Chemoprevention of OH-BBN-induced bladder cancer in mice by oltipraz, alone and in combination with 4-HPR and DFMO.
The chemopreventive efficacy of the schistosomicidal drug oltipraz (5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione) was evaluated against urinary bladder transitional cell carcinoma (TCC) induced in male C57BL/6 x DBA/2FI (BDF) mice by N-butyl-N(4-hydroxybutyl)nitrosamine (OH-BBN). Oltipraz was fed in the diet from one week prior to OH-BBN dosing until sacrifice, six months later. The agent at 250 mg/kg diet significantly reduced the incidence of TCC compared with that in carcinogen controls. Oltipraz also significantly reduced TCC incidence when fed at 500 mg/kg diet for 76 days, then at 125 mg/kg diet until the end of the test period. Treatment with this higher dose level of oltipraz also appeared to decreases the depth of tumor invasion. At lower dose levels of 100 and 200 mg/kg diet, oltipraz alone had no effect on tumor incidence. It also was tested at these dose levels in combinations with 2-difluoromethylornithine (DFMO) and with all-trans-N-(4-hydroxyphenyl)retinamide (4-HPR). Treatment with the combination of 640 mg DFMO/kg and 100 mg oltipraz/kg diet was efficacious, although DFMO alone at 640 mg/kg diet was inactive. The combination of 1280 mg DFMO/kg and 200 mg oltipraz/kg diet reduced TCC incidence significantly compared with carcinogen controls, but the effect was no greater than that of DFMO alone at 1280 mg/kg, and weight gain was suppressed compared with carcinogen controls. The depth of tumor invasion was decreased with this combination treatment. Combinations of oltipraz at 100 and 200 mg/kg diet, 4-HPR at 156 and 313 mg/kg diet, and DFMO at 640 and 1280 mg/kg diet were efficacious and without apparent toxicity. Nonetheless, the three agent combinations cannot be considered more effective than DFMO alone at 1280 mg/kg diet or the lower dose combination of oltipraz and DFMO.
Moon
R C
RC
IIT Research Institute, Chicago, IL 60616.
Kelloff
G J
GJ
Detrisac
C J
CJ
Steele
V E
VE
Thomas
C F
CF
Sigman
C C
CC
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002085:Butylhydroxybutylnitrosamine; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000518:Eflornithine / Q000008:administration & dosage; D017313:Fenretinide / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D013871:Thiones; D013876:Thiophenes; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000517:prevention & control*
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D017313:Fenretinide; D002085:Butylhydroxybutylnitrosamine; C026209:oltipraz; D000518:Eflornithine