Drug Resistance and Cancer

  • Charles S. Morrow
  • Kenneth Cowan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 330)


Systemic therapy with cytotoxic drugs is the basis of most effective treatments of disseminated cancers. Additionally, adjuvant chemotherapy can offer a significant survival advantage to selected patients following the treatment of localized disease with surgery or radiotherapy, presumably by eliminating undetected minimal or microscopic metastatic tumor. However, the responses of tumors to chemotherapeutic regimens vary and failures are frequent owing to the emergence of drug resistance. Patterns of treatment response and tumor sensitivity are conveniently divided into three groups. First, high complete response rates are common for some intrinsically drug-sensitive tumors such as childhood ALL, Hodgkin’s disease, non-Hodgkin’s lymphomas, and testicular cancer. A second group including tumors such as breast carcinomas, small cell lung cancers, and ovarian carcinomas are also usually highly responsive to initial treatments but more often become refractory to further therapy. Relapses in either group of tumors generally herald the emergence of tumor cells which are resistant to the antineoplastic agents used initially and often drugs to which the patient was never exposed. Therefore, success with salvage chemotherapies has been limited. Finally, a third common pattern of drug sensitivity is found in tumors which are intrinsically resistant to most chemotherapeutic agents. This group is represented by malignancies such as non-small cell lung cancers, malignant melanoma, and colon cancer. For these tumors, the number of active antineoplastic agents is few and significant chemotherapeutic responses are effected in a minority of cases.


Drug Resistance Multidrug Resistance Antineoplastic Agent Antineoplastic Drug High Complete Response Rate 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Andoh, T., Ishii, K., Suzuki, Y., Ikegami, Y., Kusunoki, Y. and Okada, K.: Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I. Proc. Natl. Acad. Sci., 84:5565, 1987.PubMedCrossRefGoogle Scholar
  2. 2.
    Anthony, A. C., Kane, M. A., Portillo, R. M., Elwood, P. C. and Kolhouse, J.F.: Studies of the role of a paniculate folate-binding protein in the uptake of 5-methyl-tetrahydrofolate by cultured human KB cells. J. Biol. Chem., 260:14911, 1985.Google Scholar
  3. 3.
    Armstrong, R. A.: Fluoropyrimidine activity and resistance at the cellular level. In Resistance to antineoplastic drugs. Edited by D. Kessel, Boca Raton, Florida, CRC Press, 1989, p. 317.Google Scholar
  4. 4.
    Bates, S. E., Mickley, L. A., Chen, Y.-N., Richert, N., Rudick, J., Biedler, J. L. and Fojo, A. T.: Expression of a drug resistant gene in human neuroblastoma cell lines: modulation by retinoic acid-induced differention. Mol. Cell Biol., 9:4337, 1989.PubMedGoogle Scholar
  5. 5.
    Bell, D. R., Gerlach, J. H., Kartner, N., Buick, R. N. and Ling, V: Detection of P-glycoprotein in ovarian cancer: a molecular marker associated with multidrug resistance. J. Clin. Onc., 3:311, 1985.Google Scholar
  6. 6.
    Biedler, J. L. and Riehm, H.: Cellular resistance to actinomycin D in Chinese Hamster ovary cells in vitro: cross resistance, radioautographic, and cytogenetic studies. Cancer Res., 30:1174, 1970.PubMedGoogle Scholar
  7. 7.
    Brockmann, R. W.: Mechanisms of resistance to the anticancer agents. Adv. Cancer Res., 7:129, 1963.CrossRefGoogle Scholar
  8. 8.
    Chambers, T. C., McAvoy, E. M., Jacobs, J. W. and Eilon, G.: Protein kinase C phosphorylates P-glycoprotein in multidrug resistant human KB carcinoma cells. J. Biol. Chem., 265:7679, 1990.PubMedGoogle Scholar
  9. 9.
    Chan, H. S. L., Thorner, P. S., Haddad, G. and Ling, V: Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J. Clin. Oncol., 8:689, 1990.PubMedGoogle Scholar
  10. 10.
