PSC 833, an inhibitor of P-glycoprotein inhibits 1,2-dimethylhydrazine-induced colorectal carcinogenesis in male Fischer F344 rats.
BACKGROUND
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.


METHODS
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.


RESULTS
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%.


CONCLUSIONS
Collectively, this study indicates that PSC inhibited experimental colorectal carcinogenesis initiated with 1,2-DMH in rats.
Kankesan
Janarthanan
J
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Laconi
Ezio
E
Medline
Alan
A
Thiessen
Jake J
JJ
Ling
Victor
V
Rao
Prema M
PM
Rajalakshmi
Srinivasan
S
Sarma
Dittakavi S R
DS
D019813:1,2-Dimethylhydrazine / Q000037:antagonists & inhibitors*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D003524:Cyclosporins / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D019813:1,2-Dimethylhydrazine; C070272:valspodar