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Cancer Chemotherapy and Pharmacology

, Volume 30, Issue 6, pp 444–450 | Cite as

Comparative in vitro cytotoxicity of taxol and Taxotere against cisplatin-sensitive and-resistant human ovarian carcinoma cell lines

  • Lloyd R. Kelland
  • George Abel
Original Articles Taxol, Taxotere, Platinum, Ovarian Carcinoma Cell Lines

Summary

Using the sulforhodamine B assay, we compared the cytotoxic properties of the novel microtubule agent taxol and the semi-synthetic related compound Taxotere in nine human ovarian-carcinoma cell lines, including three pairs of cell lines rendered resistant to cisplatin or carboplatin. In addition, the cytotoxicity of the commonly used anticancer drugs cisplatin and adriamycin and the topoisomerase II inhibitor etoposide was determined. The results of continuous drug exposure showed that taxol [mean concentration producing 50% growth inhibition (IC50), 1.1×10−9m; range, 2.8×10−9–5×10−10m and Taxotere (mean IC50, 5.1×10−10m; range, 7.2−3.3×10−10m) were >1,000 times more cytotoxic than either cisplatin (mean IC50, 3.1×10−6m;P<0.05) or etoposide (mean IC50, 2.3×10−6m;P<0.05) and >100 times more cytotoxic than Adriamycin (mean IC50, 6.9×10−8m;P<0.05). Taxotere was more cytotoxic than taxol; following continuous exposure, the mean difference across the cell lines was 2 orders of magnitude (range, 1.1–3.9 orders of magnitude for individual lines). Although this difference did not reach statistical significance for any individual cell line (P values ranged from 0.17 for HX/62 to 0.9 for OVCAR-3), when all IC50 values for the 96-h experiments were pooled, Taxotere was found to be significantly more potent than taxol (P=0.05). Following 2 h exposure, the mean cytotoxicity of Taxotere was 3.9-fold > that of taxol across the nine lines (range, 0.75- to 10-fold;P<0.05 for the CH1 cell line; overall pooled IC50 data,P=0.05). Although a 71-fold range of sensitivity to cisplatin was observed across the six parent cell lines (IC50 most resistant line/IC50 most sensitive line), this was largely abolished by treatment with taxol (5.6-fold range) and Taxotere (2.2-fold rante). Following continuous exposure of the three pairs of lines exhibiting acquired resistance to platinum, no cross-resistance with either Taxotere or taxol was found (resistance factors, <1.5). In the 41M and 41McisR pair of lines, in which previous studies have shown resistance to be due to reduced platinum accumulation, taxol and Taxotere exhibited some collateral sensitivity (resistance factors, 0.69 and 0.66, respectively). Taxotere and, particularly, taxol showed a pronounced concentration times exposure duration (CxT) dependence as compared with cisplatin (P<0.05). The mean loss in potency across the nine lines for 2 vs 96 h exposure was 97 for taxol, 35 for Taxotere, 30 for Adriamycin and only 9.9 for cisplatin. However, these differences in potency loss observed between taxol and Taxotere did not reach statistical significance (P=0.18). These data indicate that Taxotere is approximately 2 times more cytotoxic than taxol and shows an encouraging lack of cross-resistance in three cell lines exhibiting acquired resistance to cisplatin and carboplatin.

