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Abstract
To
determine the efficacy of a novel and safer (for gastrointestinal
tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the
growth-inhibitory effect of aspirin-PC vs. aspirin on 3 human (A2780,
SKOV3ip1, HeyA8), and a mouse (ID8) ovarian cancer cell line over an
8-day culture period. In the in vivo studies, the aspirin test drugs
were studied alone and in the presence of a VEGF-A inhibitor
(bevacizumab or B20), due to an emerging role for platelets in tumor
growth following anti-angiogenic therapy, and we examined their
underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in
blocking the growth of both human and mouse ovarian cancer cells in
monolayer culture. Using in vivo model systems of ovarian cancer, we
found that aspirin-PC significantly reduced ovarian cancer growth by
50-90% (depending on the ovarian cell line/density). The efficacy was
further enhanced in combination with Bevacizumab or B20. The
growth-inhibitory effect on ovarian tumor mass and number of tumor
nodules was evident, but less pronounced for aspirin and the VEGF
inhibitors alone. There was no detectable gastrointestinal toxicity.
Both aspirin and aspirin-PC also inhibited cell proliferation,
angiogenesis and increased apoptosis of ovarian cancer cells. In
conclusion, PC-associated aspirin markedly inhibits the growth of
ovarian cancer cells, which exceeds that of the parent drug, in both
cell culture and in mouse model systems. We also found that both
aspirin-PC and aspirin have robust anti-neoplastic action in the
presence of VEGF blocking drugs.
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