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P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo.

Abstract
We examined whether the increased expression of P-glycoprotein (P-gp) encoded by the human multidrug resistance gene MDR1 is related to the acquired multidrug resistance of lung cancer in vivo. We estimated the chemosensitivity of lung cancer xenografts (LC-6, adenocarcinoma; Lu-24, small-cell cancer) by calculation of relative tumour growth (T/C%, treated/control) in vivo, based on statistical significance determined by the Mann-Whitney U test (P < 0.01, one-sided). MDR1 gene expression levels were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) assay. P-gp production and P-gp localisation were examined by Western blotting and by immunohistochemical analysis respectively. LC-6 and Lu-24 were initially sensitive to both vincristine (VCR, 1.6 mg kg-1: LC-6, 45%; Lu-24, 39%) and doxorubicin (DOX, 12 mg kg-1: LC-6, 26%; Lu-24, 27%) in vivo. VCR-resistant variants (LC-6R, 66% and Lu-24R, 68%) selected with VCR (0.4 mg kg-1, x 9) significantly acquired cross-resistance to DOX (LC-6R, 55% and Lu-24R, 55% respectively). RT-PCR assay showed increased levels of MDR1 expression in LC-6R and Lu-24R with stable MDR1 expression levels. P-gp expression levels were elevated, and the percentage of P-gp-positive tumour cells increased in both LC-6R and Lu-24R. These results suggest that P-gp/MDR1 overexpression is related to acquired multidrug resistance in lung cancer in vivo.
AuthorsY Abe, Y Ohnishi, M Yoshimura, E Ota, Y Ozeki, Y Oshika, T Tokunaga, H Yamazaki, Y Ueyema, T Ogata, N Tamaoki, M Nakamura
JournalBritish journal of cancer (Br J Cancer) Vol. 74 Issue 12 Pg. 1929-34 (Dec 1996) ISSN: 0007-0920 [Print] England
PMID8980392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Isoenzymes
  • Vincristine
  • Glutathione Transferase
  • DNA Topoisomerases, Type II
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis)
  • Animals
  • Antigens, Neoplasm
  • DNA Topoisomerases, Type II (metabolism)
  • DNA-Binding Proteins
  • Drug Resistance, Multiple (physiology)
  • Gene Expression Regulation, Neoplastic
  • Genes, MDR (genetics)
  • Glutathione Transferase (metabolism)
  • Humans
  • Isoenzymes (metabolism)
  • Lung Neoplasms (physiopathology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Tumor Cells, Cultured
  • Vincristine (administration & dosage)

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