Goya R G, Sarkar D K, Brown O A, Hereñú C B
Institute for Biochemical Research at La Plata, Faculty of Medicine, National University of La Plata, Argentina.
Curr Gene Ther. 2004 Mar;4(1):79-87. doi: 10.2174/1566523044578086.
Pituitary adenomas constitute the most frequent neuroendocrine pathology, comprising up to 15% of primary intracranial tumors. Current therapies for pituitary tumors include surgery and radiotherapy, as well as pharmacological approaches for some types. Although all of these approaches have shown a significant degree of success, they are not devoid of unwanted side effects, and in most cases do not offer a permanent cure. Gene therapy-the transfer of genetic material for therapeutic purposes-has undergone an explosive development in the last few years. Within this context, the development of gene therapy approaches for the treatment of pituitary tumors emerges as a promising area of research. We begin by presenting a brief account of the genesis of prolactinomas, with particular emphasis on how estradiol induces prolactinomas in animals. In so doing, we discuss the role of each of the recently discovered growth inhibitory and growth stimulatory substances and their interactions in estrogen action. We also evaluate the cell-cell communication that may govern these growth factor interactions and subsequently promote the growth and survival of prolactinomas. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental prolactinomas or somatomammotropic tumors with adenoviral vector-mediated transfer of the suicide gene for the herpes simplex type 1 (HSV1) thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. In some cases, the suicide transgene has been placed under the control of pituitary cell-type specific promoters, like the human prolactin or human growth hormone promoters. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. In a different type of approach, an adenoviral vector, encoding the human retinoblastoma suppressor oncogene, has been successfully used to rescue the phenotype of spontaneous pituitary tumors of the pars intermedia in mice. We close the article by discussing the future of molecular therapies. We point out that although, gene therapy represents a key step in the development of molecular medicine, it has inherent limitations. As a consequence, it is our view that at some point, genetic therapies will have to move from exogenous gene transfer (i.e. gene therapy) to endogenous gene repair. This approach will call for radically new technologies, such as nanotechnology, whose present state of development is outlined.
垂体腺瘤是最常见的神经内分泌疾病，占原发性颅内肿瘤的15%。目前垂体瘤的治疗方法包括手术、放疗以及针对某些类型的药物治疗。尽管所有这些方法都取得了显著成功，但它们并非没有不良副作用，而且在大多数情况下并不能提供永久性治愈。基因治疗——为治疗目的转移遗传物质——在过去几年中经历了迅猛发展。在此背景下，垂体瘤基因治疗方法的开发成为一个有前景的研究领域。我们首先简要介绍催乳素瘤的发生，特别强调雌二醇如何在动物中诱导催乳素瘤。在此过程中，我们讨论最近发现的每种生长抑制和生长刺激物质的作用及其在雌激素作用中的相互作用。我们还评估了可能控制这些生长因子相互作用并随后促进催乳素瘤生长和存活的细胞间通讯。目前在垂体瘤中实施基因治疗的研究工作包括用腺病毒载体介导的单纯疱疹病毒1型（HSV1）胸苷激酶自杀基因转移来治疗实验性催乳素瘤或生长激素催乳素瘤，该基因将前药更昔洛韦转化为有毒代谢物。在某些情况下，自杀转基因已置于垂体细胞类型特异性启动子的控制之下，如人催乳素或人生长激素启动子。此外，可调节腺病毒载体系统正在实验性垂体瘤的基因治疗方法中进行评估。在另一种方法中，编码人视网膜母细胞瘤抑制癌基因的腺病毒载体已成功用于挽救小鼠中间部自发垂体瘤的表型。我们通过讨论分子治疗的未来来结束本文。我们指出，尽管基因治疗是分子医学发展中的关键一步，但它有其固有的局限性。因此，我们认为在某个时候，基因治疗将不得不从外源基因转移（即基因治疗）转向内源基因修复。这种方法将需要全新的技术，如纳米技术，本文概述了其目前的发展状况。
