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Investigational New Drugs

, Volume 12, Issue 3, pp 169–182 | Cite as

Differential cytotoxic effects of docetaxel in a range of mammalian tumor cell lines and certain drug resistant sublinesin vitro

  • Bridget T. Hill
  • Richard D. H. Whelan
  • Sharon A. Shellard
  • Siobhan McClean
  • Louise K. Hosking
Preclinical Studies

Abstract

Thein vitro cytotoxic effects of docetaxel (Taxotere®; RP56976, NSC688503) proved both time and concentration dependent. Amongst thirteen human cell lines from various tumor types, exposure to increasing concentrations of docetaxel over 24 hrs resulted in a plateau-shaped dose response curve, suggesting that increased cell kill becomes more dependent on increased exposure duration than on concentration. IC50 concentrations (reducing survival by 50%) ranged from 0.13–3.3 ng/ml, with three neuroblastoma lines proving most sensitive and three breast and two colon carcinoma lines showing least sensitivity. There was significant cross-resistance to docetaxel in the classic multidrug resistant (MDR) Chinese hamster ovarian (CHO) CHRC5 line and the human lymphoblastoid CCRF-CEMVLB1000 line, as well as in two vincristine(VCR)-selected MDR MCF-7 sublines. All four of these MDR sublines overexpress P-glycoprotein (Pgp), as did a 6fold docetaxel-selected resistant CHO subline. As an apparent corollary, in two human teratoma lines selected for etoposide resistance and showing some cross-resistance to VCR and in two CHO sublines expressing low levels of VCR resistance, yet all proving Pgp positive, no docetaxel crossresistance was identified. Verapamil modulated docetaxel resistance only in sublines expressing resistance to the drug and overexpressing Pgp. Four other human tumor sublines selected for resistance to 5-fluorouracil, cisplatin or teniposide, showed a lack of cross-resistance to docetaxel. Furthermore, cross-resistance to docetaxel was not apparant in four epipodophyllotoxin-selected resistant sublines with alterations in topoisomerase II, indicating its effectiveness against tumor cells expressing the topoisomerase II-related MDR phenotype. Our observation that docetaxel cross-resistance was not automatically expressed by classic MDR tumour cells appears of interest and of potential clinical relevance.

Key words

docetaxel in vitro cytotoxicity cross resistance P-glycoprotein docetaxel resistance 

