Pharmacotherapeutics Unit, Department of Medicine, University Putra Malaysia, Serdang, Selangor, Malaysia.
Clin Exp Pharmacol Physiol. 2013 May;40(5):307-19. doi: 10.1111/1440-1681.12083.
Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis.
肿瘤侵袭和转移已被认为是癌症患者发病率和死亡率的主要原因。癌症转移知识的许多进展产生了一系列令人印象深刻的有吸引力的药物靶点，包括酶、受体和多种信号通路。本综述总结了转移的分子发病机制和用于发现抗转移剂的新型分子靶点的鉴定。强调了几个有前途的靶点，包括受体酪氨酸激酶、参与血管生成的效应分子、基质金属蛋白酶（MMPs）、尿激酶纤溶酶原激活物、粘附分子及其受体、信号通路（如磷脂酰肌醇 3-激酶、磷酯酶 Cγ1、丝裂原活化蛋白激酶、c-Src 激酶、c-Met 激酶和热休克蛋白。本文还讨论了针对每个靶点发现和开发潜在新型治疗剂的情况。在这些靶点中，表现出显著临床效果的最有前途的药物是抗血管生成药物（如贝伐单抗）。新型药物，如 c-Met 激酶抑制剂，仍处于临床前研究阶段，其临床疗效尚未得到证实。一些治疗剂，如第一代基质金属蛋白酶抑制剂（MMPIs；如 marimastat）及其更具选择性的版本（如 prinomastat、tanomastat），已进行了临床试验。不幸的是，这些药物产生了严重的不良反应，导致其开发提前终止。在未来，第三代 MMPIs 和信号通路及粘附分子抑制剂可能成为抗癌武器库中对抗转移的有价值的新型药物类别。
