Effects of anthracycline

INTRODUCTION

Direct effects of anthracyclines on sarcomere protein stability also contribute to the

disruption of sarcomere maintenance, and thus to myocardial dysfunction. Titin is a large
myofilament protein important for modulation of sarcomere restoration and passive elastic
forces. Titin is degraded early after anthracycline exposure via a calpain-dependent mechanism.
This response predisposes isolated cardiac myocytes to necrotic cell death. Independent of
anthracyclines, it is established that titin disruption leads to the development of a
cardiomyopathy. Thus the disruption of sarcomere proteins and the suppression of sarcomere
synthesis probably contribute to the cardiac sarcopenia observed clinically after anthracycline
exposure.

BASICALLY, Trastuzumab is approved for use as either a single agent or in combination with
paclitaxel in patients with metastatic breast cancers that over-express the HER2 protein. The
reported incidence of congestive heart failure with single-agent trastuzumab is 7% and rises to
11% when trastuzumab is combined with paclitaxel. The highest incidence (28%) was noted
when trastuzumab was given with an anthracycline. In the randomized phase III study of
trastuzumab in combination with chemotherapy (doxorubicin plus cyclophosphamide or with
paclitaxel), the incidence of cardiac dysfunction was 28% in patients receiving trastuzumab plus
doxorubicin plus cyclophosphamide versus 7% for doxorubicin/cyclophosphamide alone and
11% in those receiving trastuzumab plus paclitaxel versus 1% for paclitaxel alone. The incidence
of classes III and IV (New York Heart Association Classification) cardiac failure was 19% for
trastuzumab/doxorubicin/cyclophosphamide versus 3% for doxorubicin/cyclophosphamide and
4% for trastuzumab/paclitaxel versus 1% for paclitaxel alone.