Aghi M, Hochberg F, Breakefield X O
Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston 02114, USA.
J Gene Med. 2000 May-Jun;2(3):148-64. doi: 10.1002/(SICI)1521-2254(200005/06)2:3<148::AID-JGM105>3.0.CO;2-Q.
Among the broad array of genes that have been evaluated for tumor therapy, those encoding prodrug activation enzymes are especially appealing as they directly complement ongoing clinical chemotherapeutic regimes. These enzymes can activate prodrugs that have low inherent toxicity using both bacterial and yeast enzymes, or enhance prodrug activation by mammalian enzymes. The general advantage of the former is the large therapeutic index that can be achieved, and of the latter, the non-immunogenicity (supporting longer periods of prodrug activation) and the fact that the prodrugs will continue to have some efficacy after transgene expression is extinguished. This review article describes 13 different prodrug activation schemes developed over the last 15 years, two of which - activation of ganciclovir by viral thymidine kinase and activation of 5-fluorocytosine to 5-fluorouracil - are currently being evaluated in clinical trials. Essentially all of these prodrug activation enzymes mediate toxicity through disruption of DNA replication, which occurs at differentially high rates in tumor cells compared with most normal cells. In cancer gene therapy, vectors target delivery of therapeutic genes to tumor cells, in contrast to the use of antibodies in antibody-directed prodrug therapy. Vector targeting is usually effected by direct injection into the tumor mass or surrounding tissues, but the efficiency of gene delivery is usually low. Thus it is important that the activated drug is able to act on non-transduced tumor cells. This bystander effect may require cell-to-cell contact or be mediated by facilitated diffusion or extracellular activation to target neighboring tumor cells. Effects at distant sites are believed to be mediated by the immune system, which can be mobilized to recognize tumor antigens by prodrug-activated gene therapy. Prodrug activation schemes can be combined with each other and with other treatments, such as radiation, in a synergistic manner. Use of prodrug wafers for intratumoral drug activation and selective permeabilization of the tumor vasculature to prodrugs and vectors should further increase the value of this new therapeutic modality.
在众多已被评估用于肿瘤治疗的基因中，那些编码前药激活酶的基因尤其具有吸引力，因为它们能直接补充当前正在使用的临床化疗方案。这些酶可以利用细菌和酵母酶激活固有毒性较低的前药，或者增强哺乳动物酶对前药的激活作用。前者的总体优势在于能够实现较大的治疗指数，而后者的优势在于无免疫原性（有利于前药长时间激活）以及在前基因表达消失后前药仍将具有一定疗效这一事实。这篇综述文章描述了过去15年中开发的13种不同的前药激活方案，其中两种——病毒胸苷激酶激活更昔洛韦以及5-氟胞嘧啶激活为5-氟尿嘧啶——目前正在临床试验中进行评估。基本上所有这些前药激活酶都是通过干扰DNA复制来介导毒性的，与大多数正常细胞相比，肿瘤细胞中DNA复制的速率差异很大。在癌症基因治疗中，载体将治疗基因靶向递送至肿瘤细胞，这与抗体导向前药治疗中使用抗体的情况不同。载体靶向通常通过直接注射到肿瘤块或周围组织中来实现，但基因递送效率通常较低。因此，激活的药物能够作用于未转导的肿瘤细胞很重要。这种旁观者效应可能需要细胞间接触，或者由易化扩散或细胞外激活介导以靶向邻近的肿瘤细胞。远处部位的效应被认为是由免疫系统介导的，前药激活基因治疗可以动员免疫系统识别肿瘤抗原。前药激活方案可以相互结合，并与其他治疗方法（如放疗）以协同方式联合使用。使用前药晶片进行瘤内药物激活以及使肿瘤血管对前药和载体具有选择性通透性，应该会进一步提高这种新治疗方式的价值。
