtained with this drug. These studies will be used as guidelines for developing clinical trials of gemcitabine with radiation.
吉西他滨是一种对实体瘤具有优异临床活性的核苷类似物。在细胞内，吉西他滨迅速磷酸化为其活性二磷酸和三磷酸代谢产物。吉西他滨的细胞毒性似乎与对DNA复制的多种作用有关，其中吉西他滨三磷酸既可以作为DNA合成的抑制剂，也可以作为底物。吉西他滨二磷酸抑制核糖核苷酸还原酶，以细胞特异性方式导致细胞内dNTP池水平降低。吉西他滨的这两个主要特性，即细胞内dNTP池的减少和掺入DNA，是其他也具有放射增敏特性的抗代谢抗肿瘤药物的特征。基于这些有利的代谢特性以及吉西他滨在通常接受放疗的肿瘤类型中的临床活性，评估了吉西他滨增强X射线诱导的细胞毒性的能力。吉西他滨已被证明在多种肿瘤细胞系中是一种有效的放射增敏剂，包括HT-29结肠癌细胞、胰腺癌细胞、乳腺癌细胞、非小细胞肺癌细胞和头颈癌细胞系。当在照射前至少2小时给药时，吉西他滨作为放射增敏剂最为有效。对于大多数细胞系，在非细胞毒性浓度下放射增敏作用明显。放射增敏程度随着吉西他滨浓度的增加和暴露时间的延长而增加。放射增敏不需要细胞重新分布到细胞周期中更具放射敏感性的阶段。在放射增敏条件下观察到的主要代谢效应是高水平吉西他滨三磷酸的积累，以及细胞内dATP池的选择性降低。dATP降低的模式与放射增敏的增加平行，而吉西他滨三磷酸的水平与对辐射的增强敏感性无关。与其他放射增敏剂相比，吉西他滨的优势在于它可以在比该药物典型血浆水平低1000倍的浓度下诱导放射增敏。这些研究将用作开展吉西他滨与放疗联合临床试验的指导原则。
