Advertisement

Clinical & Experimental Metastasis

, Volume 35, Issue 4, pp 309–318 | Cite as

The challenge of drug resistance in cancer treatment: a current overview

  • Michail Nikolaou
  • Athanasia Pavlopoulou
  • Alexandros G. Georgakilas
  • Efthymios KyrodimosEmail author
Research Paper

Abstract

It is generally accepted that recent advances in anticancer agents have contributed significantly to the improvement of both the disease-free survival and quality of life in cancer patients. However, in many instances, a favorable initial response to treatment changes afterwards, thereby leading to cancer relapse and recurrence. This phenomenon of acquired resistance to therapy, it is a major problem for totally efficient anticancer therapy. The failure to obtain an initial response reflects a form of intrinsic resistance. Specific cell membrane transporter proteins are implicated in intrinsic drug resistance by altering drug transport and pumping drugs out of the tumor cells. Moreover, the gradual acquisition of specific genetic and epigenetic abnormalities in cancer cells could contribute greatly to acquired drug resistance. A critical issue in the clinical setting, is that the problem of drug resistance appears to have a negative effect on also the new molecularly-targeted anticancer drugs. Several ongoing efforts are being made by the medical community aimed to the identification of such resistance mechanisms and the development of novel drugs that could overcome them. In this review, the major drug resistance mechanisms and strategies to overcome them are critically discussed, and also possible future directions are suggested.

Keywords

Drug resistance Acquired resistance Chemotherapy resistance Multidrug resistance Tumor microenvironment Cancer 

