to the nucleus (Kiyomiya, et al., 2001). The doxorubicin molecule has higher affinity to nuclear DNA
than to proteasomes, allowing it to dissociate to the genetic material. The intercalation into DNA and
inhibition of Topoisomerase II directly stop the DNA replication process, and hence stops cell
division in interphase. The generation of free radicals causes damage to macromolecules, including
DNA (Tacar, et al., 2013)
Trastuzumab is a humanised monoclonal antibody specific to the extracellular portion of HER-2 and
has been known to prolong the lifespan of patients with metastastic breast cancer and to reduce the
risk of death by 33% (Romond, et al., 2005) Although the mechanisms underlying trastuzumab's
mode of action on cancer cells is not well known, several proposed concepts have shown to be well
corroborated (Valabrega, et al., 2007). Trastuzumab is known to stop the proteolytic cleavage in
HER-2 that occurs when it is overexpressed, which will lead to the cleaved portion entering the serum.
According to Molina et al, the decrease of serum HER-2 fragments is consistent to an increased
progression free survival which implies that the prevention of this cleavage might be the mode of
action of trastuzumab (Molina, et al., 2001). Overexpression of HER2 in breast cancer is frequently
associated with increased angiogenesis. One study done on mice treated with trastuzumab showed a
more controlled angiogenesis in an experimental human HER-2 overexpressing breast tumor model,
indicating another possible mechanism of trastuzumab (Valabrega, et al., 2007)
Doxorubicin and trastuzumab are breast cancer treatments often associated with systemic side effects,
especially cardiotoxicity.
As reported in a study by Cardinale, et al., about 34% patients undergoing treatment with trastuzumab
encountered cardiotoxicity complications (Cardinale, et al., 2010) Another study yielded that the risk
of occurence of cardiotoxicity is 4% in treatment with trastuzumab alone and 27% in combination
with anthracycline and cyclophosphamide. The pathogenesis of transtuzumab induced cardiotoxicity
is still under investigation (Keefe, 2002). Other side effects associated with the administration of
trastuzumab include asthenia, fever, pain and nausea (Vogel, et al., 2002)
As for doxorubicin, administration of free form doxorubicin is not well targeted, and hence has
systemic effects like nausea, alopecia, gastrointestinal problems, and neurological problems such as
hallucinations. However the most dangerous outcome of doxorubicin, as mentioned above, is its
associated cardiomyopathy (Tacar, et al., 2013). The incidence of cardiomyopathy with doxorubicin is
dose dependent, but it is approximately 11% in general. The prognosis in patients with doxorubicin
cardiomyopathy is poor, with a mortality rate of about 50% in one year. Proposed mechanisms for
cardiomyopathy include generation of free radicals, down regulations of genes coding for contractile
proteins, and apoptosis of cardiomyocytes (Chatterjee, et al., 2010)
If both trastuzumab and doxorubicin are used together, they can be lethal, as they are both known to
cause cardiomyopathy. Neuregulins are a group of growth factors that can induce cardiomyocyte