Treatment of multidrug resistant (MDR1) murine leukemia with P-glycoprotein substrates accelerates the course of the disease.

Autor: Yang JM; The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. jyang@rwja.umdnj.edu, Yang GY, Medina DJ, Vassil AD, Liao J, Hait WN
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 1999 Dec 09; Vol. 266 (1), pp. 167-73.
DOI: 10.1006/bbrc.1999.1757
Abstrakt: The prognosis of patients with tumors expressing P-glycoprotein (P-gp), the MDR1 gene product, is generally poor. It is assumed that this is due to decreased tumor responsiveness that results from decreased drug accumulation. We observed that treatment of animals bearing MDR1-transfected leukemic cells with P-gp substrates (i.e., drugs that are transported by P-gp) significantly worsened host survival compared to treatment with vehicle or non-P-gp substrates. This effect was seen with cancer chemotherapeutic agents (paclitaxel and vincristine) and with the MDR modulator, trans-flupenthixol. To determine the mechanism(s) underlying this observation, we studied alterations in pharmacokinetics, pharmacodynamics, and metastasis. We found that the drug-induced acceleration of disease was associated with increased metastases. P-gp(+) cells treated with P-gp substrates demonstrated several pro-metastatic features, including membrane ruffling and invasion through a hepatocyte monolayer. These results suggest that the treatment of MDR tumors with P-gp substrates may produce changes in malignant behavior that could adversely affect therapeutic outcomes.
(Copyright 1999 Academic Press.)
Databáze: MEDLINE
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