Human Cell

, Volume 23, Issue 4, pp 156–163

Characterization of two independent, exposure-time dependent paclitaxel-resistant human ovarian carcinoma cell lines

  • Kuninobu Nakajima
  • Seiji Isonishi
  • Misato Saito
  • Toshiaki Tachibana
  • Hiroshi Ishikawa
Cell Line


This experiment was conducted to address the question of whether acquired paclitaxel resistance is dependent upon whether it is given as a single brief exposure or as a long-term exposure. PX2 and PX24 were established from 2008 human ovarian cancer cells by 2-h single exposure or 24-h continuous exposure to paclitaxel. PX2 acquired paclitaxel resistance faster than PX24 by twofold. Drug resistant pattern was exposure-time dependent. In 2-h exposure, PX2 showed 53.86 ± 4.96 (mean ± standard deviation [SD]) fold paclitaxel resistance while PX24 showed 9.51 ± 1.01 fold resistance (P = 0.002). In 24-h exposure, PX2 showed 2.31 ± 0.3 fold paclitaxel resistance while PX24 showed 28.1 7 ± 0.98 fold resistance (P = 0.040). PX2 and PX24 acquired cross-resistance to docetaxel and SN38 and the resistance degrees were significantly higher in PX2 than PX24. They displayed approximately twofold cisplatin collateral sensitivity. PX24 also displayed sensitivity to other platinum drugs, oxaliplatin and ZD0473, whereas PX2 acquired significant resistance to both of them. Although differential tubulin-isotype expressions were noted among 2008, PX2 and PX24, they were not significant. In electron microscopy, prominent, densely stained lysosomes were observed more in the resistant cells than 2008. Two independent, exposure-time dependent paclitaxel-resistant human ovarian carcinoma cell lines were established. Understanding the characteristics of the differential resistance pattern could be clinically beneficial for the selection of second line chemotherapy for relapsed ovarian cancer.

Key words

beta-tubuline cytotoxic pattern exposure-time dependent ovarian carcinoma cells paclitaxel-resistant 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Seidman AD, Hochhauser D, Gollub M et al. Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 1996; 14: 1877–84.PubMedGoogle Scholar
  2. 2.
    Armstrong DK, Bundy B, Wenzel L et al. for the Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34–43.CrossRefPubMedGoogle Scholar
  3. 3.
    Katsumata N, Yasuda M, Takahashi F et al. for the Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Rischin D, Webster LK, Millward MJ et al. Cremophor pharmaeokinetics in patients receiving 3-, 6-, and 24-h infusions of paclitaxel. J Natl Cancer Inst 1996; 88: 1297–301.CrossRefPubMedGoogle Scholar
  5. 5.
    Deny WB, Wilson L, Jordan MA. Substoichiometric binding of taxol suppresses microtubule dynamics. Biochemistry 1995; 34: 2203–11.CrossRefGoogle Scholar
  6. 6.
    Di Saida PJ, Sinkovics JG, Rutledge FN. Cell-mediated immunity to human malignant cells. Am J Obstet Gynecol 1972; 114: 979–89.Google Scholar
  7. 7.
    Gianni L, Kearns CM, Giani A et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13: 180–90.PubMedGoogle Scholar
  8. 8.
    Huizing MT, Keung ACF, Hilde Rosing H et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993; 11: 2127–35.PubMedGoogle Scholar
  9. 9.
    Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 1910; 40: iv-vii.Google Scholar
  10. 10.
    Isonishi S, Saitou M, Saitou M, Yasuda M, Tanaka T. Differential regulation of the cytotoxicity activity of paclitaxel by orobol and platelet derived growth factor in human ovarian carcinoma cells. Oncol Rep 2007; 18: 195–201.PubMedGoogle Scholar
  11. 11.
    Ranganathan S, Dexter DW, Benetatos CA, Chapman AE, Tew KD, Hudes GR. Increase of beta (III)- and beta (IVa)-tubulin isotopes in human prostate carcinoma cells as a result of estramustine resistance. Cancer Res 1996; 56: 2584–9.PubMedGoogle Scholar
  12. 12.
    Kavallaris M, Kuo DY-S, Burkhart CA et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes. J Clin Invest 1997; 100: 1282–93.CrossRefPubMedGoogle Scholar
  13. 13.
    Mithieux G, Audebet C, Rousset B. Association of purified thyroid lysosomes to reconstituted microtubules. Biochim Biophys Acta 1988; 969: 121–30.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhan Z, Scala S, Monks A, Hose C, Bates S, Fojo T. Resistance to paclitaxel mediated by P-glycoprotein can be modulated by changes in the schedule of administration. Cancer Chemother Pharmacol 1997; 40: 245–50.CrossRefPubMedGoogle Scholar
  15. 15.
    Stewart DJ, Chiritescu G, Dahrouge S, Banerjee S, Tomiak EM. Chemotherapy dose-response relationships in non-small cell lung cancer and implied resistance mechanisms. Cancer Treat Rev 2007; 33: 101–37.CrossRefPubMedGoogle Scholar
  16. 16.
    Roy SN, Horwitz SB. A phosphoglycoprotein associated with taxol resistance in J774.2 cells. Cancer Res 1985; 45: 3856–63.PubMedGoogle Scholar
  17. 17.
    Gore ME, Atkinson RJ, Thomas H et al. A phase II trial of ZD0473 in platinum-pretreated ovarian cancer. Eur J Cancer 2002; 38: 2416–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Fracasso PM, Blessing JA, Morgan MA, Sood AK, Hoffman JS. Phase II study of oxaliplatin in platinum-resistant and refractory ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003; 21: 2856–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Brewer CA, Blessing JA, Nagourney RA, Morgan M, Hanjani P. Cisplatin plus gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2006; 103: 446–50.CrossRefPubMedGoogle Scholar
  20. 20.
    Rose PG, Blessing JA, Ball HG et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2003; 88: 130–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Cabral FR, Brady RC, Schibler MJ. A mechanism of cellular resistance to drugs that interfere with microtubule assembly. Ann NY Acad Sci 1986; 466: 745–56.CrossRefPubMedGoogle Scholar
  22. 22.
    Rahman YE. Electron microscopy of lysosome-rich fractions from rat thymus isolated by density-gradient centrifugation before and after whole-body X-irradiation. J Cell Biol 1962; 13: 253–60.CrossRefPubMedGoogle Scholar

Copyright information

© Society and Springer Japan 2010

Authors and Affiliations

  • Kuninobu Nakajima
    • 1
  • Seiji Isonishi
    • 2
  • Misato Saito
    • 1
  • Toshiaki Tachibana
    • 3
  • Hiroshi Ishikawa
    • 4
  1. 1.Department of Obstetrics/GynecologyJikei University School of MedicineJapan
  2. 2.Department of Obstetrics/GynecologyJikei University Daisan HospitalTokyoJapan
  3. 3.Department of AnatomyJikei University School of MedicineJapan
  4. 4.Laboratory of Regenerative Medical Sciences, School of Life Dentistry at TokyoThe Nippon Dental UniversityTokyoJapan

Personalised recommendations