EFFECT OF THE MULTIDRUG INHIBITOR GG918 ON DRUG-SENSITIVITY OF HUMAN LEUKEMIC-CELLS

The drug GG918 has been specifically developed for overcoming MDR phen otype and is now in use in clinical trials. In this study, the effects of GG918 an leukemic cell were investigated using a 3 day MTT assay. Results showed that, in a highly resistant P-gp(+) leukemic cell line, 0.1 mu M of GG918 gives rise to a 40-fold sensitization to daunorubic in (DNR) (residual resistance: 2.1), a 57-fold sensitization to mitrox anirone (residual resistance: 1.5), and a 3.3-fold sensitization to id arubicin (residual resistance: 2.9). When human AB serum was added to the incubation medium, 1 mu M of GG918 was needed to observe the full P-gp modulation potency described above. The effect of 1 mu M of GG918 was tested on 27 samples of poor prognosis acute leukemia (25 AML, tw o ALL). DNR sensitization (using the MTT assay) and modulation of rhod amine 123 uptake were monitored and used as criteria for comparing the in vitro modulation potency of this new compound to the potency of 10 mu M of verapamil, which was used as reference. A good correlation (r = 0.8, P = 0.001) was observed between the results of the two tests. Eleven out of the 26 cases tested were MDR1 (+) (42%), and showed a hi gher IC50 for DNR than the negative cases (861 +/- 1284 nM vs 187 + 24 6 nM, P = 0.05). GG918 was able to modulate the in vitro resistance to DNR in eight cases (seven MDR1(+), no MDR1(-), one non-tested). Verap amil did not increase DNR toxicity in four of these eight cases, but w as more efficient in one other MDR1(+) case. In conclusion, the DNR se nsitivity of the majority of the fresh AML samples expressing P-gp cou ld be modulated in vitro by 1 mu M of GG918.