Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Sep;74(6):888–896. doi: 10.1038/bjc.1996.453

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

S Dhar 1, P Nygren 1, K Csoka 1, J Botling 1, K Nilsson 1, R Larsson 1
PMCID: PMC2074735  PMID: 8826854

Abstract

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.

Full text

PDF
888

Images in this article

892Figure 2
on p.892

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alley M. C., Scudiero D. A., Monks A., Hursey M. L., Czerwinski M. J., Fine D. L., Abbott B. J., Mayo J. G., Shoemaker R. H., Boyd M. R. 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] [Google Scholar]
  2. Alvarez M., Paull K., Monks A., Hose C., Lee J. S., 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. doi: 10.1172/JCI117910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson N. L., Esquer-Blasco R., Hofmann J. P., Anderson N. G. A two-dimensional gel database of rat liver proteins useful in gene regulation and drug effects studies. Electrophoresis. 1991 Nov;12(11):907–930. doi: 10.1002/elps.1150121110. [DOI] [PubMed] [Google Scholar]
  4. Baas F., Jongsma A. P., Broxterman H. J., Arceci R. J., Housman D., Scheffer G. L., Riethorst A., van Groenigen M., Nieuwint A. W., 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] [Google Scholar]
  5. Beck W. T., Cirtain M. C., Danks M. K., Felsted R. L., Safa A. R., Wolverton J. S., Suttle D. P., Trent J. M. Pharmacological, molecular, and cytogenetic analysis of "atypical" multidrug-resistant human leukemic cells. Cancer Res. 1987 Oct 15;47(20):5455–5460. [PubMed] [Google Scholar]
  6. Beck W. T. The cell biology of multiple drug resistance. Biochem Pharmacol. 1987 Sep 15;36(18):2879–2887. doi: 10.1016/0006-2952(87)90198-5. [DOI] [PubMed] [Google Scholar]
  7. Bellamy W. T., Dalton W. S., Gleason M. C., Grogan T. M., Trent J. M. Development and characterization of a melphalan-resistant human multiple myeloma cell line. Cancer Res. 1991 Feb 1;51(3):995–1002. [PubMed] [Google Scholar]
  8. 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. doi: 10.1002/ijc.2910580221. [DOI] [PubMed] [Google Scholar]
  9. Cole S. P., Bhardwaj G., Gerlach J. H., Mackie J. E., Grant C. E., Almquist K. C., Stewart A. J., Kurz E. U., Duncan A. M., Deeley R. G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4;258(5088):1650–1654. doi: 10.1126/science.1360704. [DOI] [PubMed] [Google Scholar]
  10. Cole S. P., Sparks K. E., Fraser K., Loe D. W., Grant C. E., Wilson G. M., Deeley R. G. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 1994 Nov 15;54(22):5902–5910. [PubMed] [Google Scholar]
  11. 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] [Google Scholar]
  12. Dalton W. S., Durie B. G., Alberts D. S., Gerlach J. H., Cress A. E. Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein. Cancer Res. 1986 Oct;46(10):5125–5130. [PubMed] [Google Scholar]
  13. Dalton W. S., Grogan T. M., Meltzer P. S., Scheper R. J., Durie B. G., Taylor C. W., Miller T. P., Salmon S. E. 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. doi: 10.1200/JCO.1989.7.4.415. [DOI] [PubMed] [Google Scholar]
  14. Dalton W. S., Grogan T. M., Rybski J. A., Scheper R. J., Richter L., Kailey J., Broxterman H. J., Pinedo H. M., Salmon S. E. 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] [Google Scholar]
  15. Danks M. K., Schmidt C. A., Cirtain M. C., Suttle D. P., Beck W. T. 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. doi: 10.1021/bi00424a026. [DOI] [PubMed] [Google Scholar]
  16. Danks M. K., Yalowich J. C., Beck W. T. 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] [Google Scholar]
  17. Doyle L. A., Ross D. D., Ordonez J. V., Yang W., Gao Y., Tong Y., Belani C. P., Gutheil J. C. An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein. Br J Cancer. 1995 Sep;72(3):535–542. doi: 10.1038/bjc.1995.370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goldin A., Venditti J. M., Macdonald J. S., Muggia F. M., Henney J. E., Devita V. T., 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. doi: 10.1016/0014-2964(81)90027-x. [DOI] [PubMed] [Google Scholar]
  19. Grindey G. B. Current status of cancer drug development: failure or limited success? Cancer Cells. 1990 Jun;2(6):163–171. [PubMed] [Google Scholar]
  20. Hall A. G., Cattan A. R. Drug resistance mechanisms in leukaemia. Baillieres Clin Haematol. 1991 Jul;4(3):655–681. doi: 10.1016/s0950-3536(09)90006-3. [DOI] [PubMed] [Google Scholar]
  21. Hochhauser D., Harris A. L. Drug resistance. Br Med Bull. 1991 Jan;47(1):178–196. doi: 10.1093/oxfordjournals.bmb.a072454. [DOI] [PubMed] [Google Scholar]
