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Spontaneous Reversal of P-Glycoprotein Expression in Multidrug Resistant Cell Lines

Green, Henrik (author)
Linköpings universitet,Hälsouniversitetet,Klinisk farmakologi
Lotfi, Kourosh (author)
Linköpings universitet,Hälsouniversitetet,Klinisk farmakologi
Zackrisson, Anna Lena (author)
Linköpings universitet,Hälsouniversitetet,Klinisk farmakologi
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Peterson, Curt (author)
Östergötlands Läns Landsting,Linköpings universitet,Hälsouniversitetet,Klinisk farmakologi,Onkologiska kliniken US
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 (creator_code:org_t)
Wiley, 2003
2003
English.
In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 93:6, s. 297-304
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Increased expression of P-glycoprotein encoded by the mdr-1 gene is a well-characterised mechanism for resistance to cancer chemotherapeutic drugs in cell lines. However, the P-glycoprotein expression after removal of the selection pressure has not fully been elucidated. The stability of P-glycoprotein expression in the presence (+) and absence (-) of vincristine (30 or 150 nM) was studied in multidrug resistant K562 cell lines (VCR30+, VCR150+, VCR30- and VCR150-) for 11 months. The P-glycoprotein protein and mdr-1 mRNA levels were determined at regular intervals using flow cytometry and real-time PCR, respectively. Chemosensitivity to a panel of antineoplastic drugs was measured using an MTT assay. The presence of vincristine (VCR30+ and VCR150+) resulted in high and stable levels of P-glycoprotein and mdr-1 mRNA during the whole period compared to wild type. As for the VCR30- and VCR150- subcultures, the expressions of P-glycoprotein and mdr-1 mRNA were stable for five months, and then the levels decreased rapidly. Concomitantly, the sensitivity to drugs known as P-glycoprotein substrates was restored. In conclusion, resistant cells growing in the presence of the inducing drug have a stable P-glycoprotein expression and resistance level, but removing the inducing drug may result in a sudden and rapid lowering of P-glycoprotein and mdr-1 mRNA levels as long as five months after drug withdrawal.

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