Keywords

Carboplatin Taxol Adriamycin Taxotere Sulforhodamine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Advanced Ovarian Cancer Trialists Group (1991) Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Br Med J 303: 884Google Scholar
  2. 2.
    Barasoain I, Ines C de, Diaz F, Andreu JM, Peyrot V, Leynadier D, Garcia P, Briand C, Sousa G de, Rahmani R (1991) Interaction of tubulin and cellular microtubules with Taxotere (RP 56976), a new semisynthetic analog of taxol (abstract). Proc Am Assoc Cancer Res 32: 1952Google Scholar
  3. 3.
    Bissery MC, Bayssas M, Lavelle F (1990) Preclinical evaluation of intravenous Taxotere (RP56976, NSC 628503), a taxol analog (abstract). Proc Am Assoc Cancer Res 31: 417Google Scholar
  4. 4.
    Bissery MC, Guenard D, Gueritte-Voegelein F, Lavelle F (1991) Experimental antitumor activity of Taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 51: 4845Google Scholar
  5. 5.
    Bissett D, Cassidy J, Setanoians A, Chadwick GA, Wilson P, Kaye SB, Kerr DJ (1992) Phase I study of taxotere administered as a 24 h infusion (abstract). Ann Oncol 3 [Suppl 1]: 122Google Scholar
  6. 6.
    Cabral FR (1983) Isolation of Chinese hamster ovary cell mutants requiring the continuous presence of taxol for cell division. J Cell Biol 97: 30Google Scholar
  7. 7.
    Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936Google Scholar
  8. 8.
    Chabner BA (1991) Taxol. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds) Principles and practice of oncology, vol 5, number 9. J. B. Lippincott, Philadelphia, pp 1–10Google Scholar
  9. 9.
    Denis JN, Greene AE, Guenard D, Gueritte-Voegelein F, Mangatal L, Potier P (1988) A highly efficient, practical approach to natural taxol. J Am Chem Soc 110: 5917Google Scholar
  10. 10.
    Eisenhauer E, Swerton K, Sturgeon J, Fine S, O'Reilly S, Canetta R (1990) Carboplatin therapy for recurrent ovarian carcinoma: National Cancer Institute of Canada experience and a review of the literature. In: Bunn P, Canetta R, Ozols R, Rozencweig M (eds) Carboplatin: current perspectives and future directions. W. B. Saunders, Philadelphia, pp 133–140Google Scholar
  11. 11.
    Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein mediated multidrug resistance. Annu Rev Biochem 58: 137Google Scholar
  12. 12.
    Enzig AI, Wiernik P, Sasloff J, Garl S, Runowicz C, O'Hanlon KA, Goldberg G (1990) Phase II study of taxol in patients with advanced ovarian cancer (abstract). Proc Am Assoc Cancer Res 31: 1114Google Scholar
  13. 13.
    Extra JM, Rousseau F, Bourhis J, Dieras V, Marty M (1991) Phase I trial of Taxotere (RP 56976, NSC 628503) (abstract). Proc Am Assoc Cancer Res 32: 1225Google Scholar
  14. 14.
    Giavazzi R, Nicoletti I, Massazza G, D'Incalci M (1992) Evaluation of taxol (NSC 125973) and taxotere (RP 56976 NSC 628503) activity on human ovarian carcinoma xenografts (abstract). Ann Oncol 3 [Suppl 1]: 123Google Scholar
  15. 15.
    Gore ME, Fryatt I, Wiltshaw E, Dawson T, Robinson BA, Calvert AH (1989) Cisplatin/carboplatin cross-resistance in ovarian cancer. Br J Cancer 60: 767Google Scholar
  16. 16.
    Gueritte-Voegelein F, Guenard D, Lavelle F, Le Goff MT, Mangatal L, Potier P (1991) Relationships between the structure of taxol analogues and their antimitotic activity. J Med Chem 34: 992Google Scholar
  17. 17.
    Hill BT, Whelan RDH, Shellard SA, McClean S, Hosking LK (1992) Differential cytotoxic effects of taxotere in a range of mammalian tumour cell lines in vitro (abstract). Ann Oncol 3 [Suppl 1]: 120Google Scholar
  18. 18.
    Hills CA, Kelland LR, Abel G, Siracky J, Wilson AP, Harrap KR (1989) Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes. Br J Cancer 59: 527Google Scholar
  19. 19.
    Horwitz SB, Lothstein L, Manfredi JJ, Mellado W, Parness J, Roy SN, Schiff PB, Sorbara L, Zeheb R (1986) Taxol: mechanisms of action and resistance. Ann NY Acad Sci 466: 733Google Scholar
  20. 20.
    Keepers YP, Pizao PE, Peters GF, Ark-Otte J van, Winograd B, Pinedo HM (1991) Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays for in vitro chemosensitivity testing. Eur J Cancer 27: 897Google Scholar
  21. 21.
    Kelland LR, Murrer BA, Abel G, Giandomenico CM, Mistry P, Harrap KR (1992) Ammine/amine platinum(IV) dicarboxylates: a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin-resistant human ovarian carcinoma cell lines. Cancer Res 52: 822Google Scholar
