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Etude de la toxicité cardiaque des médicaments anti-cancéreux

Abstract : Despite the development of new anti-cancer drugs such as anti-tyrosine kinases or anti-angiogenic therapy, cancer mortality remains high. These new molecules associated with advances in cancer surgery, radiotherapy and chemotherapy have succeeded in improving life expectancy in these patients. It has also allowed a long-term evaluation of the cardiovascular impact of these therapies. Many chemotherapy drugs, such as anthracyclines, lead to impaired cardiac function. The pathophysiological mechanisms of this cardiac dysfunction are complex, intricate and remain partially unknown. To reduce this cardiotoxicity, different pathways concerning administration modalities, drug presentation and the co-prescription of cardioprotective molecules are being explored. Better understanding of the mechanisms involved in this cardiotoxicity is necessary to prevent its onset. Furthermore the impact of cancer and cancer treatment on cardiovascular outcomes must be clarified in order to ensure appropriate follow-up in these patients. In the experimental part of our work, the objectives were to study plasma and tissue oxidative stress in the short and long term after anthracycline administration and also changes in myocardial gene expression induced by this therapy. At the same time, the potential cardioprotective effect of angiotensin converting enzyme inhibitors and alpha-lipoic acid was evaluated. Consistent with the literature, the administration of anthracyclines induced an increase in oxidative stress, in both the short and long-term after the end of the treatment. A disturbance in myocardial gene expression was found a long time after the end of the treatment, which explains why anthracycline cardiomyopathy may appear years after discontinuation of the chemotherapy. Neither angiotensin converting enzyme inhibitors nor alpha-lipoic acid was able to prevent the imbalance in cardiac oxidant / antioxidant species. Our work highlights the many facets and complexity of anthracycline cardiotoxicity and the need for new research to prevent it. As for the clinical part, among female patients hospitalized for myocardial infarction, we compared the management, the characteristics and the prognosis in patients with a history of breast cancer with those in patients without a history of breast cancer. Although our populations were comparable in terms of cardiovascular risk factors, type of infarction, revascularization technique and treatment administered during the acute phase, patients with a history of breast cancer seemed to have a worse cardiovascular prognosis following the myocardial infarction. A history of breast cancer appears to be an independent factor of rhythm-related and non-rhythm-related cardiovascular adverse events during this period. These new data should be confirmed by larger studies, but they already show that patients treated with anthracyclines need specific cardiovascular monitoring for both ischemic and rhythm-related adverse events.
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Carole Richard. Etude de la toxicité cardiaque des médicaments anti-cancéreux. Médecine humaine et pathologie. Université de Bourgogne, 2011. Français. ⟨NNT : 2011DIJOMU03⟩. ⟨tel-00938753⟩

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