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Expression of beta-tubulin isotypes in human ovarian carcinoma xenografts and in a sub-panel of human cancer cell lines from the NCI-anticancer drug screen: Correlation with sensitivity to microtubule active agents

  1. Author:
    Nicoletti, M. I.
    Valoti, G.
    Giannakakou, P.
    Zhan, Z. R.
    Kim, J. H.
    Lucchini, V.
    Landoni, F.
    Mayo, J. G.
    Giavazzi, R.
    Fojo, T.

  2. Author Address

    Mario Negri Inst Pharmacol Res, Dept Oncol, Via Gavazzeni 11, I-24125 Bergamo, Italy. Mario Negri Inst Pharmacol Res, Dept Oncol, I-24125 Bergamo, Italy. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Univ Ulsan, Asan Med Ctr, Dept Obstet & Gynecol, Seoul, South Korea. San Gerardo Hosp, Dept Pathol, I-20052 Monza, Italy. San Gerardo Hosp, Dept Gynecol Oncol, I-20052 Monza, Italy. NCI, Frederick Canc Res & Dev Ctr, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. Nicoletti MI Mario Negri Inst Pharmacol Res, Dept Oncol, Via Gavazzeni 11, I-24125 Bergamo, Italy.
    1. Year: 2001
  2. Journal: Clinical Cancer Research
    1. 7
    2. 9
    3. Pages: 2912-2922
  4. Type of Article: Article
  1. Abstract:

    Paclitaxel resistance has been associated with overexpression of P-glycoprotein and alterations involving tubulin. To investigate the clinical relevance of these in vitro resistance mechanisms, we established 12 human ovarian carcinoma xenografts, using samples from patients before the start of therapy or after paclitaxel treatment. These xenografts showed a wide range of sensitivity to paclitaxel, and in 4 of them, very low levels of multidrug resistance-1 expression were detected. Using quantitative PCR and human specific primers, the expression of five beta -tubulin isotypes was determined. HM40 was the predominant, accounting for 84.7-98.7% of all tubulin; expression of the other four isotypes (H beta9, H beta4, H%beta, and H beta2) was also detected but at lower levels. No correlation could be demonstrated between isotype expression and paclitaxel sensitivity in these 12 xenografts. A similar pattern of beta -tubulin isotype expression was observed in a subset of cell lines from the National Cancer Institute-Anticancer Drug Screen. In these cell lines, however, a significant correlation between increased expression of H beta4 isotype and resistance to paclitaxel was found. Taken together, these results suggest that altered expression of specific R-tubulin isotypes may not play a significant role in paclitaxel sensitivity in vivo and argue against a possible significance in a clinical setting.

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