Treatment and survival study in the C57BL/6J-APC(Min)/+(Min) mouse with R-flurbiprofen.
Our previous studies with the mouse model of familial adenomatous polyposis (FAP), C57BL/6J-APC(Min)/+ or Min mouse, demonstrated the optimal dose for adenoma reduction with R-flurbiprofen was 10 mg/kg/day as an undivided dose. Divided doses exhibited no increased efficaciousness. This study examines 10 mg/kg R-flurbiprofen daily (qd) on survival as well as a second daily (q.o.d.) schedule and compares it with sulindac sulfone. The q.o.d. schedule at 10 mg/kg was equally efficacious as qd treatment at the same dose. For the q.o.d. group, tumor number decreased similarly (p<0.01); while body weight gain (p<0.01), hematocrit and average tumor area (both, p<0.05) were improved compared with qd treatment. Treatment with R-flurbiprofen (10 mg/kg/day) increased survival significantly (p=0.0004, log-rank) compared to vehicle treated animals. Major biological endpoints (hematocrit, weight gain, tumor number, average and total area [99% reduction]) were significantly improved in treated animals (p<0.01). Sulindac sulfone treatment (50 mg/kg/day) of the Min mouse produced no significant biological benefit. The dose schedule study suggests that for tumor reduction it is necessary to attain a threshold drug-level but not necessarily sustain it over 24 hrs (pharmacodynamic t1/2 >> pharmacokinetic t1/2). During the period of administration R-flurbiprofen dramatically prolongs survival for the mouse model of the human disease, FAP.
Wechter
W J
WJ
Loma Linda University Medical Center, Department of Medicine, California 92350, USA. chemendo@e2.empirenet.com
Murray
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Kantoci
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Quiggle
D D
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Leipold
D D
DD
Gibson
K M
KM
McCracken
J D
JD
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D000483:Alleles; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D005260:Female; D005480:Flurbiprofen / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013467:Sulindac / Q000627:therapeutic use; D016019:Survival Analysis; D014456:Ulcer / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013467:Sulindac; D005480:Flurbiprofen