| Summary: |
Anticancer therapy should be considered a cardiovascular risk. The number of cancer survivors is hugely increasing, as well as
chemotherapyrelated
long term cardiotoxicity, namely heart failure (HF)[1]. HF strongly impacts on the life of quality and lifeexpectancy
and is a heavy burden to health care systems. The prosecution of early cardioprotective therapy is critical for
patient care. Available biomarkers are poor predictors of early cardiotoxicity or very challenging and costly[1]. Anthracyclines
[e.g. doxorubicin (DOX)], cyclophosphamide (CTX), and mitoxantrone (MTX) are first hand clinical weapons on cancer (MTX and
CTX also have other clinical uses). They are major causes of chemotherapyrelated
HF and cardiotoxicity[2], which can reach up
to 30% of patients [1](Table 1).
The cardiotoxicity mechanisms of anticancer drugs are largely unknown, and a link between cardiotoxicity and drug metabolism
has not been yet stablished for most drugs[3]. The metabolites of DOX and CTX may be involved in their cardiotoxicity [46].
In
an exploratory FCTfunded
project (EXPL/DTPFTO/
0290/2012), we showed that MTXmetabolism
increased the drug's
cytotoxicity[7]. Moreover, aging and HF share some characteristics[8]. Within that project, we showed that MTX increased
markers of cardiac aging, namely impaired proteasome activity, increased protein carbonylation and fibrosis[9, 10].
AIMS
We aim to answer to the following questions:
IS ANTICANCER DRUG METABOLISM A CRUCIAL FACTOR FOR THE DEVELOPMENT OF CARDIOTOXICITY? ARE ANTICANCER
DRUGS PROMOTORS OF CARDIAC AGING?
Drug metabolism profile and cardiac aging markers can be very valuable candidates for early detection of cardiotoxicity,
allowing early clinical intervention and therefore increasing patient's quality of life. |