Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes

Maria Kavallaris, Dennis Yi-Shin Kuo, Catherine A. Burkhart, Donna Lee Regl, Murray D. Norris, Michelle Haber, Susan Band Horwitz

Research output: Contribution to journalArticle

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Abstract

The treatment of advanced ovarian cancer with taxol is hindered by the development of drug resistance. The cellular target for taxol is the microtubule that is stabilized by the drug. Taxol preferentially binds to the β subunit of tubulin of which there are six distinct isotypes in mammalian cells. We have used highly specific oligonucleotides and polymerase chain reaction to analyze expression of all six β-tubulin genes. Human lung cancer cells (A549) were selected in 12 and 24 nM taxol resulting in cell lines that were 9- and 17-fold resistant, respectively. These cells displayed an altered ratio of classes I, II, III, and IVa β-tubulin isotypes. Ovarian tumors, seven untreated primary and four taxol-resistant tumor-bearing ascites, displayed significant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), and IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appears to be related to the resistance phenotype, as the basal levels of the class III and IVa isotypes in the untreated tumors were extremely low. This is the first report of altered expression of specific β-tubulin genes in taxol-resistant ovarian tumors and we propose that the latter may play a role in clinical resistance to taxol.

Original languageEnglish (US)
Pages (from-to)1282-1293
Number of pages12
JournalJournal of Clinical Investigation
Volume100
Issue number5
StatePublished - Sep 1 1997

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Tubulin
Paclitaxel
Neoplasms
Ascites
Drug Resistance
Microtubules
Ovarian Neoplasms
Genes
Lung Neoplasms
Phenotype
Cell Line
Polymerase Chain Reaction
Pharmaceutical Preparations

Keywords

  • Carcinoma
  • Drug resistance
  • Lung
  • Microtubules
  • Polymerase chain reaction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes. / Kavallaris, Maria; Kuo, Dennis Yi-Shin; Burkhart, Catherine A.; Regl, Donna Lee; Norris, Murray D.; Haber, Michelle; Band Horwitz, Susan.

In: Journal of Clinical Investigation, Vol. 100, No. 5, 01.09.1997, p. 1282-1293.

Research output: Contribution to journalArticle

Kavallaris, Maria ; Kuo, Dennis Yi-Shin ; Burkhart, Catherine A. ; Regl, Donna Lee ; Norris, Murray D. ; Haber, Michelle ; Band Horwitz, Susan. / Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes. In: Journal of Clinical Investigation. 1997 ; Vol. 100, No. 5. pp. 1282-1293.
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