  22. 22.
    Kelland LR, Mistry P, Abel G, Loh SY, O'Neill CF, Murrer BA, Harrap KR (1992) Mechanism-related circumvention of cisplatin acquired resistance using two pairs of human ovarian carcinoma cell lines by ammine/amine platinum(IV) dicarboxylates. Cancer Res (in press)Google Scholar
  23. 23.
    Lavelle F, Fizames C, Gueritte-Voegelein F, Guenard D, Potier P (1989) Experimental properties of RP56976, a taxol derivative (abstract). Proc Am Assoc Cancer Res 30: 2254Google Scholar
  24. 24.
    Mangatal L, Adeline MT, Guenard D, Gueritte-Voegelein F, Potier P (1989) Application of the vicinal oxyamination reaction with asymmetric induction to the hemisynthesis of taxol and analogues. Tetrahedron 45: 4177Google Scholar
  25. 25.
    McGuire WP, Rowinsky EK (1991) Old drugs revisited, new drugs, and experimental approaches in ovarian cancer therapy. Semin Oncol 18: 255Google Scholar
  26. 26.
    McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC (1989) Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111: 273Google Scholar
  27. 27.
    Mistry P, Kelland LR, Abel G, Sidhar S, Harrap KR (1991) The relationships between glutathione, glutathione-S transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br J Cancer 64: 215Google Scholar
  28. 28.
    Ozols RF (1991) Ovarian cancer: new clinical approaches. Cancer Treat Rev 18 [Suppl A]: 77Google Scholar
  29. 29.
    Parkin DM, Laara E, Muir CS (1988) Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 41: 184Google Scholar
  30. 30.
    Ringel I, Horwitz SB (1981) Studies with RP 56976 (Taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 83: 288Google Scholar
  31. 31.
    Rowinsky EK, Donehower RC, Jones RJ, Tucker RW (1988) Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res 48: 4093Google Scholar
  32. 32.
    Rowinsky EK, Cazenave LA Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 82: 1247Google Scholar
  33. 33.
    Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA, Ettinger DS, Lubejko BG, Clark B, Sartorius SE, Cornblath DR, Hendricks CB, Donehower RC (1991) Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 9: 1692Google Scholar
  34. 34.
    Roy SN, Horwitz SB (1985) A phosphoglycoprotein associated with taxol resistance in J774.2 cells. Cancer Res 45: 3856Google Scholar
  35. 35.
    Rubinstein LV, Showmaker RH, Paull KD, Simon RM, Tosini S, Skehan P, Scudeiro DA, Monks A, Boyd MR (1990) Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J Natl Cancer Inst 82: 1113Google Scholar
  36. 36.
    Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 22: 665Google Scholar
  37. 37.
    Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer drug screening. J Natl Cancer Inst 82: 1107Google Scholar
  38. 38.
    Swindell CS, Krauss NE, Horwitz SB, Ringel I (1991) Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2′ configurations. J Med Chem 34: 1176Google Scholar
  39. 39.
    Thigpen T, Blessing J, Ball H, Hummel S, Barret R (1990) Phase II trial of taxol as second-line therapy for ovarian carcinoma: a Gynecologic Oncology Group study (abstract). Proc Am Soc Clin Oncol 9: 604Google Scholar
  40. 40.
    Von Hoff D, Kuhn J, Irvin B, Rodriguez G, Weiss G, New P, Vreeland F, Bayassas M, Burris H (1992) Phase I clinical trial of RP56976 (taxotere) given as a 6 hour infusion every three weeks (abstract). Ann Oncol 3 [Suppl 1]: 121Google Scholar
  41. 41.
    Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT (1971) Plant antitumor agents: VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent fromTaxus brevifolia. J Am Chem Soc 93: 2325Google Scholar
  42. 42.
    Wiernik PH, Schwartz EL, Strauman JJ, Dutcher JP, Lipton RB, Paietta E (1987) Phase I clinical and pharmacokinetic study of taxol. Cancer Res 47: 2486Google Scholar
  43. 43.
    Wiernik PH, Schwartz EL, Einzig A, Strauman JJ, Lipton RB, Dutcher JP (1987) Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma. J Clin Oncol 5: 1232Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Lloyd R. Kelland
    • 1
  • George Abel
    • 1
  1. 1.Drug Development SectionThe Institute of Cancer ResearchSuttonUK

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