Kankesan Janarthanan, Laconi Ezio, Medline Alan, Thiessen Jake J, Ling Victor, Rao Prema M, Rajalakshmi Srinivasan, Sarma Dittakavi S R
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Anticancer Res. 2006 Mar-Apr;26(2A):995-9.
The expression of P-glycoprotein (Pgp) is intimately associated with cancer development. In order to explore the therapeutic value of Pgp as a target for chemotherapy, we studied the effect of PSC 833 (PSC), a potent inhibitor of Pgp, on 1,2-dimethylhydrazine (1,2-DMH)-initiated colorectal carcinogenesis in rats.
Male Fischer 344 rats, initiated with 1,2-DMH coupled with partial hepatectomy, were exposed to dietary 1% orotic acid for 22 weeks. They were then fed either the AIN93G basal diet (BD) or BD containing PSC (a daily dose of 15 mg/kg body weight) for 35 weeks.
PSC significantly inhibited colorectal tumor multiplicity by 53% and tumor burden by 74%. PSC-mediated inhibition was evident in tumors as small as 2 mm in diameter and remained effective throughout the course of tumor growth. Histological assessment showed that PSC significantly inhibited tumor progression to colorectal adenocarcinoma by 63%.
Collectively, this study indicates that PSC inhibited experimental colorectal carcinogenesis initiated with 1,2-DMH in rats.