    Chen, C., Chin, J. E., Ueda, K., Clark, D. P., Pastan, I., Gottesman, M. M. and Roninson, I. B.: Internal depletion and homology with bacterial transport proteins in the mdr1 gene for multidrug-resistant human cells. Cell, 47:381, 1986.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen, Y.-N., Mickley, L. A., Schwartz, A. M., Acton, E. M., Hwang, J. and Fojo, A. T.: Characterization of Adriamycin resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein. J. Biol. Chem., 265:10073, 1990.PubMedGoogle Scholar
  12. 12.
    Chin, K., Tanaka, S., Darlington, G., Pastan, I. and Gottesman, M. M.: Heat shock and arsenate increase expression of multidrug resistance (MDR1) gene in human renal carcinoma cells. J. Biol. Chem., 265:221, 1990.PubMedGoogle Scholar
  13. 13.
    Chin, K.-V., Chauhan, S. S., Pastan, I. and Gottesman, M. M.: Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. Cell Growth Differentiation, 1:361, 1990.PubMedGoogle Scholar
  14. 14.
    Choi, K., Chen, C., Kriegler, M. and Roninson, I. B.: An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell, 53:519, 1988.PubMedCrossRefGoogle Scholar
  15. 15.
    Cowan, K. H., Batist, G., Tulpule, A., Sinha, B. K. and Myers, C. E.: Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. Proc. Natl. Acad. Sci., 83:9328, 1986.PubMedCrossRefGoogle Scholar
  16. 16.
    Dalton, W. S., Grogan, T. M., Rybski, J. A., Scheper, R. J., Richter, L., Kailey, J., Broxterman, H. J., Pinedo, H. M. and 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, 73:747, 1989.PubMedGoogle Scholar
  17. 17.
    Danks, M. K, Schmidt, C. A., Cirtain, M. C., Suttle, D. P. and Beck, W. T.: Altered catalytic activity of and DNA cleavage by DNA topoisomerase II from human leukemia cells selected for resistance to VM-26. Biochemistry, 27:8861, 1988.PubMedCrossRefGoogle Scholar
  18. 18.
    Deffie, A. M., Batra, J. K. and Goldenberg, G. J.: Direct correlation between DNA topoisomerase II activity and cytotoxicity in Adriamycin-sensitive and resistant P388 leukemia cell lines. Cancer Res., 49:58, 1989.PubMedGoogle Scholar
  19. 19.
    Drahovsky, D. and Kreis, W.: Studies on drug resistance. IL Kinase patterns in P815 neoplasms sensitive and resistant to 1-ß-D-arabinofuranosyl cytosine. Biochem. Pharmacol, 19:940, 1970.PubMedCrossRefGoogle Scholar
  20. 20.
    Endicott, J. A. and Ling, V.: The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu. Rev. Biochem., 58:137, 1989.PubMedCrossRefGoogle Scholar
  21. 21.
    Fairchild, C. R., Ivy, S. P., Kao-Shaw, C.-S., Whang-Peng, J., Rosen, N., Israel, M. A., Melera, P. W., Cowan, K. H. and Goldsmith, M. E.: Isolation of amplified and overexpressed DNA sequences from adriamycin-resistant human breast cancer cells. Cancer Res., 47:5141, 1987.PubMedGoogle Scholar
  22. 22.
    Fairchild, C. R., Ivy, S. P., Rushmore, T., Lee, G., Koo, P., Goldsmith, M.E., Myers, C. E., Farber, E. and Cowan, K. H.: Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas. Proc. Natl. Acad. Sci., 84:7701, 1987.PubMedCrossRefGoogle Scholar
  23. 23.
    Fairchild, C. R., Moscow, J. A., O’Brien, E. E. and Cowan, K. H.: Multidrug resistance in cells transfected with human genes encoding a variant P-glycoprotein and glutathione S-transferase-pi. Mol. Pharmacol., 37:801, 1990.PubMedGoogle Scholar
  24. 24.
    Farber, E.: Cellular biochemistry of the stepwise development of cancer with chemicals. Cancer Res., 44:5463, 1984.PubMedGoogle Scholar
  25. 25.
    Giovanella, B. C., Stehlin, J. S., Wall, M. E., Wani, M. C., Nicholas, A. W., Liu, L. F., Silber, R. and Potmesil, M.: DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science, 246:1046, 1989.PubMedCrossRefGoogle Scholar
  26. 26.
