Synergistic effect of celecoxib on 5-fluorouracil-induced apoptosis in hepatocellular carcinoma patients.
BACKGROUND
Cyclooxygenase-2 (COX-2) enzyme over expression is reported in many human HCC cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with HCC. COX-2 is often increased and involved in drug resistance and poor prognosis.


METHODS
Between January 2001 and December 2007, 15 patients with MDR-positive-HCC from 34 HCC patients based on tissue and serum liver of glypican-3 and fitting the preset eligibility criteria, were treated with a combination regimen with intravenous infusion of (5-FU) 750 mg once per week, 100mg/day cyclophosphamide (Endoxan) and 400 mg/day celecoxib taken orally in divided doses, while the rest of the patients received only 5-FU and Endoxan. Twenty-one patients (62%) had liver disease associated with hepatitis C virus (HCV) and 5 patients with hepatitis B virus (62%).


RESULTS
We found that celecoxib reduced P-glycoprotein with activation of caspase-3 and marked regression of tumor sizes. Sera angiogenic factors (VEGF & bFGF) levels measurement in HCC patients indicated that, the sera levels of both angiogenic factors were reduced significantly (p < 0.05) after treatment. Based on the tumor markers AFP & Glypican-3, 11 of the patients had a PR (11/15), including 3 patients who had normalization of AFP, and four patients had CR (4/15).


CONCLUSIONS
These data suggest that the combination of 5-FU, Endoxan and Celecoxib is highly effective palliative regimen for patients with HCC with good performance status (score ≤ 3). The study suggests a framework for Celecoxib-based combination treatment of HCC.
Department of Biochemistry, Alexandria University, Egypt. arbassiouny@yahoo.com
Ahmad R
AR
Bassiouny
Amira
A
Zaky
Hashem M
HM
Neenaa
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D053673:Glypicans / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D053673:Glypicans; D011720:Pyrazoles; D013449:Sulfonamides; D003520:Cyclophosphamide; D053148:Caspase 3; D000068579:Celecoxib; D005472:Fluorouracil