Genetic components of adverse effects of cisplatin therapy

描述（由申请人提供）：我们将确定目前完全未知的遗传学在顺铂化疗不良后果中的作用的重要性。顺铂和其他铂类药物是目前世界上最常用的细胞毒性抗癌药物之一。然而，这些药物也具有急性副作用（例如骨髓抑制伴随后的发热性中性粒细胞减少症等），其可能需要减少剂量并因此损害治疗的成功，以及慢性和迟发性作用，其在治疗结束后持续或出现许多年，并且包括对各种器官（肾、心脏、血管和神经系统）的损害和频繁出现新的癌症。这些慢性和晚期影响降低了生活质量，缩短了癌症幸存者的寿命。随着大量癌症幸存者的预防，检测和治疗这些癌症治疗的负面后遗症正在成为肿瘤学的主要任务。事实上，癌症幸存者中出现的第二种癌症已经代表了美国最大的新癌症群体之一。没有明确的原因是已知的幸存者的个人倾向的各种形式的负面影响的治疗和没有信息的作用遗传学的主机。鉴于人类遗传学对包括许多癌症在内的大多数常见疾病发生的影响，我们将在小鼠模型中确定遗传学对顺铂不良反应影响的三个主要特征：顺铂毒性的品系间遗传变异的范围和程度，对肾脏和心血管系统损害的不同症状和途径的遗传控制的分离或同一性，顺铂诱发肿瘤的发生频率和组织分布的遗传学。这将包括组织病理学分析和基本的实验室测量和“原理证明”测试，以确定导致遗传变异的一个或多个基因的染色体连锁。如果是阳性的，这些结果将为更全面的遗传分析开辟道路，最终确定可以接受特定预防和早期检测的高危人群。 在乎发现负责顺铂治疗的负面影响的基因也将揭示其药理学预防和治疗的新的潜在靶点。

DESCRIPTION (provided by applicant): We will determine the significance of the presently completely unknown role of genetics in adverse consequences of cisplatin chemotherapy. Cisplatin and other platinating drugs are now one of the most commonly used cytotoxic anti-cancer drugs worldwide. However, these drugs have also acute adverse effects (such as myelosuppression with ensuing febrile neutropenia, and others) that can require reduction of dose and thus compromise the success of treatment, as well as chronic and late effects that persist or appear many years after end of treatment and include damage to various organs kidney, heart, blood vessels, and nervous system) and frequent appearance of novel cancers. These chronic and late effects lower quality of life and shorten the lifespan of cancer survivors. With large numbers of cancer survivors the prevention, detection, and treatment of these negative sequelae of cancer treatment are becoming a major task in oncology. In fact, the second cancers arising in cancer survivors represent already one of the largest groups of new cancers in the USA. Nothing definite is known about the causes of individual propensity of survivors to various forms of the negative effects of treatment and there is no information on the role of genetics of the host. In view of the influence of genetics in humans on occurrence of most common diseases including many cancers, we will determine in a mouse model three principal characteristics of genetic influence on cisplatin adverse effects: extent and degree of inter-strain genetic variation of cisplatin toxicity, separateness or identity of genetic control o different symptoms and pathways of damage to kidney and cardiovascular system, and the genetics of frequency and tissue distribution of cisplatin induced tumors. This will include the histopathological analysis and basic laboratory measurements and a "proof of principle" test to define chromosomal linkage of one or more genes contributing to the genetic variation. If positive, these results will open way to a more comprehensive genetic analysis that would eventually identify high risk individuals who could receive specific prevention and early detection care. Discovery of genes responsible for the negative effects of cisplatin treatment would also reveal new potential targets for their pharmacological prevention and treatment.