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References

  1. 1.
    Guéritte-Voegelein F, Guénard D, Lavelle F, Le Goff MT, Mangatal L, Potier P: Relationship between the structure and taxol analogues and their antimitotic activity. J Medicinal Chem 34:992–998, 1991Google Scholar
  2. 2.
    Ringel I, Horwitz SB: Studies with RP56976 (taxotere): A semisynthetic analogue of taxol. J. Natl Cancer Inst 83:288–291, 1991PubMedGoogle Scholar
  3. 3.
    Barasoain I, de Ines C, Diaz F, Andreu JM, CSIC Madrid Peyrot V, Leynadier D, Garcia P, Briand C: Interaction of tubulin and cellular microtubules with RP 56976 (Taxotere) a new semisynthetic analog of taxol. Proc Am Assoc Cancer Res 32:329, 1991Google Scholar
  4. 4.
    Hill BT, Whelan RDH, Shellard SA, McClean S, Hosking LK: Differential cytotoxic effects of Taxotere in a range of mammalian tumour cell linesin vitro. Proceedings of the 7th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands, p 120, 1992Google Scholar
  5. 5.
    Aapro M, Braakhuis B, Dietel M: Superior activity of taxotere(Ter) over taxol(Tol)in vitro. Proc Am Assoc Cancer Res 33:516, 1992Google Scholar
  6. 6.
    Riou J.-F, Naudin A, Lavelle F: Effects of taxotere on murine and human tumor cell lines. Biochem Biophys Res Commun 187:164–170, 1992PubMedGoogle Scholar
  7. 7.
    Alberts DS, Garcia D, Fanta, P: Comparative cytotoxicities of taxol and taxoterein vitro against fresh human ovarian cancers. Proc Am Soc Clin Oncol 11:226, 1992Google Scholar
  8. 8.
    Hanauske A-R, Degen D, Hilsenbeck SG, Bissery MC, Von Hoff DD: Effects of Taxotere and taxol onin vitro colony formation of freshly explanted human tumour cells. Anti-Cancer Drugs 3:121–124, 1992PubMedGoogle Scholar
  9. 9.
    Vogel MM, Hilsenbeck H, Depenbrock H, DanhauserRiedl S, Block T, Nekarda H, Fellbaum Ch, Aapro MS, Bissery MC, Rastetter J, Hanauske A-R: Preclinical acitivity of taxotere (RP 56796, NSC628503) against freshly explanted clonogenic human tumour cells: Comparison with taxol and conventional antineoplastic agents. Eur J Cancer 29A:2009–2014, 1993PubMedGoogle Scholar
  10. 10.
    Bissery M.-C, Guenard D, Guéritte-Voegelein G, Lavelle F: Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 51:4845–4852, 1991PubMedGoogle Scholar
  11. 11.
    Harrison SD, Jr Dykes DJ, Shepherd RV: Response of human tumor xenografts to taxotere. Proc Am Assoc Cancer Res 33:526, 1992Google Scholar
  12. 12.
    Boven E, Venema-Gaberscek E, Erkelens CAM, Bissery MC, Pinedo HM: Antitumor activity of taxotere (RP 56976, NSC 628503), a new taxol analog, in experimental ovarian cancer. Annals Oncol 4:321–324, 1993Google Scholar
  13. 13.
    Bech-Hansen NTG, Till TE, Ling V: Pleiotropic phenotype of colchicine resistant CHO cells: Cross-resistance and collateral sensitivity. J Cell Physiol 88:23–32, 1976PubMedGoogle Scholar
  14. 14.
    McClean S, Hosking LK, Hill BT: Expression of Pglycoprotein-mediated drug resistance in Chinese hamster ovary cells survivingin vitro exposure to a single lethal X-ray dose of 30Gy. Int J Radiat Biol 63:765–773, 1993PubMedGoogle Scholar
  15. 15.
    Hill BT, Deuchars K, Hosking LK, Ling V, Whelan RDH: Overexpression of P-glycoprotein in mammalian tumor cell lines after fractionated X-irradiationin vitro. J Natl Cancer Inst 82:607–612, 1990PubMedGoogle Scholar
  16. 16.
    Hill BT: Preclinical screening for drugs effective against 5-fluorouracil-resistant cells with a murine L5178Y cell linein vitro. J Natl Cancer Inst 71:335–340, 1983PubMedGoogle Scholar
  17. 17.
    Foley GE, Lazarus H, Farber S, Uzman BG, Boone BA, McCarthy RE: Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia. Cancer 18:522–529, 1965PubMedGoogle Scholar
  18. 18.
    Kartner N, Everden-Porelle D, Bradley G, Ling V: Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 316:820–823, 1985PubMedGoogle Scholar
  19. 19.
    Danks MK, Yalowich JC, Beck WT: Atypical multiple drug resistance in a human leukemic cell line selected for resistance to teniposide. Cancer Res 47:1297–1301, 1987PubMedGoogle Scholar
  20. 20.
