Carcinogenesis Advance Access published online on September 11, 2003
Carcinogenesis, doi:10.1093/carcin/bgg159
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
* Corresponding author. E-mail: sarma.dittakavi{at}utoronto.ca.
Received 19 June 2003
; revised 30 July 2003
; accepted 19 August 2003
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 30mg of PSC/kg body weight (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. The rats were euthanized 10 and 25 weeks thereafter. Cumulative results indicate that PSC30 exhibited a 40% decrease in the incidence of hepatocellular carcinoma (HCC; 15/18 in the basal diet group compared to 8/17 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 to controls. In experiment 2, 15mg of PSC /kg body weight (PSC15) was fed for 20 weeks to rats similarly initiated and promoted for 35 weeks. PSC15 inhibited the incidence of HCC by 75% (4/4 in the basal diet group compared to 1/4 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.
P-glycoprotein, PSC 833, hepatic nodules, hepatocellular carcinoma
Effect of PSC 833, an inhibitor of P-glycoprotein on 1,2-dimethylhydrazine-induced liver carcinogenesis in rats
2 Department of Experimental Pathology, University of Cagliari, Cagliari, Italy
3 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
4 Department of Pharmacy, University of Toronto, Toronto, ON, Canada
5 BC Cancer Agency and University of British Columbia, Vancouver, BC, Canada
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