    Glisson, B., Gupta, R., Smallwood-Kentro, S. and Ross, W.: Characterization of acquired epipodophylotoxin resistance in a Chinese hamster ovary cell line: loss of drug-stimulated DNA cleavage activity. Cancer Res., 46:1934, 1986.PubMedGoogle Scholar
  27. 27.
    Goldenberg, G. J., Vanstone, C. L., Isreals, L. G., Isle, D. and Bihler, D.: Evidence for a transport carrier of nitrogen mustard in nitrogen mustard-sensitive and-resistant L5178Y lymphoblasts. Cancer Res., 30:2285, 1970.PubMedGoogle Scholar
  28. 28.
    Goldstein, L. J., Fojo, A. T., Ueda, K., Crist, W., Green, A., Brodeur, G., Pastan, I. and Gottesman, M. M.: Expression of the multidrug resistant, MDR1, gene in neuroblastoma. J. Clin. Oncol., 8:128, 1990.PubMedGoogle Scholar
  29. 29.
    Goldstein, L. J., Galski, H., Fojo, A., Willingham, M., Lai, S.-L., Gazdar, A., Pirker, R., Green, A., Crist, W., Brodeur, G. M., Lieber, M., Cossman, J., Gottesman, M. M. and Pastan, I.: Expression of a multidrug resistance gene in human cancers. J. Natl. Cancer Inst., 81:116, 1989.PubMedCrossRefGoogle Scholar
  30. 30.
    Gottesman, M. M. and Pastan, I.: Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharmacol. Sci., 9:54, 1988.PubMedCrossRefGoogle Scholar
  31. 31.
    Gros, P., Ben Neriah, Y., Croop, J. M. and Houseman, D. E.: Isolation and expression of a complimentary DNA that confers multidrug resistance. Nature, 323:728, 1986.PubMedCrossRefGoogle Scholar
  32. 32.
    Gros, P., Croop, J. and Houseman, D.: Mammalian multidrug resistant gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell, 47:371, 1986.PubMedCrossRefGoogle Scholar
  33. 33.
    Haber, D. A., Beverly, S. M., Kiely, M. L. and Schimke, R. T.: Properties of altered dehydrofolate reductase encoded by amplified genes in cultured mouse fibroblasts. J. Biol. Chem., 256:9501, 1981.PubMedGoogle Scholar
  34. 34.
    Hill, B. T., Bailey, B. D., White, J. C. and Goldman, I. D.: Characteristics of transport of 4-amino antifolates and folate compounds by two cell lines of LY5178Y lymphoblasts, one with impaired transport of methotraxate. Cancer Res., 39:2440, 1979.PubMedGoogle Scholar
  35. 35.
    Hill, B. T., Deuchars, K., Hosking, L. K., Ling, V. and Whelan, R. D. H.: Over expression of P-glycoprotein in mammalian tumor cell lines after fractionated X irradiation in vitro. J. Natl Cancer Inst., 82:607, 1990.PubMedCrossRefGoogle Scholar
  36. 36.
    Hill, B. T., Price, L. A. and Goldie, J. H.: The value of adriamycin in overcoming resistance to methotrexate in cell culture. Eur. J. Cancer, 12:541, 1976.PubMedGoogle Scholar
  37. 37.
    Houghton, J. A., Maroda, S. J., Phillips, J. O. and Houghton, P. J.: Biochemical determents of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice. Cancer Res., 41:144, 1981.PubMedGoogle Scholar
  38. 38.
    Hunt, S. W. and Hoffee, P. A.: Amplification of adenosine deaminase gene sequence in deoxycoformycin-resistant rat hepatoma cells. J. Biol. Chem., 258:13185, 1983.PubMedGoogle Scholar
  39. 39.
    Juliano, R. L. and Ling, V: A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem. Biophys. Acta, 455:1252, 1976.Google Scholar
  40. 40.
    Keith, W. N., Stallard, S. and Brown, R.: Expression of mdr1 and GST π in human breast tumors: comparison to in vitro sensitivity. Br. J. Cancer, 61:712, 1990.PubMedCrossRefGoogle Scholar
  41. 41.
