E-7869 (R-flurbiprofen) inhibits progression of prostate cancer in the TRAMP mouse.
E-7869 (R-flurbiprofen) is a single enantiomer of a racemic nonsteroidal anti-inflammatory drug. E-7869 does not inhibit either cyclooxygenase-1 or cyclooxygenase-2. We used the transgenic adenocarcinoma mouse prostate (TRAMP) mouse, a prostate cancer model, to evaluate the effect of this drug on prostate cancer progression. Sixty 12-week-old male TRAMP mice were placed randomly into five groups. The animals were treated by daily oral gavage with vehicle (1% carboxymethylcellulose) or E-7869 for 18-weeks. During the course of the study, two diets were used. Three groups (vehicle, 15-mg/kg, and 20-mg/kg drug treatments) received a Teklad diet containing 2.4% saturated fat [a high saturated fat (HSF) diet], and two groups (vehicle and 20 mg/kg drug treatment) received an AIN-93G diet containing 1.05% saturated fat [a low saturated fat (LSF) diet]. At necropsy, the urogenital system and periaortic lymph nodes were removed and weighed. The prostate lobes, seminal vesicles, lungs, and periaortic lymph nodes were preserved and sectioned for histological evaluation. The lung and periaortic lymph nodes were graded as to the presence (+) or absence (-) of metastasis; the urogenital tissues were graded on a 1-6 scale for degree of neoplasia/carcinoma. For both diets, the urogenital wet weights and lymph node wet weights in the 20-mg/kg treatment groups were significantly lower as compared to vehicle control groups. In addition, treatment with 20 mg/kg E-7869 in the LSF diet group resulted in a significantly lower primary tumor incidence (P < 0.05) and reduced incidence of metastasis. In this treatment group, the reduced incidence of metastasis was not statistically significant because the LSF diet itself resulted in a remarkably lower incidence of metastasis in the vehicle control group (10% LSF versus 40% HSF). Treatment with 20 mg/kg E-7869 on the HSF diet resulted in a significantly lower incidence of metastasis (P < 0.05) and a reduction in the primary tumor incidence. These results suggest that E-7869 is a promising chemopreventive and treatment for human prostate cancer.
Wechter
W J
WJ
Encore Pharmaceutical Inc, Laboratory of Chemical Endocrinology, Loma Linda University, California 92350, USA. WWechter@compuserve.com
Leipold
D D
DD
Murray
E D
ED
Quiggle
D
D
McCracken
J D
JD
Barrios
R S
RS
Greenberg
N M
NM
D000230:Adenocarcinoma / Q000178:diet therapy / Q000188:drug therapy* / Q000517:prevention & control / Q000556:secondary; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005480:Flurbiprofen / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006400:Hematocrit; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000178:diet therapy / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D013237:Stereoisomerism; D014566:Urogenital System / Q000187:drug effects / Q000473:pathology
D004041:Dietary Fats; D005480:Flurbiprofen