Chemoresistenz des Nierenzellkarzinoms: Stellenwert der Kalziumantagonisten

Mickisch, G.; Kössig, Jutta; Tschada, R.; Keilhauer, Gerhard; Schlick, E.; Alken, P.

doi:10.1055/s-2008-1060617

Cited by 1 publication

(1 citation statement)

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“…(R)-verapamil is a verapamil stereoisomer that can be given in large amounts in vivo because it has less cardiovascular activity than the (L)-isomer (22) but exhibits similar potency to overcome MDR compared to racemic verapamil in vitro (23). It is currently in phase 1 clinical trials as a MDRreversing agent of potential clinical interest.…”

Section: Resultsmentioning

confidence: 99%

Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance.

Mickisch

Merlino

Galski

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

141

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The development ofpreclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression ofthe MDR] gene, which encodes a M, 170,000 glycoprotein that functions as a plasma membrane energydependent multidrug efflux pump. We have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lymphocytes are protected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDRI gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, inclng verapamil isomers, quinidine, and quinine. Verapamil and quinine, both at levels suitable for human trials that produced only partial sensitization of the MDRl-transgenic mice, were fully sensitizing when used in combination. We conclude that MDRJ-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse mulddrug resistance in animals.

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Section: Resultsmentioning

confidence: 99%