    Hill BT, Whelan RDH, Hosking LK: Use of human neuroblastoma continous cell lines forin vitro drug sensitivity screening. Invest New Drugs 6:11–18, 1988PubMedGoogle Scholar
  21. 21.
    Hill BT, Whatley SA, Bellamy AS, Jenkins LY, Whelan RDH: Cytotoxic effects and biological activity of spirogermaniumin vitro. Cancer Res 42:2852–2856, 1982PubMedGoogle Scholar
  22. 22.
    Hill BT, Bellamy AS, Metcalfe S, Hepburn PJ, Masters JRW, Whelan RDH: Identification of synergistic combinations of spirogermanium with 5-fluorouracil or cisplatin using a range of human tumour cell linesin vitro. Invest New Drugs 2:29–33, 1984PubMedGoogle Scholar
  23. 23.
    Hill BT, Hosking LK, Hay C, Whelan RDH: Differential expression of drug resistance and patterns of cross resistance in human colon carcinoma cell lines selected by exposure to antitumour drugs or to X-irradiationin vitro. Proceedings of the International Conference on Biology and Treatment of Gastrointestinal Malignancies, Frankfurt, Germany, p 49, 1992Google Scholar
  24. 24.
    Hill BT, Whelan RDH, Gibby EM, Sheer D, Hosking LK, Shellard SA, Rupniak HT: Establishment and characterisation of three new human ovarian carcinoma lines and evaluation of their potential in experimental chemotherapy. Int J Cancer 39:219–225, 1987PubMedGoogle Scholar
  25. 25.
    Dempke WCM, Hosking LK, Hill BT: Expression of collateral sensitivity to cisplatin, methotrexate, and fluorouracil in a human ovarian carcinoma cell line following exposure to fractionated X-irradiationin vitro. Semin Oncol 19 (Supplement 3):66–72, 1992Google Scholar
  26. 26.
    Dempke WCM, Whelan RDH, Hill BT: Expression of resistance to etoposide and vincristinein vitro andin vivo after X-irradiation of ovarian tumour cells. Anti-Cancer Drugs 3:395–399, 1992PubMedGoogle Scholar
  27. 27.
    Soule HD, Vazquez J, Long A, Alberts S, Brenan MA: A human line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51:1409–1416, 1973PubMedGoogle Scholar
  28. 28.
    Whelan RDH, Hill BT: Differential expression of steroid receptors, HSP27 and pS2 in a series of drug resistant breast tumor cell lines derived following exposure to antitumour drugs or to fractionated X-irradiation. Breast Cancer Res Treat 26:23–39, 1993PubMedGoogle Scholar
  29. 29.
    Dempke WCM, Shellard SA, Hosking LK, FichtingerSchepman AMJ, Hill BT: Mechanisms associated with the expression of cisplatin resistance in a human ovarian tumor cell line following exposure to fractionated X-irradiationin vitro. Carcinogenesis 13:1209–1215, 1992PubMedGoogle Scholar
  30. 30.
    Hogan B, Fellows M, Avner P, Jacob F: Isolation of a human teratoma cell line which expresses F9 antigen. Nature 270:515–518, 1977PubMedGoogle Scholar
  31. 31.
    Hill BT, Whelan RDH, Hosking LK, Shellard SA, Bedford P, Lock RB: Interactions between antitumour drugs and radiation in mammalian tumour cell lines: Differential drug responses and mechanisms of resistance following fractionated X-irradiation or continuous drug exposurein vitro. NCI Monogr 6:177–182, 1988PubMedGoogle Scholar
  32. 32.
    Hill BT, Shellard SA, Hosking LK, Dempke WCM, Fichtinger-Schepman AMJ, Tone T, Scanion KJ, Whelan RDH: Characterization of a cisplatin-resistant human ovarian carcinoma cell line expressing cross-resistance to 5-fluorouracil but collateral sensitivity to methotrexate. Cancer Res 52:3110–3118, 1992PubMedGoogle Scholar
  33. 33.
    Darbre P, Yates J, Curtis S, King RJB: Effect of estradiol on human breast cancer cells in culture. Cancer Res 43:349–354, 1983PubMedGoogle Scholar
  34. 34.
    Keydar I, Chen L, Karbey S, Weiss FR, Delarea J, Radu M, Chaitcik S, Brenner HJ: Establishment and characterization of a cell line of human breast carcinoma origin. Eur J Cancer 15:659–670, 1979PubMedGoogle Scholar
  35. 35.
    Courtenay VD, Mills J: Anin vitro colony assay for human tumours grown in immune-suppressed mice and treatedin vivo with cytotoxic agents. Br J Cancer 37:261–268, 1978PubMedGoogle Scholar
  36. 36.
    Whelan RDH, Hill BT: The influence of agarose concentration on the cloning efficiency of a series of established human cell lines. Cell Biol Int Rep 5:1137–1142, 1981PubMedGoogle Scholar
  37. 37.
