Rhodamine 123 efflux modulation in the presence of low or high serum from CD56+ hematopoietic cells or CD34+ leukemic blasts by B9309-068, a newly designed pyridine derivative.
The newly designed pyridine derivative B9309-068 and a series of structurally different compounds were tested for their ability to modulate rhodamine 123 (RHO) efflux from CD56+ hematopoietic cells in the presence of either 10% fetal calf serum or undiluted human AB serum. Furthermore, efflux modulation was investigated on CD34+ blast populations obtained from four patients with relapsed state AML. Target cells were specified throughout by labeling with peridinine chlorophyll protein (PerCP)-conjugated monoclonal antibodies, allowing clear differentiation from RHO emission spectrum by flow cytometry. In the presence of low serum each compound efficiently modulated RHO efflux without significant differences in the range of final concentrations (1.0-3.0 microM). At 0.1 microM, however, RHO efflux was differentially modulated following the series GF120918 approximately B9309-068 > PSC 833 > DNIG approximately DVER. With CD56+ cells in the presence of undiluted human AB serum at a final modulator concentration of 0.1 microM, all chemosensitizers tested were found to be inefficient. At final concentrations of 0.3 microM or higher, distinct RHO efflux modulation was found with the following efficacies: B9309-068 approximately GF120918 > PSC 833 >> DVER approximately DNIG. The efficacies seen in undiluted human AB serum at 3.0 microM were comparable to those seen on CD56+ cells at final modulator concentrations of 0.1 microM in low serum. Our results identify the pyridine derivative B9309-068 as a promising compound for modulating P-glycoprotein-mediated drug resistance under conditions resembling the clinical setting. Nonetheless, modulation potencies of a series of structurally very different chemosensitizers was revealed to be substantially diminished at high serum concentrations in vitro.
Universitäts-Kinderklinik, Tübingen, Germany.
J F
JF
Beck
F
F
Buchholz
W R
WR
Ulrich
R
R
Boer
K H
KH
Sanders
D
D
Niethammer
V
V
Gekeler
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000166:Acridines / Q000494:pharmacology; D018952:Antigens, CD34 / Q000276:immunology; D001798:Blood Proteins / Q000494:pharmacology*; D019002:CD56 Antigen / Q000276:immunology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D015870:Gene Expression; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011743:Pyrimidines / Q000494:pharmacology*; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D018952:Antigens, CD34; D001798:Blood Proteins; D019002:CD56 Antigen; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D007546:Isoquinolines; D009025:Morpholines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011743:Pyrimidines; D020112:Rhodamine 123; D012235:Rhodamines; D044005:Tetrahydroisoquinolines; D014700:Verapamil; C114000:B9309-068; C083501:Elacridar; C070272:valspodar; C054074:niguldipine