R-flurbiprofen chemoprevention and treatment of intestinal adenomas in the APC(Min)/+ mouse model: implications for prophylaxis and treatment of colon cancer.
We used the C57BL/6J-APC(Min)/+ mouse (Min mouse) to evaluate the chemopreventive effects of R-flurbiprofen (R-FB), the noncyclooxygenase-inhibiting enantiomer of FB. Weanling Min mice were administered 6 weeks of oral treatment with R-FB using 2.5-25 mg/kg of R-FB once per day (q.d.), 2.5-10 mg/kg of R-FB twice per day (b.i.d.), and 5 mg/kg of R-FB b.i.d. challenged with a high saturated fat diet. At necropsy we determined tumor and ulcer numbers, tumor size, and plasma levels of R- and S-FB. A linear dose response was observed from 2.5 to 10 mg/kg of R-FB, regardless of whether the drug was administered as a single or divided dose. Reductions in tumor number were significant (P < or = 0.02) for doses of R-FB from 2.5 to 25 mg/kg/day. A dose of 5 mg/kg R-FB b.i.d. was able to overcome the doubling in tumor number associated with the high saturated fat diet. At 20 and 25 mg/kg/day R-FB, we obtained the maximum response with up to 90% inhibition of total tumor number. At these doses, however, there was toxicity and animal deaths. This toxicity was associated with ulceration, presumably resulting from the in vivo epimerization of R- to S-FB that occurs in the mouse. Thus, we evaluated the oral pharmacokinetics of R-FB and its conversion to S-FB in wild-type mice. These kinetics experiments revealed inversion rates of 7.3 and 11.0% for the 2.5 and 10 mg/kg R-FB doses, respectively. S-FB administered alone (0.5 and 2.0 mg/kg q.d.), in doses mimicking the concentrations of S-FB associated with the R to S epimerization of the doses of R-FB used in our experiments, had little or no antitumor efficacy (P > 0.05). Thus, we conclude that R-FB itself, not the S-FB resulting from epimerization in the mouse, inhibits adenoma formation in the Min mouse. In humans, where there is no R to S epimerization, it is possible that larger doses of R-FB can be used without causing cyclooxygenase inhibition and its resulting ulcerogenicity and other side effects. To assess the effect of R-FB on established adenomas, we allowed 40 Min mice to remain untreated until 70 days of age (the time of necropsy in the previous experiments) and then treated them for an additional 42 days with 10 mg/kg R-FB q.d. or 5 mg/kg R-FB b.i.d.. Both drug-treated groups demonstrated tumor numbers significantly less than that of the vehicle control (P < 0.01). Our results suggest that prophylaxis and treatment trials of R-FB should be extended to humans.
Wechter
W J
WJ
Laboratory of Chemical Endocrinology, Loma Linda University School of Medicine, California 92350, USA.
Kantoci
D
D
Murray
E D
ED
Quiggle
D D
DD
Leipold
D D
DD
Gibson
K M
KM
McCracken
J D
JD
D000236:Adenoma / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D011125:Adenomatous Polyposis Coli / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D016588:Anticarcinogenic Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001835:Body Weight; D002455:Cell Division / Q000187:drug effects; D018890:Chemoprevention; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005480:Flurbiprofen / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D017491:Genes, APC; D006579:Heterozygote; D007410:Intestinal Diseases / Q000139:chemically induced; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015394:Molecular Structure; D014456:Ulcer / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D004041:Dietary Fats; D005480:Flurbiprofen