Transport of the multidrug resistance modulators verapamil and azidopine in wild type and daunorubicin resistant Ehrlich ascites tumour cells

Reversal of vinblastine transport by chlorpromazine in membrane vesicles from multidrug-resistant human CCRF-CEM leukaemia cells

“…1990) and the immune suppressor cyclosporin A (Nooter et al 1989). These compounds are not only xvery different from each other in structure but also have quite different effects on cellular physiology and are often cytotoxic on their oi-n. Verapamil is a competitive inhibitor with respect to some substrates of P-gl coprotein (Sehested et al 1990) but is non-competitixe w-ith others (Pereira et al 1994). Howexer.…”

Effect of anthracycline analogs on photolabelling of p-glycoprotein by [125I]iodomycin and [3H]azidopine: relation to lipophilicity and inhibition of daunorubicin transport in multidrug resistant cells

“…Further, we have studied the inhibitory effects of AZP, vincristine, and detergents on the photoreaction of these compounds with Pgp. Material and methods Chemicals Duanorubicin (DNR); AdriamycinR (Doxorubicin/HCl, DOX); 4'-deoxy-4'-iododoxorubicin (DIDOX); and 4-demethoxy-DNR were kindly supplied from Farmitalia, Carlo Erba (Milan, Italy). N,N-dibenzyl-DNR was a gift from Dr Nicholas Bachur, (Baltimore, MD) and Nbenzyladriamycin-14-valerate (AD 198) (Dan0, 1971) displaying both the MDR phenotype (Sehested et al, 1990) and as recently shown, decreased amount of topoisomerase II (Friche et al, 1991). Resistance to DNR was developed and maintained in vivo in mice as previously described in detail (Dan0, 1971).…”

“…The aim of this study was to examine these analogs for their ability to compete for ligand binding to Pgp and thus service as inhibitors for the outward drug transport system in MDR cells. Anthracycline inter-actions with Pgp were assessed using the specific photolabelling of the protein with [251I]iodomycin, a ['251]iodinated Bolton-Hunter derivative of DNR (Busche et al, 1989a) (Sehested et al, 1990) as well as in whole cells (Safa et al, 1987;Friche et al, 1990c). Further, we have studied the inhibitory effects of AZP, vincristine, and detergents on the photoreaction of these compounds with Pgp. Material and methods Chemicals Duanorubicin (DNR); AdriamycinR (Doxorubicin/HCl, DOX); 4'-deoxy-4'-iododoxorubicin (DIDOX); and 4-demethoxy-DNR were kindly supplied from Farmitalia, Carlo Erba (Milan, Italy).…”

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“…This is in sharp contrast to the rates of influx of the cytostatic drug doxorubicin, which is accumulated into cells with rate constants on the order of 1O-5 to low4 s-l for a lo6 cells/ml suspension [6,7]. Likewise, this also differs from the uptake of verapamil, another MDR modulator, which is shown to accumulate within both sensitive and resistant cells over a period of two hours before reaching steady-state levels [8]. These results are in agreement with the previous study [5] in which significant levels of modulation of vinblastine accumulation were observed within the first 5 min of incubation.…”

“…Due to the low value of the partition coefficient, the intracellular concentration of PZ will be only slightly higher than that found extracellularly, and this steadystate concentration will be rapidly approached. This is in direct contrast to verapamil, in which only a small percentage of the modulator in the external incubation media is accumulated very slowly into cells [8]. Thus, modulation by PZ can be rapidly induced or decreased solely through changes in the extracellular concentration of modulator.…”