الفهرس 
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Abstract
Breast cancer is often considered as one of the most chemosensitive solid tumors,
yet most initially responsive tumors relapse and develop resistance to a broad spectrum of
drugs known as Multidrug resistance (MDR). Consequently, metastatic breast cancer
finally becomes refractory to cytotoxic drugs and is typically incurable by chemotherapy.
Multidrug resistance (MDR) is a major factor limiting the effectiveness of cancer
chemotherapy. A number of different mechanisms can mediate the development of MDR,
including increased drug efflux from the cell by adenosine triphosphate (ATP)-dependent
transporters, increased drug detoxification, changes in drug effectiveness are also
documented, and the often-observed pleiotropic resistance of MDR cells to the apoptosis
inducing agents.
Among the cellular mechanisms proposed to mediate MDR, is the overexpression
of a family of plasma membrane efflux transporters, namely ATP-binding cassette (ABC)
transporters. It is believed that overexpression of these ABC transporters, such as Pglycoprotein
(P-gp), in cancer cells limits intracellular accumulation of cytotoxic agents,
necessary for efficient cell killing through the active extrusion of the cytotoxic agents by
these ATP-dependent transporters.
P-gp is a 170-kDa membrane glycoprotein, encoded by the MDR-1 gene.
Physiologically, P-gp functions as a xenobiotic pump in the intestine, liver, kidney, and
placenta as well as in the blood brain and blood testes barriers. It is a transporter protein
that extrudes a broad range of structurally diverse compounds out of the cell protecting the
organism from cytotoxic agents in the environment and diet. P-gp can also significantly
undermine the efficacy of cancer chemotherapy because many of the therapeutic drugs are
also substrates of P-gp. A previous study has shown P-gp expression to be predictive of
poor response to chemotherapy and decreased overall survival. The anticancer drugs most
effectively extruded from tumor cells by P-gp are doxorubicin, daunorubicin, and
methotrexate.
In drug resistance, the hypothesis is that if P-gp-mediated extrusion of these
anticancer drugs is inhibited, then the chemosensitivity to these drugs may be increased.
Considerable efforts have been expended on finding chemo sensitizers that will inhibit the
function of P-gp and thereby reverse multidrug resistance. A number of noncytotoxic drugs
have been demonstrated to reverse the P-glycoprotein mediated resistance, including
quinolines (chloroquine, quinine and primaquine). Chloroquine is known to reverses drug
resistance through decreasing cytotoxic drug binding to p-gp.
The aim of the current study is to Estimate the prognostic significance of Pglycoprotein
in breast cancer patients through correlateting its expression to the Disease
free survival (DFS) and Overall survival (OS) of the patients , Determine if the addition of
Chloroquine to chemotherapy regimen could improve the DFS and OS of the patients and
Monitor Chloroquine effect on doxorubicin plasma clearance in blood samples of patients.
SUMMARY
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The study included 40 females recently diagnosed breast cancer distributed into
two groups;20 patients in the control group receiving the stander chemotherapy regimen
consisting of 6 cycles of either FAC and 20 patients in the cholroquine group receiving the
stander chemotherapy regimen plus a daily dose of 150 mg chloroquine beginning 5 days
before chemotherapy till end of chemotherapy cycles. Tissue samples (from tumor mass
and normal breast tissue) were taken for determination of P-gp expression. Blood samples
were taken from both groups at third chemotherapy cycle for determination of doxorubicin
concentration and Patients were followed up for 2 years to assess time to relapse.
This study showed a statically significant correlation between P-gp expression and
failure of chemotherapy. In addition, patients with P-gp expressing tumor have trible risk
to relapse compared with patients with P-gp negative expressing tumor after 2 years
follow-up. There was no significant difference between survival curves in presence and
abscense of choloquine. This study found a possible implication of the P-gp gene in
resistance and outcome. The current study shows that P-gp expression is significally
associated with poor survival of breast cancer patient enrolled in this study. While using
of chlorquine as modulator to P-gp did not improve the survival of patients with P-gp
positive tumors.