ORAL DICLOFENAC COMBINED WITH INTRA-PORTAL PIRARUBICIN - INCREASED EFFICACY ON LIVER VX2 TUMOR AND HEPATOTOXICITY IN RABBITS

VX2 is a carcinoma established in rabbits and producing an autocrine g rowth factor, prostaglandin E2. Pirarubicin is a potent anti-VX2 agent . We investigated whether the oral intake of enprostil - a synthetic p rostaglandin E2 - or of diclofenac - a potent non-steroidal anti-infla mmatory drug-increases the efficacy and decreases the hepatotoxicity o f pirarubicin when injected in the portal trunk. Enprostil increased t he number of hepatic tumoral nodules and induced hepatic alterations, especially venous dilatation. Paradoxically the combination of enprost il and pirarubicin was at least as effective as pirarubicin or diclofe nac on VX2 cells. However, the toxicity was increased, especially with respect to sclerosing cholangitis. Diclofenac proved to be as effecti ve as pirarubicin, and the addition of oral diclofenac to local piraru bicin injection increased its antitumoral effect (P < 0.02). However, the combination of diclofenac and pirarubicin was more toxic than pira rubicin alone and induced centrolobular necrosis and sclerosing cholan gitis.