Pancreatic cancer is an aggressive disease with an extremely poor prognosis. It is the forth
leading cause of cancer-related fatalities, with an estimated one-year and five-year survival
rate of 21% and 5%, respectively. Despite recent progress, the median survival time is 6-10
months for patients with locally advanced disease and 3-6 months for metastatic disease (1).
The anti-metabolite gemcitabine has become the standard chemotherapy for locally advanced and
metastatic pancreatic cancer, after demonstrating an improved rate of clinical benefit
response and an overall survival advantage over 5-FU (2). In addition to its clinical
effectiveness gemcitabine has a manageable toxicity profile, making it an attractive agent to
investigate in combination with newer agents. Series of phase III trials were conducted
examining the efficacy of the combination of gemcitabine and a second cytotoxic agent,
including 5-FU, cisplatin, oxaliplatin and irinotecan. These gemcitabine doublets
demonstrated no survival advantage over single-agent gemcitabine (3-6). However, the
rationale for continuing to study gemcitabine-based combinations remains compelling.
Curcumin (diferuloylmethane) is a natural compound derived from the rhizome of Curcuma Longa,
an East Indian plant, commonly called turmeric. It has been shown to possess potent
anti-inflammatory and anti-oxidative properties, for which it has a long history of dietary
use as a food additive. Curcumin has also a potent anti-proliferative effects against a
variety of cancer cell lines in vitro, which stem from its ability to modulate many
intracellular signal transduction pathways (7). Human phase I-II studies found curcumin to be
safe, and indicated no dose-limiting toxicity when taken by mouth at doses up to 10 g/day (8,
9). This data, together with the dismal therapeutic options available for pancreatic cancer
patients, suggest that curcumin warrants investigation in this setting. Investigators from MD
Anderson Cancer Center and Rambam Medical Center in Haifa, have recently initiated,
separately, a phase II study of single agent Curcumin in patients with pancreatic cancer
(10).
One of the lessons learned from cancer research in recent decades is that combination
strategies can provide dramatic improvement in a therapy's safety and efficacy over
mono-therapeutic regiments, especially if the combined drugs differ in their mode of action.
In a recent paper that was accepted for publication we demonstrated, in vitro, the mechanism,
clinical importance and implications of a novel combinatorial therapy, of celecoxib and
curcumin, that was discovered in our lab, in inhibiting the growth of several pancreatic cell
lines. P-34 (expressing high levels of COX -2), MiaPaca (Expressing low levels of COX-2) and
Panc-1 (no expression of COX -2) cell lines were exposed to different concentrations of
celecoxib (0-40µM), curcumin (0-20µM) and their combination. In P-34 cells, curcumin
synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth
inhibition was associated with inhibition of proliferation and induction of apoptosis.
These experiments further demonstrate, for the first time, that the combination effect is
correlated with synergistic augmentation of apoptosis and involves down-regulation of COX-2
protein.
The present study evaluates gemcitabine in combination with curcumin and celecoxib for
patients with pancreatic cancer.
Jun 30,2005
All
18 Years
N/A
18 Years
N/A