Tossicità cardiaca da farmaci chemioterapici di vecchia e nuova generazione

Cardiovascular diseases and cancer respectively represent the first and second cause of death in industrialized countries. These two conditions may become synergistic if we consider the cardiovascular complications of anti-cancer therapy. During the past three decades, the development of effective screening and treatment strategies for many cancers has resulted in an enormous population of long-term cancer survivors. For this reason it’s currently an important emerging concept to focus our attention to the life quality of cancer survivors. For all these reasons in the last years a recognition of the importance of cardiotoxic side effects has increased. Anthracyclines are among the most commonly used chemotherapeutic agents. Drugs such as doxorubicin and epirubicin are effective in the treatment of both solid tumours such as breast and ovarian cancers, and haematological malignancies such as lymphoma and leukaemia. Their cardiotoxic effects are well known. The action of anthracyclines is aspecific and affect cancer cell as healthy cells. Recently, the advent of target therapy has vastly improved the treatment and prognosis of multiple types of cancer. The goal of these agents is to improve specificity in the elimination of tumor cells while minimizing toxicity on healthy cells. Despite this goal, unexpected cardiotoxicity has arisen for many target compounds. For example Imatinib mesilate, a bcr-abl, PDGF, SCF and c-kit inhibitor, used for the treatment of chronic myelogenous leukemia, is associated with left ventricular dysfunction and severe congestive heart failure in patients. By providing detailed information on drug-related cardiovascular complications and new insights on the pathogenetic mechanisms of cardiotoxicity of antineoplastic therapy, an attempt was made to open innovative prospectives to impact on an emerging relevant clinical issue. The recently introduced, although timely known, concept that the heart is not a post mitotic organ and contains a stem cell pool responsible for myocardial cell turnover may offer a new way in understanding cardiotoxicity. Specifically, beyond cardiomyocytes or parenchymal cells, an alternative cellular target of anticancer therapy is proposed to explain a major clinical problem in oncology. The demonstration that the adult mammalian heart possesses a cell turnover regulated by primitive cells suggests that this cell population may be implicated in the onset and development of cardiovascular effects of anti-cancer strategies. Thus, our hypothesis is that a potential mechanism of doxorubicin- and kinase inhibitor-mediated toxicity could be the ablation or suppression of the proliferation of the stem/progenitor cell compartment of the heart. Given the limited ability of adult cardiomyocytes to reenter the cell cycle and proliferate, and the acute nature of cardiac injury, intrinsic mechanisms to repair the heart are not robust. Although these cardiac stem/progenitor cell populations are relatively quiescent, stress can induce these cells to generate significant numbers of new cardiomyocytes. The physiological significance of the replication of small subsets of progenitor cells is still under debate, but it is possible that these cell populations are collateral targets of some of the small molecule kinase inhibitor anticancer agents. In fact, adverse effects of cancer therapeutics on stem and progenitor cells may be exacerbated by kinase inhibitor-mediated effects on energy metabolism in the adult cardiomyocyte, as noted above for sunitinib. For example, treatment of juvenile mice with the anthracycline doxorubicin impairs cardiac progenitor cell function and vascularization, leading to cardiotoxicity as the mice age. This is similar to the effect observed in children treated with doxorubicin who developed heart failure later in life. Experimentally, infusion of cardiac stem cells can rescue rats from the cardiotoxicity of doxorubicin, leading the authors of the study to hypothesize that cardiac stem cells are a key target of doxorubicin- induced cardiotoxicity. In other studies, inhibition in mice of KIT the receptor for stem cell factor, resulted in enhanced cardiomyocyte proliferation and better-preserved left ventricular function when the mice were subjected to pressure overload. Although beneficial in the short term, chronic inhibition of KIT in this model raised concerns about long-term maintenance of the progenitor pool in the heart. Although the biological significance of these findings in humans is not known, concerns regarding the effects of kinase inhibitors on stem and progenitor cells or on immature cardiomyocytes that are capable entering the cell cycle should continue to be an active area of research. With this intention analyses on human heart sample, on sperimental model and on in vitro cells have been performed, in order to evaluate if these drugs affect the stem cell compartment.