    Liu, L.: DNA topoisomerase poisons as antitumor drugs. Anna. Rev. Biochem., 58:351, 1989.CrossRefGoogle Scholar
  42. 42.
    Ma, D. D., Scurr, R. D., Davey, R. A., Mackertich, S. M., Dowden, G. and Bell, D. R.: Detection of a multidrug resistant phenotype in acute nonlymphoblastic leukaemia. Lancet, 1(8525): 135, 1987.PubMedCrossRefGoogle Scholar
  43. 43.
    Mannervik, B. and Danielson, U. H.: Glutathione transferases-structure and catalytic activity. Critical Reviews in Biochemistry, 23:283, 1988.PubMedCrossRefGoogle Scholar
  44. 44.
    Marquardt, D., McCrone, S. and Center, M. S.: Mechanisms of multidrug resistance in HL60 cells: detection of resistance-associated proteins with antibodies against synthetic peptides that correspond to the deduced sequences of P-glycoprotein. Cancer Res., 50:1426, 1990.PubMedGoogle Scholar
  45. 45.
    Marsh, W. and Center, M.: Adriamycin resitance in HL60 cells and accompanying modification of a surface membrane protein contained in drug-sensitive cells. Cancer Res., 47:5080, 1987.PubMedGoogle Scholar
  46. 46.
    McGrath, T., Latoud, C., Arnold, S. T., Safa, A. R., Felsted, R. L. and Center, M. S.: Mechanisms of multidrug resistance in HL60 cells. Analysis of resistance associated membrane proteins and levels of mdr gene expression. Biochem. Pharmacol., 38:3611, 1989.PubMedCrossRefGoogle Scholar
  47. 47.
    Mickisch, G., Bier, H., Bergler, W., Bak, M., Tschada, R. and Alken, P.: P-170 glycoprotein, glutathione and associated enzymes in relation to chemoresistance of primary human renal cell carcinomas. Urol. Int., 45:170, 1990.PubMedCrossRefGoogle Scholar
  48. 48.
    Mickley, L. A., Bates, S. E., Richert, N. D., Currier, S., Tanaka, S., Foss, F., Rosen, N. and Fojo, A. T.: Modulation of the expression of a multidrug resistance gene (mdr 1/P-glycoprotein) by differentiating agents. J. Biol. Chem., 264:18031, 1989.PubMedGoogle Scholar
  49. 49.
    Morrow, C. S. and Cowan, K. H.: Glutathione 5-transferases and drug resistance. Cancer Cells, 2:15, 1990.PubMedGoogle Scholar
  50. 50.
    Moscow, J. A., Townsend, A. J. and Cowan, K.H.: Elevation of the π class glutathione S-transferase activity in human breast cancer cells by transfection of the GST π gene and its effect on sensitivity to toxins. Mol. Pharmacol., 36:22, 1989.PubMedGoogle Scholar
  51. 51.
    Nakagawa, K., Saijo, N., Tsuchida, S., Sakai, M., Tsunokawa, Y., Yokota, J., Muramatsu, M., Sato, K., Tekada, M. and Tew, K. D.: Glutathione S-transferase π as a determinant of drug resistance in transfectant cell lines. J. Biol. Chem., 265:4296, 1990.PubMedGoogle Scholar
  52. 52.
    Ohtsu, T., Ishida, Y., Tobinai, K., Minato, K., Hamada, H., Ohkodu, E., Tsuruo, T. and Shimoyama, M.: A novel multidrug resistance in cultured leukemia and lymphoma cells detected by a monoclonal antibody to 85kD protein, MRK20. Japan. J. Cancer Res., 80:1133, 1989.CrossRefGoogle Scholar
  53. 53.
    Per, S.-R., Mattern, M. R., Mirabelli, C. K., Drake, F. H., Johnson, R. K. and Crooke, S. T.: Characterization of a subline of P388 leukemia resistant to amsacrine: evidence of altered topoisomerase II function. Mol. Pharmacol., 32:17, 1987.PubMedGoogle Scholar
  54. 54.
    Pommier, Y., Kerrigan, D., Schwartz, R. E., Swack, J. A. and A., M.: Altered DNA topoisomerase II activity in Chinese hamster cells resistant to topoisomerase II inhibitors. Cancer Res., 46:3075, 1986.PubMedGoogle Scholar
  55. 55.
