Stem cell-derived cardiomyocytes for detection of cardiotoxicity in cancer therapeutics

近年来，癌症治疗方法有了很大的改进，但不幸的是，它可能会造成心脏损伤。在一些癌症临床试验中，超过四分之一的患者受到影响，心脏问题是增加化疗剂量的常见障碍。考虑到癌症治疗旨在破坏快速生长的干细胞样细胞，而新的心脏疗法正在鼓励干细胞介导的修复，这是可以理解的。一个特别的问题是，癌症治疗往往是给老年人部分的人口可能有潜在的心脏病。由于多种原因，目前的动物模型并不总是预测心脏效应。首先，许多新的癌症治疗方法，如单克隆抗体，通常对人体组织具有特异性，在动物身上可能看不到副作用。第二，许多问题只有在长期治疗后才会产生影响，或者当存在潜在的心脏损伤时，由于对动物的压力严重，很难在动物中建立模型。第三，当使用药物组合时，心脏损伤通常更严重，并且在动物筛选中重现所有组合是困难和昂贵的。我们已经开发了单心脏细胞测定，使用从人类胚胎干细胞系或从成人皮肤制成的类似干细胞生长的跳动细胞。这些可以模拟被认为是化疗心脏毒性作用基础的许多方面，因为它们的人类起源和快速生长的性质，以及它们对抗肿瘤药物靶向的途径的依赖。我们已经开发了使用这些细胞的检测方法，并找到了同时测试大量抗肿瘤化合物的方法。同样，它们可以用来测试大量潜在的保护剂，以抵消毒性作用。我们将首先筛选已知的心脏毒性和非心脏毒性药物。最后，我们与？干细胞用于更安全的药物？，这是一个工业界、政府和学术界之间的非盈利性合作，将允许对通过动物筛选但随后被证明对人体有害的化合物进行测试。我们与该联盟的互动为这些检测方法的未来商业化提供了一条道路。除了减少这一领域的基础科学实验的数量外，我们的工作还有可能大大减少工业中使用的动物实验的数量和严重程度。

Cancer therapies have improved greatly over recent years, but unfortunately can produce cardiac damage. More than a quarter of patients in some cancer clinical trials have been affected, and heart problems are a frequent barrier to increased dose of chemotherapy. This is understandable when considering that cancer therapies aim to destroy fast growing stem-like cells, while new cardiac therapies are encouraging stem cell-mediated repair. A particular problem is that cancer therapies are often given to aging sections of the population likely to have underlying cardiac disease. Current animal models do not always predict the cardiac effects for a number of reasons. First, many new cancer therapies such as monoclonal antibodies are often specific for human tissue and side-effects may not be seen in animals. Second, many problems only have effects after prolonged treatment, or when there is underlying cardiac damage, which is hard to model in animals because of the severity of the stress to the animal. Third, cardiac damage is often worse when combinations of agents are used, and it is difficult and expensive to reproduce all the combinations in the animal screens. We have developed single cardiac cell assays, using beating cells grown from human embryonic stem cell lines or similar stem cells made from adult human skin. These can model many aspects thought to underlie the cardiotoxic effect of chemotherapy because of their human origin and fast-growing nature, and their reliance on the kind of pathways that are targeted by anti-tumour agents. We have developed assays using these cells, and have found ways to test large numbers of anti-tumour compounds simultaneously. Equally, they can be used to test large numbers of potentially protective agents to offset the toxic effects. We will initially screen known cardiotoxic and non-cardiotoxic agents. Finally, our links with ?Stem Cells for Safer Medicines?, a not-for profit collaboration between industry, government and academics, will allow the testing of compounds which passed animal screens but which subsequently proved to be dangerous in man. Our interaction with this consortium gives a path for future commercial introduction of these assays. In addition to reducing the number of basic scientific experiments in this area, our work has the potential to decrease enormously the number and severity of animal experiments used in industry.