Serum can inhibit reversal of multidrug resistance by chemosensitisers.
Abstract: The purpose of this study was to evaluate to what extent the ability of various chemosensitisers (CS) to reverse P-glycoprotein-associated multidrug resistance (MDR) is reduced when tested in physiological serum protein concentrations. Utilising drug sensitivity and accumulation assays, the CS were tested in medium containing 10% fetal bovine serum and in 100% horse or human serum. Two RPMI 8226 human myeloma sublines were used which express different levels of P-glycoprotein. The CS were tested at various concentrations, including clinically achievable blood levels. When using the CS at high doses, wide differences were observed in the extent CS activity was diminished by serum. Verapamil, cyclosporin A and quinine were not affected, quinidine and medroxyprogesterone acetate were moderately inhibited, and amiodarone and trifluoperazine were largely inactivated. When the CS were used at concentrations achievable in humans, the activity of all agents except quinine was markedly reduced by serum. With respect to the extent to which CS activity was diminished by serum, good statistical correlation (r > 0.90, P < 0.001) was found between the use of cytotoxicity and drug accumulation assays, horse and human serum or cell lines with high and low levels of P-glycoprotein, respectively. These studies demonstrated that physiological serum protein concentrations can profoundly diminish the MDR reversing activity of particular CS. Some drugs, such as amiodarone and trifluoperazine, are largely inactivated by serum when used at a wide range of concentrations. Other agents, such as verapamil and cyclosporin A, are essentially unaffected when used at high doses but markedly inhibited at concentrations achievable in humans. These data suggest that in vitro studies of CS in medium containing low serum protein concentrations can result in misleading conclusions regarding the potential clinical activity of such agents.
Publication Date: 1996-05-01 PubMed ID: 9081367DOI: 10.1016/0959-8049(96)00004-4Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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This research analyzes the degree to which serum protein concentrations can disrupt the action of chemosensitisers in reversing multidrug resistance linked to P-glycoprotein in myeloma cells.
Study Design and Methodology
- The study utilized drug sensitivity and accumulation assays to test various chemosensitisers (CS).
- These CS were tried in media containing 10% fetal bovine serum and 100% horse or human serum.
- The research used two RPMI 8226 human myeloma sublines, which express different levels of P-glycoprotein; a protein that contributes to multidrug resistance.
- The CS were administered at different concentrations, which included levels that can be achieved in a clinical setting.
Results
- At high doses, there were significant variations in the degree to which the activity of CS was impacted by serum. Some CS like Verapamil, cyclosporin A, and quinine showed no effect, while others were either moderately inhibited (quinidine and medroxyprogesterone acetate) or largely inactivated (amiodarone and trifluoperazine).
- When CS were administered at concentrations realistically achievable in humans, the activity of all agents, except quinine, was significantly diminished by the serum.
- There was a strong statistical correlation (r > 0.90, P < 0.001) between results from cytotoxicity and drug accumulation tests, horse and human serum, and cell lines with high and low levels of P-glycoprotein.
Conclusion
- The study demonstrated that physiological serum protein concentrations can substantially affect the multidrug resistance reversing activity of certain CS.
- Drugs like amiodarone and trifluoperazine lost most of their activity when exposed to serum at a wide range of concentrations.
- Other CS such as Verapamil and cyclosporin A remained unaffected at high doses, but their action was substantially hindered at levels achievable in humans.
- This finding suggests that in vitro studies of CS in media with low serum protein concentration can lead to false conclusions about their potential clinical activity.
Cite This Article
APA
Lehnert M, de Giuli R, Kunke K, Emerson S, Dalton WS, Salmon SE.
(1996).
Serum can inhibit reversal of multidrug resistance by chemosensitisers.
Eur J Cancer, 32A(5), 862-867.
https://doi.org/10.1016/0959-8049(96)00004-4 Publication
Researcher Affiliations
- Department C of Internal Medicine, Kantonsspital, St Gallen, Switzerland.
MeSH Terms
- Animals
- Antineoplastic Agents / antagonists & inhibitors
- Antineoplastic Agents / pharmacokinetics
- Antineoplastic Agents / pharmacology
- Blood Proteins / pharmacology
- Cattle
- Cell Death / drug effects
- Culture Media
- Dose-Response Relationship, Drug
- Drug Interactions
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Horses
- Humans
- Tumor Cells, Cultured / drug effects
- Tumor Cells, Cultured / metabolism
Grant Funding
- 23074 / PHS HHS
- 43043 / PHS HHS
- CA 17094 / NCI NIH HHS
Citations
This article has been cited 5 times.- Nielsen RB, Holm R, Pijpers I, Snoeys J, Nielsen UG, Nielsen CU. Combinational Inhibition of P-Glycoprotein-Mediated Etoposide Transport by Zosuquidar and Polysorbate 20.. Pharmaceutics 2023 Jan 14;15(1).
- Nielsen RB, Holm R, Pijpers I, Snoeys J, Nielsen UG, Nielsen CU. Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition.. Int J Pharm X 2021 Dec;3:100089.
- Bardelmeijer HA, Ouwehand M, Beijnen JH, Schellens JH, van Tellingen O. Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice.. Invest New Drugs 2004 Aug;22(3):219-29.
- van Zuylen L, Nooter K, Sparreboom A, Verweij J. Development of multidrug-resistance convertors: sense or nonsense?. Invest New Drugs 2000 Aug;18(3):205-20.
- Rose JM, Peckham SL, Scism JL, Audus KL. Evaluation of the role of P-glycoprotein in ivermectin uptake by primary cultures of bovine brain microvessel endothelial cells.. Neurochem Res 1998 Feb;23(2):203-9.
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