IN-VITRO AND IN-VIVO REVERSAL OF MULTIDRUG-RESISTANCE BY GF120918, ANACRIDONECARBOXAMIDE DERIVATIVE

l]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF1209 18) has been selected from a chemical program aimed at identifying an optimized inhibitor of multidrug resitance (MDR). The potency of GF120 918 is assessed by dose-dependent sensitization of CH(R)C5, OV1/DXR an d MCF7/ADR cells to the cytotoxicity of doxorubicin and vincristine re spectively: GF120918 fully reverses multidrug resistance at 0.05 to 0. 1 muM and is half maximally active at 0.02 muM. The spectrum of drugs sensitized by GF120918 coincides with those having the classical MDR p henotype. In CH(R)C5 cells, 0.01-0.1 muM GF120918 enhances the uptake of [H-3]daunorubicin and blocks the efflux from preloaded cells. It is also shown that GF120918 is still active several hours after being ta ken away from the culture medium showing that it is not, like verapami l, effluxed rapidly by P-glycoprotein. GF120918 effectively competes w ith [H-3]azidopine for binding P-glycoprotein, pointing to this transp ort membrane protein as its likely site of action. After i.v. administ ration to mice, GF120918 penetrates thoroughly various organs that hav e a tissue level/blood level ratio above 10. It is eliminated from org ans and blood with a half-time of approximately 2.7 h. It is well abso rbed after p.o. administration. In mice implanted i.p. with the MDR P3 88/Dox tumor, a single i.v. or p.o. dose of GF120918 restores sensitiv ity of the tumor to a single i.p. dose (5 mg/kg) of doxorubicin admini stered 1 h later. A statistically significant effect is observed at 1 mg/kg GF120918 i.v. and maximal effect is reached at 5 mg/kg. Similarl y, whereas neither drug alone is effective, GF120918 (10 mg/kg i.p.) a ssociated with doxorubicin (5 mg/kg i.p.) inhibits the growth of the m oderately MDR C26 tumor implanted s.c. as assessed by tumor size at da y 19. GF120918 does not modify significantly the distribution or the e limination of doxorubicin in mice ruling out the possibility that the antitumor effects seen might be explained by pharmacokinetic interacti ons.