Effect of the multidrug inhibitor GG918 on drug sensitivity of human leukemic cells.
The drug GG918 has been specifically developed for overcoming MDR phenotype and is now in use in clinical trials. In this study, the effects of GG918 on leukemic cell were investigated using a 3 day MTT assay. Results showed that, in a highly resistant P-gp(+) leukemic cell line, 0.1 microM of GG918 gives rise to a 40-fold sensitization to daunorubicin (DNR) (residual resistance: 2.1), a 57-fold sensitization to mitoxantrone (residual resistance: 1.5), and a 3.3-fold sensitization to idarubicin (residual resistance: 2.9). When human AB serum was added to the incubation medium, 1 microM of GG918 was needed to observe the full P-gp modulation potency described above. The effect of 1 microM of GG918 was tested on 27 samples of poor prognosis acute leukemia (25 AML, two ALL). DNR sensitization (using the MTT assay) and modulation of rhodamine 123 uptake were monitored and used as criteria for comparing the in vitro modulation potency of this new compound to the potency of 10 microM 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 higher IC50 for DNR than the negative cases (861 +/- 1284 nM vs 187 +/- 246 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). Verapamil did not increase DNR toxicity in four of these eight cases, but was more efficient in one other MDR1(+) case. In conclusion, the DNR sensitivity of the majority of the fresh AML samples expressing P-gp could be modulated in vitro by 1 microM of GG918.
Zhou
D C
DC
Laboratoire de Cinétique et Cultures Cellulaires, Université Paris VI, and Formation de Recherche Associée Claude Bernard, Hôtel Dieu de Paris, France.
Simonin
G
G
Faussat
A M
AM
Zittoun
R
R
Marie
J P
JP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000166:Acridines / Q000494:pharmacology*; D000208:Acute Disease; D002463:Cell Membrane Permeability / Q000187:drug effects; D018432:Drug Resistance, Multiple; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007546:Isoquinolines / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy*; D008942:Mitoxantrone / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D007546:Isoquinolines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D044005:Tetrahydroisoquinolines; D008942:Mitoxantrone; D014700:Verapamil; C083501:Elacridar; D015255:Idarubicin