Bropirimine as neoadjuvant therapy decreases residual disease and expression of markers PCNA and TGF-beta 1 in a rat orthotopic prostate adenocarcinoma.
The role of bropirimine in prostate cancer remains unexplored. To address the efficacy of this immune modulator as neoadjuvant therapy we utilized the orthotopic placement of the Dunning AT-3 tumor. 2.4-2.6 x 10(6) Dunning AT-3 cells were injected into the ventral prostates of 50 Copenhagen X Fischer rats. Animals were then divided into 5 groups consisting of: 1) untreated controls; 2) those treated with ventral prostatectomy alone (performed 10-12 days following tumor cell inoculation); 3) those treated with ventral prostatectomy plus bropirimine (10 mg/kg) on postimplantation days 1, 3, 5, 10 and 11; 4) those treated with ventral prostatectomy plus bropirimine (100 mg/kg), at the same schedule; and 5) those treated with ventral prostatectomy plus bropirimine (500 mg/kg), at the same schedule. Animals were sacrificed 10 days after prostatectomy, autopsied, and residual disease was weighed. Prostate weights upon removal following neoadjuvant treatment and residual disease remaining after 20-22 days were expressed in grams (g). Following prostatectomy, mean prostate weights were: Group 2, 0.67 +/- 0.11; Group 3, 0.53 +/- 0.11; Group 4, 0.54 +/- 0.12; Group 5, 0.44 +/- 0.09. The effect of bropirimine was significant (p = 0.0001) by multiple regression analysis. In addition, mean residual tumor weights (expressed in grams) after 20-22 days were: Group 1, 12.7 +/- 1.9; Group 2, 6.7 +/- 4.8; Group 3, 5.2 +/- 5.9; Group 4, 3.8 +/- 3.5; and Group 5, 2.8 +/- 3.5. The effect of bropirimine was not significant (p = 0.07) by multiple regression analysis. However, prostatectomy alone, by Student's test, significantly (p = 0.04) reduced residual mean tumor weights by 47% and the additional effect of bropirimine upon residual disease was significant (p = 0.038) if a Chi-square analysis is applied. Finally, a multivariate analysis of the overall effect of bropirimine in rats treated with prostatectomy was significant (p = 0.002). The effect of bropirimine on expression of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta 1 (TGF-beta 1) was also evaluated immunohistochemically and expression of both tumor markers was significantly reduced (p < 0.05). We conclude that bropirimine may have a role as a neoadjuvant therapy when combined with prostatectomy.
Lievano
G
G
Hektoen Institute for Medical Research, Department of Urology, Rush Presbyterian St. Lukes Medical Center, Chicago, IL USA.
Di Domenico
D
D
Brown
J
J
Bridges
P
P
Rubenstein
M
M
Shaw
M
M
Guinan
P
P
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008297:Male; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000276:immunology; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D003596:Cytosine; C033560:bropirimine