| Abstract: |
Many efforts have been done to elucidate the mechanism of action of verapamil as a demosensirizcr in multidrug-rcsistance (MDR), however there are no previous studies describing te extracellular effects of vcrapamil on MDR. These investigations, therefore describe the effect of D,L-verapamil, its enantiomers and metabolites on vincristine binding to different serum oteins, in particular to AGP in vitro using physiologically relevant concentrations. The effect of ttse chemoscnsitizcrs and AGP on vincristine accumulation (ex-vivo) using intact lymphocytes from healthy subjects, tumor patients with eLL and sensitive (CEM) and resistant (CEM- VBL lOa) suhl i nes is also demonstrated. The results can be summarized as follows:I. Vincristine binds to AUP, liSA, GIISA and native serum from both healthy subjects and tumor patients by approximately 50 %, 34 %, 27 % and 60 % respectively and the binding is ixIependcnt of vincr istine concentration over a wide concentration range (0.002-2.0 ftg/ml). The finding that vincristine binds strongly to AUP has not been previously reported.D,L-verapamil at a concentration of 20 ftg/ml reduces the binding of vincristine to AGP by lore than 50 %, to native serum by 30 %, to lISA by 45 % and to GHSA by 24 % .D,L-verapamil, its individual isomers and the metabolite norverapamil interact to a similar ’lent with vincristine at binding sites on AGP and these interactions are much greater than that erved with dealkylated verapamil (D617).The extent of interaction appears similar to that with P-gp in MDR studies with resistant and sensitive Cell-lines, Thus, AGP may be useful a model for studies with chemosensiuzers in MDR.Verapamil/vincristine interact ions on AG P are dependent on the concentration of both it and AGP Out not on We coucentruuou or vrncnsune. Fhe v.ncrrsune Oljh.lll1g W r\lJi’ 10 be a non-saturable binding.
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