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Br J Cancer. 1996 Sep; 74(6): 888–896.
PMCID: PMC2074735

Anti-cancer drug characterisation using a human cell line panel representing defined types of drug resistance.


Differential drug response in a human cell line panel representing defined types of cytotoxic drug resistance was measured using the non-clonogenic fluorometric microculture cytotoxicity assay (FMCA). In total 37 drugs were analysed; eight topoisomerase II inhibitors, eight anti-metabolites, eight alkylating agents, eight tubulin-active agents and five compounds with other or unknown mechanisms of action, including one topoisomerase I inhibitor. Correlation analysis of log IC50 values obtained from the panel showed a high degree of similarity among the drugs with a similar mechanism of action. The mean percentage of mechanistically similar drugs included among the ten highest correlations, when each drug was compared with the remaining data set, was 100%, 92%, 88% and 52% for the topoisomerase II inhibitors, alkylators, tubulinactive agents and anti-metabolites respectively. Classification of drugs into the four categories representing different mechanisms of action using a probabilistic neural network (PNN) analysis resulted in 29 (91%) correct predictions. The results indicate the feasibility of using a limited number of cell lines for prediction of mechanism of action of anti-cancer drugs. The present approach may be well suited for initial classification and evaluation of novel anti-cancer drugs and as a potential tool to guide lead compound optimisation.

