title: Bropirimine as neoadjuvant therapy decreases residual disease and expression of markers PCNA and TGF-beta 1 in a rat orthotopic prostate adenocarcinoma.
abstract: 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.
authors.affiliation: Hektoen Institute for Medical Research, Department of Urology, Rush Presbyterian St. Lukes Medical Center, Chicago, IL USA.
authors.forename: G
authors.initials: G
authors.lastname: Lievano
authors.forename: D
authors.initials: D
authors.lastname: Di Domenico
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.forename: P
authors.initials: P
authors.lastname: Bridges
authors.forename: M
authors.initials: M
authors.lastname: Rubenstein
authors.forename: M
authors.initials: M
authors.lastname: Shaw
authors.forename: P
authors.initials: P
authors.lastname: Guinan
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D003596:Cytosine; C033560:bropirimine