    Puchalski, R. B. and Fahl, W. E.: Expression of recombinant glutathione S-transferase π, Ya or Yb1 confers resistance to alkylating agents. Proc. Natl. Acad. Sci., 87:1990.Google Scholar
  56. 56.
    Riordan, J. R. and Ling, V: Genetic and biochemical characterization of multidrug resistance. Pharmacol. Ther., 28:51, 1985.PubMedCrossRefGoogle Scholar
  57. 57.
    Rothenberg, M. L., Mickley, L. A., Cole, D. E., Balis, F. M., Tsuruo, T., Poplack, D. and Fojo, A. T: Expression of the mdr1 gene/P-170 gene in patients with acute lymphoblastic leukemia. Blood, 74:1388, 1989.PubMedGoogle Scholar
  58. 58.
    Safa, A. R., Glover, C. J., Meyers, M. B., Biedler, J. L. and Felsted, R. L.: Vinblastine photoaffinity labeling of a high molecular weight surface membrane glycoprotein specific for multidrug-resistant cells. J. Biol. Chem., 261:6137, 1986.PubMedGoogle Scholar
  59. 59.
    Sato, H., Gottesman, M. M., Goldstein, L., J., Pastan, I., Block, A., Sandberg, A. A. and Preisler, H. D.: Expression of the multidrug reistance gene in myeloid leukemias. Leukemia Res., 14:11, 1990.CrossRefGoogle Scholar
  60. 60.
    Schneider, J., Bak, M., Efferth, T. H., Kaufmann, M., Mattren, J. and Volm, M.: P-glycoprotein expression in treated and untreated breast cancer. Br. J. Cancer, 60:815, 1989.PubMedCrossRefGoogle Scholar
  61. 61.
    Sirotnak, F.M., Moccio, D.M., Kelleher, L.E. and Goutsas, L.J.: Relative frequency and kinetic properties of transport defective phenotypes among methotrexate-resistant L1210 clonal cell lines derived in vivo. Cancer Res., 41:4447, 1981.PubMedGoogle Scholar
  62. 62.
    Staats, J., Marquardt, D. and Center, M. S.: Characteristics of a membraneassociated protein kinase of multidrug-resistant HL60 cells which phosphorylates P-glycoprotein. J. Biol. Chem., 265:4084, 1990.PubMedGoogle Scholar
  63. 63.
    Steuart, C. D. and Burke, P. J.: Cytidine deaminase and the development of resistance to cytosine arabinoside. Nature (London) New Biol., 233:109, 1971.CrossRefGoogle Scholar
  64. 64.
    Teicher, B. A., Cucchi, C. A., Lee, J. B., Flatow, J. L., Rosowsky, A. and Frei, E., III: Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. Cancer Res., 46:4379, 1986.PubMedGoogle Scholar
  65. 65.
    Thorgeirsson, S. S., Huber, B. E., Sorrel, S., Fojo, A., Pastan, I. and Gottesman, M. M.: Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating liver. Science, 236:1120, 1987.PubMedCrossRefGoogle Scholar
  66. 66.
    Townsend, A J. and Cowan, K. H.: Glutathione S-transferases and antineoplastic drug resistance. Cancer Bull., 41:31, 1989.Google Scholar
  67. 67.
    Ueda, K., Cardarelli, C., Gottesman, M. M. and Pastan, I.: Expression of a full-length cDNA from the human mdr1 gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc. Natl. Acad. Sci., 84:3004, 1987.PubMedCrossRefGoogle Scholar
  68. 68.
    Zhang, H., D’Arpa, P. and Liu, L. E: A model for tumor cell killing by topoisomerase poisons. Cancer Cells, 2:23, 1990.PubMedGoogle Scholar
  69. 69.
    Zwelling, L. A., Hinds, M., Chan, D., Mayes, J., Sie, K. L., Parker, E., Silberman, L., Radcliffe, A., Beran, M. and Blick, M.: Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II. J. Biol. Chem., 264:16411, 1989.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Charles S. Morrow
    • 1
  • Kenneth Cowan
    • 1
  1. 1.Medicine Branch, Division of Cancer TreatmentNational Cancer InstituteBethesdaUSA

Personalised recommendations