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Selected References

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  • Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988 Feb 1;48(3):589–601. [PubMed]
  • Anderson NL, Esquer-Blasco R, Hofmann JP, Anderson NG. A two-dimensional gel database of rat liver proteins useful in gene regulation and drug effects studies. Electrophoresis. 1991 Nov;12(11):907–930. [PubMed]
  • Alvarez M, Paull K, Monks A, Hose C, Lee JS, Weinstein J, Grever M, Bates S, Fojo T. Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Invest. 1995 May;95(5):2205–2214. [PMC free article] [PubMed]
  • Baas F, Jongsma AP, Broxterman HJ, Arceci RJ, Housman D, Scheffer GL, Riethorst A, van Groenigen M, Nieuwint AW, Joenje H. Non-P-glycoprotein mediated mechanism for multidrug resistance precedes P-glycoprotein expression during in vitro selection for doxorubicin resistance in a human lung cancer cell line. Cancer Res. 1990 Sep 1;50(17):5392–5398. [PubMed]
  • Beck WT. The cell biology of multiple drug resistance. Biochem Pharmacol. 1987 Sep 15;36(18):2879–2887. [PubMed]
  • Beck WT, Cirtain MC, Danks MK, Felsted RL, Safa AR, Wolverton JS, Suttle DP, Trent JM. Pharmacological, molecular, and cytogenetic analysis of "atypical" multidrug-resistant human leukemic cells. Cancer Res. 1987 Oct 15;47(20):5455–5460. [PubMed]
  • Bellamy WT, Dalton WS, Gleason MC, Grogan TM, Trent JM. Development and characterization of a melphalan-resistant human multiple myeloma cell line. Cancer Res. 1991 Feb 1;51(3):995–1002. [PubMed]
  • Botling J, Liminga G, Larsson R, Nygren P, Nilsson K. Development of vincristine resistance and increased sensitivity to cyclosporin A and verapamil in the human U-937 lymphoma cell line without overexpression of the 170-kDa P-glycoprotein. Int J Cancer. 1994 Jul 15;58(2):269–274. [PubMed]
  • Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4;258(5088):1650–1654. [PubMed]
  • Cole SP, Sparks KE, Fraser K, Loe DW, Grant CE, Wilson GM, Deeley RG. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 1994 Nov 15;54(22):5902–5910. [PubMed]
  • Csoka K, Liliemark J, Larsson R, Nygren P. Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol. 1995 Aug;22(4 Suppl 11):47–53. [PubMed]
  • Dalton WS, Durie BG, Alberts DS, Gerlach JH, Cress AE. Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein. Cancer Res. 1986 Oct;46(10):5125–5130. [PubMed]
  • Dalton WS, Grogan TM, Rybski JA, Scheper RJ, Richter L, Kailey J, Broxterman HJ, Pinedo HM, Salmon SE. Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: association with level of drug resistance and drug accumulation. Blood. 1989 Feb 15;73(3):747–752. [PubMed]
  • Dalton WS, Grogan TM, Meltzer PS, Scheper RJ, Durie BG, Taylor CW, Miller TP, Salmon SE. Drug-resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol. 1989 Apr;7(4):415–424. [PubMed]
  • Danks MK, Yalowich JC, Beck WT. Atypical multiple drug resistance in a human leukemic cell line selected for resistance to teniposide (VM-26). Cancer Res. 1987 Mar 1;47(5):1297–1301. [PubMed]
  • Danks MK, Schmidt CA, Cirtain MC, Suttle DP, Beck WT. Altered catalytic activity of and DNA cleavage by DNA topoisomerase II from human leukemic cells selected for resistance to VM-26. Biochemistry. 1988 Nov 29;27(24):8861–8869. [PubMed]
  • Doyle LA, Ross DD, Ordonez JV, Yang W, Gao Y, Tong Y, Belani CP, Gutheil JC. An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein. Br J Cancer. 1995 Sep;72(3):535–542. [PMC free article] [PubMed]
  • Goldin A, Venditti JM, Macdonald JS, Muggia FM, Henney JE, Devita VT., Jr Current results of the screening program at the Division of Cancer Treatment, National Cancer Institute. Eur J Cancer. 1981 Feb;17(2):129–142. [PubMed]
  • Grindey GB. Current status of cancer drug development: failure or limited success? Cancer Cells. 1990 Jun;2(6):163–171. [PubMed]
  • Hall AG, Cattan AR. Drug resistance mechanisms in leukaemia. Baillieres Clin Haematol. 1991 Jul;4(3):655–681. [PubMed]
  • Hochhauser D, Harris AL. Drug resistance. Br Med Bull. 1991 Jan;47(1):178–196. [PubMed]
  • Jensen PB, Jensen PS, Demant EJ, Friche E, Sørensen BS, Sehested M, Wassermann K, Vindeløv L, Westergaard O, Hansen HH. Antagonistic effect of aclarubicin on daunorubicin-induced cytotoxicity in human small cell lung cancer cells: relationship to DNA integrity and topoisomerase II. Cancer Res. 1991 Oct 1;51(19):5093–5099. [PubMed]
  • Kramer RA, Zakher J, Kim G. Role of the glutathione redox cycle in acquired and de novo multidrug resistance. Science. 1988 Aug 5;241(4866):694–697. [PubMed]
  • Larsson R, Nygren P. A rapid fluorometric method for semiautomated determination of cytotoxicity and cellular proliferation of human tumor cell lines in microculture. Anticancer Res. 1989 Jul-Aug;9(4):1111–1119. [PubMed]
