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.
Cisplatin is one of the most powerful drugs against many cancer types, but it has many damaging effects for patients, which may develop even tens of years after the cure of the original cancer. This includes incurable damages to kidneys, blood circulation, nervous system, and even development of new cancers. It would be very useful if one could identify the patients who are at a high risk of such potential late effects so that one could select an optimal and least harmful treatment for everybody. The aim is to find the genes that determine individual susceptibility to toxic effects. We have developed a method how to find these genes first in mice so one can search for similar genes in humans. In this application we propose to search for the genes influencing toxicity of cisplatin.