  22. Jensen P. B., Jensen P. S., Demant E. J., Friche E., Sørensen B. S., Sehested M., Wassermann K., Vindeløv L., Westergaard O., Hansen H. H. 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] [Google Scholar]
  23. Kramer R. A., 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. doi: 10.1126/science.3399900. [DOI] [PubMed] [Google Scholar]
  24. 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. doi: 10.1016/0959-8049(94)90136-8. [DOI] [PubMed] [Google Scholar]
  25. 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. doi: 10.1002/ijc.2910500204. [DOI] [PubMed] [Google Scholar]
  26. 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] [Google Scholar]
  27. 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] [Google Scholar]
  28. 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. doi: 10.1002/ijc.2910460114. [DOI] [PubMed] [Google Scholar]
  29. Lee J. S., Paull K., Alvarez M., Hose C., Monks A., Grever M., Fojo A. T., Bates S. E. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 1994 Oct;46(4):627–638. [PubMed] [Google Scholar]
  30. Liang P., Pardee A. B. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992 Aug 14;257(5072):967–971. doi: 10.1126/science.1354393. [DOI] [PubMed] [Google Scholar]
  31. Marsoni S., Hoth D., Simon R., Leyland-Jones B., De Rosa M., Wittes R. E. Clinical drug development: an analysis of phase II trials, 1970-1985. Cancer Treat Rep. 1987 Jan;71(1):71–80. [PubMed] [Google Scholar]
  32. Mirski S. E., Gerlach J. H., Cole S. P. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 1987 May 15;47(10):2594–2598. [PubMed] [Google Scholar]
  33. Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K., Vistica D., Hose C., Langley J., Cronise P., Vaigro-Wolff A. 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. doi: 10.1093/jnci/83.11.757. [DOI] [PubMed] [Google Scholar]
  34. Mulcahy R. T., Bailey H. H., Gipp J. J. 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. doi: 10.1007/BF00686114. [DOI] [PubMed] [Google Scholar]
  35. Nagourney R. A., Evans S. S., Messenger J. C., Su Y. Z., Weisenthal L. M. 2 chlorodeoxyadenosine activity and cross resistance patterns in primary cultures of human hematologic neoplasms. Br J Cancer. 1993 Jan;67(1):10–14. doi: 10.1038/bjc.1993.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nygren P., Csoka K., Jonsson B., Fridborg H., Bergh J., Hagberg H., Glimelius B., Brodin O., Tholander B., Kreuger A. 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. doi: 10.1038/bjc.1995.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nygren P., Fridborg H., Csoka K., Sundström C., de la Torre M., Kristensen J., Bergh J., Hagberg H., Glimelius B., Rastad J. 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. doi: 10.1002/ijc.2910560517. [DOI] [PubMed] [Google Scholar]
  38. 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] [Google Scholar]
  39. 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. doi: 10.1002/ijc.2910480419. [DOI] [PubMed] [Google Scholar]
  40. 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. doi: 10.1007/BF01116583. [DOI] [PubMed] [Google Scholar]
  41. 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. doi: 10.1038/bjc.1993.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Paull K. D., Shoemaker R. H., Hodes L., Monks A., Scudiero D. A., Rubinstein L., Plowman J., Boyd M. R. 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. doi: 10.1093/jnci/81.14.1088. [DOI] [PubMed] [Google Scholar]
  43. Weinstein J. N., Kohn K. W., Grever M. R., Viswanadhan V. N., Rubinstein L. V., Monks A. P., Scudiero D. A., Welch L., Koutsoukos A. D., Chiausa A. J. Neural computing in cancer drug development: predicting mechanism of action. Science. 1992 Oct 16;258(5081):447–451. doi: 10.1126/science.1411538. [DOI] [PubMed] [Google Scholar]
  44. Weinstein J. N., Myers T., Buolamwini J., Raghavan K., van Osdol W., Licht J., Viswanadhan V. N., Kohn K. W., Rubinstein L. V., Koutsoukos A. D. 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. doi: 10.1002/stem.5530120106. [DOI] [PubMed] [Google Scholar]
  45. Weisenthal L. M. Antineoplastic drug screening belongs in the laboratory, not in the clinic. J Natl Cancer Inst. 1992 Apr 1;84(7):466–469. doi: 10.1093/jnci/84.7.466. [DOI] [PubMed] [Google Scholar]
  46. van Kalken C. K., Pinedo H. M., Giaccone G. Multidrug resistance from the clinical point of view. Eur J Cancer. 1991;27(11):1481–1486. doi: 10.1016/0277-5379(91)90036-d. [DOI] [PubMed] [Google Scholar]
  47. van Osdol W. W., Myers T. G., Paull K. D., Kohn K. W., Weinstein J. N. 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. doi: 10.1093/jnci/86.24.1853. [DOI] [PubMed] [Google Scholar]

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

RESOURCES