  • Larsson R, Nygren P. Pharmacological modification of multi-drug resistance (MDR) in vitro detected by a novel fluorometric microculture cytotoxicity assay. Reversal of resistance and selective cytotoxic actions of cyclosporin A and verapamil on MDR leukemia T-cells. Int J Cancer. 1990 Jul 15;46(1):67–72. [PubMed]
  • Larsson R, Nygren P, Ekberg M, Slater L. Chemotherapeutic drug sensitivity testing of human leukemia cells in vitro using a semiautomated fluorometric assay. Leukemia. 1990 Aug;4(8):567–571. [PubMed]
  • Larsson R, Kristensen J, Sandberg C, Nygren P. Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorometric microculture cytotoxicity assay (FMCA). Int J Cancer. 1992 Jan 21;50(2):177–185. [PubMed]
  • Larsson R, Fridborg H, Liliemark J, Csoka K, Kristensen J, de la Torre M, Nygren P. In vitro activity of 2-chlorodeoxyadenosine (CdA) in primary cultures of human haematological and solid tumours. Eur J Cancer. 1994;30A(7):1022–1026. [PubMed]
  • Lee JS, Paull K, Alvarez M, Hose C, Monks A, Grever M, Fojo AT, Bates SE. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 1994 Oct;46(4):627–638. [PubMed]
  • Liang P, Pardee AB. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992 Aug 14;257(5072):967–971. [PubMed]
  • Marsoni S, Hoth D, Simon R, Leyland-Jones B, De Rosa M, Wittes RE. Clinical drug development: an analysis of phase II trials, 1970-1985. Cancer Treat Rep. 1987 Jan;71(1):71–80. [PubMed]
  • Mirski SE, Gerlach JH, Cole SP. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 1987 May 15;47(10):2594–2598. [PubMed]
  • Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991 Jun 5;83(11):757–766. [PubMed]
  • Mulcahy RT, Bailey HH, Gipp JJ. Up-regulation of gamma-glutamylcysteine synthetase activity in melphalan-resistant human multiple myeloma cells expressing increased glutathione levels. Cancer Chemother Pharmacol. 1994;34(1):67–71. [PubMed]
  • Nagourney RA, Evans SS, Messenger JC, Su YZ, Weisenthal LM. 2 chlorodeoxyadenosine activity and cross resistance patterns in primary cultures of human hematologic neoplasms. Br J Cancer. 1993 Jan;67(1):10–14. [PMC free article] [PubMed]
  • Nygren P, Larsson R. Verapamil and cyclosporin A sensitize human kidney tumor cells to vincristine in absence of membrane P-glycoprotein and without apparent changes in the cytoplasmic free Ca2+ concentration. Biosci Rep. 1990 Apr;10(2):231–237. [PubMed]
  • Nygren P, Larsson R. Differential in vitro sensitivity of human tumor and normal cells to chemotherapeutic agents and resistance modulators. Int J Cancer. 1991 Jun 19;48(4):598–604. [PubMed]
  • Nygren P, Kristensen J, Jonsson B, Sundström C, Lönnerholm G, Kreuger A, Larsson R. Feasibility of the fluorometric microculture cytotoxicity assay (FMCA) for cytotoxic drug sensitivity testing of tumor cells from patients with acute lymphoblastic leukemia. Leukemia. 1992 Nov;6(11):1121–1128. [PubMed]
  • Nygren P, Fridborg H, Csoka K, Sundström C, de la Torre M, Kristensen J, Bergh J, Hagberg H, Glimelius B, Rastad J, et al. Detection of tumor-specific cytotoxic drug activity in vitro using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients. Int J Cancer. 1994 Mar 1;56(5):715–720. [PubMed]
  • Nygren P, Csoka K, Jonsson B, Fridborg H, Bergh J, Hagberg H, Glimelius B, Brodin O, Tholander B, Kreuger A, et al. The cytotoxic activity of Taxol in primary cultures of tumour cells from patients is partly mediated by Cremophor EL. Br J Cancer. 1995 Mar;71(3):478–481. [PMC free article] [PubMed]
  • Ohta S, Nishio K, Kubo S, Nishio M, Ohmori T, Takahashi T, Saijo N. Characterisation of a vindesine-resistant human small-cell lung cancer cell line. Br J Cancer. 1993 Jul;68(1):74–79. [PMC free article] [PubMed]
  • Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, Plowman J, Boyd MR. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst. 1989 Jul 19;81(14):1088–1092. [PubMed]
  • van Kalken CK, Pinedo HM, Giaccone G. Multidrug resistance from the clinical point of view. Eur J Cancer. 1991;27(11):1481–1486. [PubMed]
  • van Osdol WW, Myers TG, Paull KD, Kohn KW, Weinstein JN. Use of the Kohonen self-organizing map to study the mechanisms of action of chemotherapeutic agents. J Natl Cancer Inst. 1994 Dec 21;86(24):1853–1859. [PubMed]
  • Weinstein JN, Kohn KW, Grever MR, Viswanadhan VN, Rubinstein LV, Monks AP, Scudiero DA, Welch L, Koutsoukos AD, Chiausa AJ, et al. Neural computing in cancer drug development: predicting mechanism of action. Science. 1992 Oct 16;258(5081):447–451. [PubMed]
  • Weinstein JN, Myers T, Buolamwini J, Raghavan K, van Osdol W, Licht J, Viswanadhan VN, Kohn KW, Rubinstein LV, Koutsoukos AD, et al. Predictive statistics and artificial intelligence in the U.S. National Cancer Institute's Drug Discovery Program for Cancer and AIDS. Stem Cells. 1994 Jan;12(1):13–22. [PubMed]
  • Weisenthal LM. Antineoplastic drug screening belongs in the laboratory, not in the clinic. J Natl Cancer Inst. 1992 Apr 1;84(7):466–469. [PubMed]

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