Effect of PSC 833, an inhibitor of P-glycoprotein, on 1,2-dimethylhydrazine-induced liver carcinogenesis in rats.
The present study explores the hypothesis that over-expression of P-glycoprotein (Pgp, product of mdr1) is intimately associated with liver cancer development and therefore inhibitors of Pgp should inhibit the development of liver cancer. Accordingly, we determined the effect of PSC833 (PSC), a potent inhibitor of Pgp, on experimental liver carcinogenesis in rats. To study the effects of PSC on liver cancer development, a daily dose of 30 mg PSC/kg body wt (PSC30) was chosen based on an initial dose-response experiment. Accordingly in experiment 1, PSC30 was fed to rats initiated by 1,2-dimethylhydrazine coupled with two-thirds partial hepatectomy and promoted for 22 weeks with 1% dietary orotic acid. Surprisingly, in contrast to our earlier observations in rats without hepatic nodules, in rats bearing hepatic nodules, PSC30 was found to be toxic. Because of this, PSC30 diet was discontinued after 5 weeks and the rats were transferred to basal diet (BD). The rats were killed 10 and 25 weeks thereafter. Cumulative results indicate that PSC30 exhibited a 40% decrease in the incidence of hepatocellular carcinoma (HCC; 15 of 18 in the BD group compared with eight of 17 in the PSC30 group; P = 0.08) coupled with significant reduction of tumor multiplicity (54%; P < 0.05) and tumor burden (61%; P < 0.005) compared with controls. In experiment 2, 15 mg PSC/kg body wt (PSC15) was fed for 20 weeks to rats similarly initiated and promoted for 35 weeks. PSC15 inhibited the incidence of HCC by 75% (four of four in the BD group compared to one of four in the PSC30 group; P = 0.15) and significantly reduced tumor burden by 55% (P < 0.05). The lack of statistical significance of inhibition on tumor incidence reflects the small sample size. Taken together the results indicate a possible intrinsic role for Pgp in liver cancer development and introduce another promising unexplored therapeutic approach in liver cancer treatment.
Kankesan
Janarthanan
J
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Yusuf
Aroon
A
Laconi
Ezio
E
Vanama
Ramesh
R
Bradley
Grace
G
Thiessen
Jake J
JJ
Ling
Victor
V
Rao
Prema M
PM
Rajalakshmi
Srinivasan
S
Sarma
Dittakavi S R
DS
D019813:1,2-Dimethylhydrazine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight; D002273:Carcinogens; D003524:Cyclosporins / Q000494:pharmacology*; D004127:Dimethylhydrazines / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000188:drug therapy; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009963:Orotic Acid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002273:Carcinogens; D003524:Cyclosporins; D004127:Dimethylhydrazines; D009963:Orotic Acid; D019813:1,2-Dimethylhydrazine; C070272:valspodar