PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
 
Br J Cancer. 1993 December; 68(6): 1104–1109.
PMCID: PMC1968657

Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines.

Abstract

The cytotoxicity of paclitaxel against eight human tumour cell lines has been studied with in vitro clonogenic assays. The fraction of surviving cells fell sharply after exposure for 24 h to paclitaxel concentrations ranging from 2 to 20 nM; the paclitaxel IC50 was found to range between 2.5 and 7.5 nM. Increasing the paclitaxel concentration above 50 nM, however, resulted in no additional cytotoxicity after a 24 h drug exposure. Cells incubated in very high concentrations of paclitaxel (10,000 nM) had an increase in survival compared with cells treated with lower concentrations of the drug. Prolonging the time of exposure of cells to paclitaxel from 24 to 72 h increased cytotoxicity from 5 to 200 fold in different cell lines. Exponentially growing cells were more sensitive to paclitaxel than were cells in the plateau phase of growth. Cremophor EL, the diluent in which the clinical preparation of paclitaxel is formulated, antagonised paclitaxel at concentrations of 0.135% (v/v). These data suggest that paclitaxel will be most effective clinically when there is prolonged exposure of tumour to the drug. Further, it appears that modest concentrations (i.e., 50 nM) should be as effective as higher concentrations of paclitaxel. Finally, we have noted that Cremophor EL is a biologically active diluent and, at high concentrations (0.135% v/v), can antagonise paclitaxel cytotoxicity.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 1987 Feb 15;47(4):936–942. [PubMed]
  • Chuang LF, Israel M, Chuang RY. Cremophor EL inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced protein phosphorylation in human myeloblastic leukemia ML-1 cells. Anticancer Res. 1991 Jul-Aug;11(4):1517–1521. [PubMed]
  • Cook JA, Mitchell JB. Viability measurements in mammalian cell systems. Anal Biochem. 1989 May 15;179(1):1–7. [PubMed]
  • Drewinko B, Patchen M, Yang LY, Barlogie B. Differential killing efficacy of twenty antitumor drugs on proliferating and nonproliferating human tumor cells. Cancer Res. 1981 Jun;41(6):2328–2333. [PubMed]
  • Hill BT, Whelan RD. Comparative cell killing and kinetic effects of vincristine or vindesine in mammalian cell lines. J Natl Cancer Inst. 1981 Aug;67(2):437–443. [PubMed]
  • Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst. 1991 Dec 18;83(24):1797–1805. [PubMed]
  • Horwitz SB, Lothstein L, Manfredi JJ, Mellado W, Parness J, Roy SN, Schiff PB, Sorbara L, Zeheb R. Taxol: mechanisms of action and resistance. Ann N Y Acad Sci. 1986;466:733–744. [PubMed]
  • Liebmann JE, Hahn SM, Cook JA, Lipschultz C, Mitchell JB, Kaufman DC. Glutathione depletion by L-buthionine sulfoximine antagonizes taxol cytotoxicity. Cancer Res. 1993 May 1;53(9):2066–2070. [PubMed]
  • Manfredi JJ, Horwitz SB. Taxol: an antimitotic agent with a new mechanism of action. Pharmacol Ther. 1984;25(1):83–125. [PubMed]
  • Markman M, Rowinsky E, Hakes T, Reichman B, Jones W, Lewis JL, Jr, Rubin S, Curtin J, Barakat R, Phillips M, et al. Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study. J Clin Oncol. 1992 Sep;10(9):1485–1491. [PubMed]
  • McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989 Aug 15;111(4):273–279. [PubMed]
  • Riondel J, Jacrot M, Picot F, Beriel H, Mouriquand C, Potier P. Therapeutic response to taxol of six human tumors xenografted into nude mice. Cancer Chemother Pharmacol. 1986;17(2):137–142. [PubMed]
  • Riou JF, Naudin A, Lavelle F. Effects of Taxotere on murine and human tumor cell lines. Biochem Biophys Res Commun. 1992 Aug 31;187(1):164–170. [PubMed]
  • Rowinsky EK, Donehower RC, Jones RJ, Tucker RW. Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res. 1988 Jul 15;48(14):4093–4100. [PubMed]
  • Rowinsky EK, Burke PJ, Karp JE, Tucker RW, Ettinger DS, Donehower RC. Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res. 1989 Aug 15;49(16):4640–4647. [PubMed]
  • Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst. 1990 Aug 1;82(15):1247–1259. [PubMed]
  • Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979 Feb 22;277(5698):665–667. [PubMed]
  • Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1561–1565. [PubMed]
  • Woodcock DM, Jefferson S, Linsenmeyer ME, Crowther PJ, Chojnowski GM, Williams B, Bertoncello I. Reversal of the multidrug resistance phenotype with cremophor EL, a common vehicle for water-insoluble vitamins and drugs. Cancer Res. 1990 Jul 15;50(14):4199–4203. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK