Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodelling, Bad Nauheim, Germany.
Expert Opin Investig Drugs. 2010 Jan;19(1):117-31. doi: 10.1517/13543780903485642.
For many cancers, there has been a shift from management with traditional, nonspecific cytotoxic chemotherapies to treatment with molecule-specific targeted therapies that are used either alone or in combination with traditional chemotherapy and radiation therapy. Accumulating data suggest that multi-targeted agents may produce greater benefits than those observed with single-targeted therapies, may have acceptable tolerability profiles, and may be active against a broader range of tumour types. Thus, regulation of cyclic nucleotide signalling is properly regarded as a composite of multiple component pathways involved in diverse aspects of tumour cell function. The impairment of cAMP and/or cGMP generation by overexpression of PDE isoforms that has been described in various cancer pathologies, and the effects of PDE inhibitors in tumour models in vitro and in vivo, may offer promising insight into future cancer treatments because of the numerous advantages of PDE inhibitors.
In this review, we focus on the expression and regulation of cyclic nucleotide phosphodiesterases (PDEs) in tumour progression and provide evidence that PDE inhibitors may be effective agents for treating cancer; the review covers literature from the past several years.
PDEs have been studied in a variety of tumours; data have suggested that the levels of PDE activity are elevated and, therefore, the ratio of cGMP to cAMP is affected. In addition, PDE inhibitors may be potential targets for tumour cell growth inhibition and induction of apoptosis. This review explores the prospects of targeting PDEs with therapeutic agents for cancer, as well as the shortcomings of this approach such as dose-limiting side effects, toxicity/efficacy ratio and selectivity towards tumour tissue. In addition, it includes opinions and suggestion for developing PDE inhibition for cancer treatment from initial concept to potential therapeutic application and final relevance in clinical use.
Impaired cAMP and/or cGMP generation upon overexpression of PDE isoforms has been described in various cancer pathologies. Inhibition of selective PDE isoforms, which raises the levels of intracellular cAMP and/or cGMP, induces apoptosis and cell cycle arrest in a broad spectrum of tumour cells and regulates the tumour microenvironment. Therefore, the development and clinical application of inhibitors specific for individual PDE isoenzymes may selectively restore normal intracellular signalling, providing antitumour therapy with reduced adverse effects.
对于许多癌症，已经从管理与传统的非特异性细胞毒性化疗转向治疗与分子特异性靶向治疗，这些治疗方法单独使用或与传统化疗和放射治疗联合使用。越来越多的数据表明，多靶点药物可能比单一靶点治疗产生更大的益处，可能具有可接受的耐受性谱，并且可能对更广泛的肿瘤类型有效。因此，环核苷酸信号的调节被恰当地视为涉及肿瘤细胞功能各个方面的多个组成部分途径的组合。在各种癌症病理中已经描述了 PDE 同工型的过度表达导致的 cAMP 和/或 cGMP 产生受损，以及 PDE 抑制剂在体外和体内肿瘤模型中的作用，这可能为未来的癌症治疗提供有希望的见解，因为 PDE 抑制剂具有许多优势。
涵盖的领域在这篇综述中，我们专注于肿瘤进展中环核苷酸磷酸二酯酶（PDEs）的表达和调节，并提供证据表明 PDE 抑制剂可能是治疗癌症的有效药物；综述涵盖了过去几年的文献。
读者将获得 PDE 已在各种肿瘤中进行了研究；数据表明 PDE 活性水平升高，因此 cGMP 与 cAMP 的比值受到影响。此外，PDE 抑制剂可能是肿瘤细胞生长抑制和诱导细胞凋亡的潜在靶点。这篇综述探讨了用治疗剂靶向 PDE 治疗癌症的前景，以及这种方法的缺点，如剂量限制的副作用、毒性/疗效比和对肿瘤组织的选择性。此外，它还包括了从最初的概念到潜在的治疗应用以及最终在临床应用中的相关性，对开发 PDE 抑制用于癌症治疗的意见和建议。
在各种癌症病理中已经描述了 PDE 同工型的过度表达导致的 cAMP 和/或 cGMP 产生受损。抑制选择性 PDE 同工型可提高细胞内 cAMP 和/或 cGMP 的水平，诱导广泛的肿瘤细胞凋亡和细胞周期停滞，并调节肿瘤微环境。因此，针对个体 PDE 同工酶的抑制剂的开发和临床应用可能会选择性地恢复正常的细胞内信号，提供减少不良反应的抗肿瘤治疗。