    Lefevre D, Riou J-F, Ahomadegbe JC, Zhou D, Benard J, Riou G: Study of molecular markers of resistance tom-AMSA in a human breast cancer cell line. Biochem Pharmacol 41:1967–1979, 1991CrossRefPubMedGoogle Scholar
  38. 38.
    Bruce WR, Meeker BE, Valeriote FA: Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administeredin vivo. J Natl Cancer Inst 37:233–245, 1966PubMedGoogle Scholar
  39. 39.
    Rowinsky EK, Donehower RC, Jones RJ, Tucker RW: Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res 48:4093–4100, 1988PubMedGoogle Scholar
  40. 40.
    Lopes NM, Adams EG, Pitts TW, Bhuyan BK: Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 32:235–242, 1993PubMedGoogle Scholar
  41. 41.
    Burns H, Kuhn RIJ, Kalter S, Smith L, Shaffer D, Fields S, Weiss G, Eckardt J, Rodriguez G, Rinaldi D, Wall J, Cook G, Smith S, Vreeland F, Bayssas M, LeBail N, Von Hoff D: Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion. J Clin Oncol 11:950–958, 1993PubMedGoogle Scholar
  42. 42.
    Bisset D, Setanoians A, Cassidy J, Graham MA, Chadwick GA, Wilson P, Auzannet V, Le Bail N, Kaye S B, Kerr DJ: Phase I pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion. Cancer Res 53:523–527, 1993PubMedGoogle Scholar
  43. 43.
    Extra J.-M, Rousseau F, Bruno R, Clavel M, Le Bail N, Marty M: Phase I and pharmacokinetic study of taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res 53:1037–1042, 1993PubMedGoogle Scholar
  44. 44.
    Pazdur R, Newman RA, Newman BM, Fuentes A, Benvenuto J, Bready B, Moore DJr, Jaiyesimi I, Vreeland F, Bayssas MMG, Raber MN: Phase I trial of taxotere: Five-day schedule. J Natl Cancer Inst 84:1781–1788, 1992PubMedGoogle Scholar
  45. 45.
    Lehnert M, Emerson S, Dalton WS, Salmon SE: Reversal of resistance to taxol and taxotere in a human myeloma cell line model of MDR1. Proc Am Assoc Cancer Res 33:481, 1992Google Scholar
  46. 46.
    Rose WC: Taxol: a review of its preclinicalin vivo antitumor activity. Anti-Cancer Drugs 3:311–321, 1993Google Scholar
  47. 47.
    Kelland LR, Abel G: Comparativein vitro cytotoxicity of taxol and taxotere against cisplatin-sensitive and-resistant human ovarian carcinoma cell lines. Cancer Chemother Pharmacol 30:444–450, 1992PubMedGoogle Scholar
  48. 48.
    Bissery MC, Vrignaud P, Bayssas M, Lavelle F: Taxotere synergistic combination with cyclophosphamide, etoposide and 5-fluorouracil in mouse tumor models. Proc Am Assoc Cancer Res 34:299, 1993Google Scholar
  49. 49.
    Bissery MC, Vrignaud P, Bayssas M, Lavelle F:In vivo evaluation of taxotere (RP56976, NSC628503) in combination with cisplatinum, doxorubicin, or vincristine. Proc Am Assoc Cancer Res 33:443, 1992Google Scholar
  50. 50.
    McClean S, Whelan RDH, Hosking LK, Hodges GM, Thompson FH, Meyers MB, Schuurhuis GJ, Hill BT: Characterisation of the P-glycoprotein overexpressing drug resistance phenotype exhibited by Chinese hamster ovary cells following theirin vitro exposure to fractionated X-irradiation. Biochim Biophys Acta 1177:117–126, 1993PubMedGoogle Scholar
  51. 51.
    Hill BT, Whelan RDH, McClean S: Overexpression and post-translational regulation of P-glycoprotein resulting from exposure of human ovarian tumour cells to fractionated X-irradiation. Proc Am Soc Clin Oncol 12:118, 1993Google Scholar
  52. 52.
    Hill BT, Whelan RDH, Hurst HC, McClean S: Identification of a distinctive P-glycoprotein-mediated resistance phenotype in human ovarian carcinoma cells following theirin vitro exposure to fractionated X-irfiation. Cancer 73:2990–2994, 1994PubMedGoogle Scholar
  53. 53.
    Hill BT, Whelan RDH, Hosking LK, Shellard SA, Hinds MD, Mayes J, Zwelling LA: A lack of detectable modification of topoisomerase II activity in a series of human tumor cell lines expressing only low levels of etoposide resistance. Int J Cancer 47:899–902, 1991PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Bridget T. Hill
    • 1
  • Richard D. H. Whelan
    • 1
  • Sharon A. Shellard
    • 1
  • Siobhan McClean
    • 1
  • Louise K. Hosking
    • 1
  1. 1.Laboratory of Cellular ChemotherapyImperial Cancer Research FundLondonEngland

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