Modulation of P-glycoprotein mediated drug accumulation in multidrug resistant CCRF VCR-1000 cells by chemosensitisers.
P-glycoprotein (PGP) mediated transport of cytostatic drugs out of resistant cancer cells is a major cause of experimental and probably also of clinical multidrug resistance, which often leads to treatment failure during chemotherapy. The broad substrate specificity of PGP strongly restricts effective chemotherapy and diminishes the patients' prognosis. Inhibition of PGP's pumping function by chemosensitisers is one way to restore cellular responsiveness to otherwise ineffective cytostatics. Clinical trials with several chemosensitisers are under way. To date, it is not clear whether a certain chemosensitiser potentiates the action of different cytostatic drugs, transported by PGP equally well, or whether the chemosensitising potency is dependent on the cytostatic drugs used. Therefore, we compared the effects of five potent chemosensitisers on cellular accumulation using [3H]daunomycin, [3H]vincristine and rhodamine-123 as substrates for PGP. The acridonecarboxamide derivative GF 120918 was the most potent compound and a half-maximal effect was seen at concentrations ranging from 5 nM for rhodamine-123 accumulation to 14 and 19 nM for [3H]vincristine or [3H]daunomycin accumulation, respectively. The new chemosensitiser B9203-016 was slightly less effective than GF 120918 in all three test systems. Dexniguldipine was of intermediate potency with half-maximal effects at concentrations between 62 and 194 nM. The cyclic undecapeptide SDZ PSC 833 showed somewhat lower potency ranging from 151 to 331 nM. Cyclosporin A was less potent than SDZ PSC 833. Furthermore, enhancement of drug accumulation produced by each chemosensitiser was similar, regardless of which PGP substrate was measured, that is, the rank order of potency to increase accumulation was the same in each of the assays used. Our data point to similar, if not identical, mechanisms of drug transport by PGP and inhibition of drug transport by chemosensitisers at least for the substrates rhodamine-123, vincristine and daunomycin.
Boer
R
R
Byk Gulden, Konstanz, Germany.
Gekeler
V
V
Ulrich
W R
WR
Zimmermann
P
P
Ise
W
W
Schödl
A
A
Haas
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003630:Daunorubicin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000378:metabolism*; D014750:Vincristine / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012235:Rhodamines; D020112:Rhodamine 123; D014750:Vincristine; D003630:Daunorubicin