| 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.
METHODS
To answer to the proposed questions and find new early cardiac biomarkers, 7 tasks are planned (4 in vitro and the last 3 in vivo) with a broad team and multidisciplinary techniques.
T  |
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.
METHODS
To answer to the proposed questions and find new early cardiac biomarkers, 7 tasks are planned (4 in vitro and the last 3 in vivo) with a broad team and multidisciplinary techniques.
TASK 1- Synthesis and purification of main metabolites of MTX, DOX, and CTX.
TASK 2- Identification of major metabolites of MTX, DOX, and CTX after incubation with human hepatic microsomal and S9 fractions, using HPLCUV,
GCMS, and LCMS methods. Mice cardiac pooled S9 fractions will also be used.
TASK 3- Human cardiomyocytes will be incubated with MTX, DOX, and CTX. Cytotoxicity and aging will be evaluated, specially focusing on proteomic, mitochondria, autophagy markers, proteasome and βgalactosidase activity data.
TASK 4- Human cardiomyocytes will be exposed to the extracts obtained after MTX, DOX, and CTX metabolism (TASK 2) or to the main metabolites synthetized on TASK 1.
TASK 5- In vivo evaluation of the metabolic profile and aging biomarkers after administration of human clinically relevant doses of MTX, DOX, and CTX to adult CD1 mice. Early and late cardiotoxicity will be evaluated.
TASK 6- In vivo enzymatic induction and inhibition to study the correlation between cardiotoxicity and the plasma/cardiac levels of the parent drug or their metabolites. Adult CD1 mice will be pretreated with cytochrome P450 inducers or inhibitors.
TASK 7- Explore the cardiotoxicity of DOX, MTX, and CTX in different aged mice, focusing on the different drug metabolism profile and aging markers. Infant (2 weeks) and elderly mice (15 months) will be compared to adult mice (3 months).
TEAM
The team joins 4 research centres, a total of 8 researchers and 2 consultants, and most of them have already worked together.
The 3 centres based on University of Porto:1)UCIBIOToxicology Laboratory (UCIBIO/TOX) of the Faculty of Ph |