Abbreviations

MDR

Multidrug resistance

ABC

Adenosine triphosphate-binding cassette

DHFR

Dihydrofolate reductase

NER

Nucleotide excision repair

MTD

Maximum tolerated dose

Notes

Acknowledgements

Dr. A.G. Georgakilas acknowledges funding from DAAD Grant “DNA Damage and Repair and Their Relevance to Carcinogenesis” (No. 57339330).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627.  https://doi.org/10.1146/annurev.med.53.082901.103929 PubMedCrossRefGoogle Scholar
  2. 2.
    Clynes M (1998) Multiple drug resistance in cancer 2: molecular, cellular and clinical aspects. Kluwer Academic Publishers, DodrechtCrossRefGoogle Scholar
  3. 3.
    Ebos JM (2015) Prodding the beast: assessing the Impact of treatment-induced metastasis. Cancer Res 75(17):3427–3435.  https://doi.org/10.1158/0008-5472.CAN-15-0308 PubMedCrossRefGoogle Scholar
  4. 4.
    Sherlach KS, Roepe PD (2014) Drug resistance associated membrane proteins. Front Physiol 5:108.  https://doi.org/10.3389/fphys.2014.00108 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7(3):339–348.  https://doi.org/10.15171/apb.2017.041 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Gottesman MM, Ludwig J, Xia D, Szakacs G (2006) Defeating drug resistance in cancer. Discov Med 6(31):18–23PubMedGoogle Scholar
  7. 7.
    Pavlopoulou A, Oktay Y, Vougas K, Louka M, Vorgias CE, Georgakilas AG (2016) Determinants of resistance to chemotherapy and ionizing radiation in breast cancer stem cells. Cancer Lett 380(2):485–493.  https://doi.org/10.1016/j.canlet.2016.07.018 PubMedCrossRefGoogle Scholar
  8. 8.
    Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, Daenen LG, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Strieter RM, Bertolini F, Voest EE, Benezra R, Kerbel RS (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14(3):263–273.  https://doi.org/10.1016/j.ccr.2008.08.001 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S (2014) Drug resistance in cancer: an overview. Cancers 6(3):1769–1792.  https://doi.org/10.3390/cancers6031769 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Joo WD, Visintin I, Mor G (2013) Targeted cancer therapy—are the days of systemic chemotherapy numbered? Maturitas 76(4):308–314.  https://doi.org/10.1016/j.maturitas.2013.09.008 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kummar S, Gutierrez M, Doroshow JH, Murgo AJ (2006) Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br J Clin Pharmacol 62(1):15–26.  https://doi.org/10.1111/j.1365-2125.2006.02713.x PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Groenendijk FH, Bernards R (2014) Drug resistance to targeted therapies: deja vu all over again. Mol Oncol 8(6):1067–1083.  https://doi.org/10.1016/j.molonc.2014.05.004 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5(3):219–234.  https://doi.org/10.1038/nrd1984 PubMedCrossRefGoogle Scholar
  14. 14.
    Synold TW, Dussault I, Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7(5):584–590.  https://doi.org/10.1038/87912 PubMedCrossRefGoogle Scholar
  15. 15.
    Liu YY, Han TY, Giuliano AE, Cabot MC (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15(3):719–730.  https://doi.org/10.1096/fj.00-0223com PubMedCrossRefGoogle Scholar
  16. 16.
    Torgovnick A, Schumacher B (2015) DNA repair mechanisms in cancer development and therapy. Front Genet 6:157.  https://doi.org/10.3389/fgene.2015.00157 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74(6):957–967PubMedCrossRefGoogle Scholar
  18. 18.
    Fojo T (2007) Multiple paths to a drug resistance phenotype: mutations, translocations, deletions and amplification of coding genes or promoter regions, epigenetic changes and microRNAs. Drug Resist Updates 10 (1–2):59–67.  https://doi.org/10.1016/j.drup.2007.02.002 CrossRefGoogle Scholar
  19. 19.
    Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481(7381):306–313.  https://doi.org/10.1038/nature10762 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194(4260):23–28PubMedCrossRefGoogle Scholar
  21. 21.
    Goldie JH, Coldman AJ (1979) A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63(11–12):1727–1733PubMedGoogle Scholar
  22. 22.
    Goldie JH, Coldman AJ (1985) Genetic instability in the development of drug resistance. Semin Oncol 12(3):222–230PubMedGoogle Scholar
  23. 23.
    Coldman AJ, Goldie JH (1986) A stochastic model for the origin and treatment of tumors containing drug-resistant cells. Bull Math Biol 48(3–4):279–292PubMedCrossRefGoogle Scholar
  24. 24.
    Woodhouse JR, Ferry DR (1995) The genetic basis of resistance to cancer chemotherapy. Ann Med 27(2):157–167PubMedCrossRefGoogle Scholar
  25. 25.
    Angerer WP (2001) An explicit representation of the Luria-Delbruck distribution. J Math Biol 42(2):145–174PubMedCrossRefGoogle Scholar
  26. 26.
    Dewanji A, Luebeck EG, Moolgavkar SH (2005) A generalized Luria-Delbruck model. Math Biosci 197(2):140–152.  https://doi.org/10.1016/j.mbs.2005.07.003 PubMedCrossRefGoogle Scholar
  27. 27.
    Frank SA (2003) Somatic mosaicism and cancer: inference based on a conditional Luria-Delbruck distribution. J Theor Biol 223(4):405–412PubMedCrossRefGoogle Scholar
  28. 28.
    Haeno H, Iwasa Y, Michor F (2007) The evolution of two mutations during clonal expansion. Genetics 177(4):2209–2221.  https://doi.org/10.1534/genetics.107.078915 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Iwasa Y, Nowak MA, Michor F (2006) Evolution of resistance during clonal expansion. Genetics 172(4):2557–2566.  https://doi.org/10.1534/genetics.105.049791 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Komarova NL, Mironov V (2005) On the role of endothelial progenitor cells in tumor neovascularization. J Theor Biol 235(3):338–349.  https://doi.org/10.1016/j.jtbi.2005.01.014 PubMedCrossRefGoogle Scholar
  31. 31.
    Komarova NL, Wodarz D (2005) Drug resistance in cancer: principles of emergence and prevention. Proc Natl Acad Sci USA 102(27):9714–9719.  https://doi.org/10.1073/pnas.0501870102 PubMedCrossRefGoogle Scholar
  32. 32.
    Beketic-Oreskovic L, Duran GE, Chen G, Dumontet C, Sikic BI (1995) Decreased mutation rate for cellular resistance to doxorubicin and suppression of mdr1 gene activation by the cyclosporin PSC 833. J Natl Cancer Inst 87(21):1593–1602PubMedCrossRefGoogle Scholar
  33. 33.
    Chen G, Jaffrezou JP, Fleming WH, Duran GE, Sikic BI (1994) Prevalence of multidrug resistance related to activation of the mdr1 gene in human sarcoma mutants derived by single-step doxorubicin selection. Cancer Res 54(18):4980–4987PubMedGoogle Scholar
  34. 34.
    Dumontet C, Duran GE, Steger KA, Beketic-Oreskovic L, Sikic BI (1996) Resistance mechanisms in human sarcoma mutants derived by single-step exposure to paclitaxel (Taxol). Cancer Res 56(5):1091–1097PubMedGoogle Scholar
  35. 35.
    Jaffrezou JP, Chen G, Duran GE, Kuhl JS, Sikic BI (1994) Mutation rates and mechanisms of resistance to etoposide determined from fluctuation analysis. J Natl Cancer Inst 86(15):1152–1158PubMedCrossRefGoogle Scholar
  36. 36.
    Chen KG, Wang YC, Schaner ME, Francisco B, Duran GE, Juric D, Huff LM, Padilla-Nash H, Ried T, Fojo T, Sikic BI (2005) Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line. Cancer Res 65(20):9388–9397.  https://doi.org/10.1158/0008-5472.CAN-04-4133 PubMedCrossRefGoogle Scholar
  37. 37.
    Matsumoto Y, Takano H, Fojo T (1997) Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype. Cancer Res 57(22):5086–5092PubMedGoogle Scholar
  38. 38.
    Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New Engl J Med 366(10):883–892.  https://doi.org/10.1056/NEJMoa1113205 PubMedCrossRefGoogle Scholar
  39. 39.
    Lee AJ, Swanton C (2012) Tumour heterogeneity and drug resistance: personalising cancer medicine through functional genomics. Biochem Pharmacol 83(8):1013–1020.  https://doi.org/10.1016/j.bcp.2011.12.008 PubMedCrossRefGoogle Scholar
  40. 40.
    Swanton C (2012) Intratumor heterogeneity: evolution through space and time. Cancer Res 72(19):4875–4882.  https://doi.org/10.1158/0008-5472.CAN-12-2217 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Alt FW, Kellems RE, Bertino JR, Schimke RT (1992) Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. 1978. Biotechnology 24:397–410PubMedGoogle Scholar
  42. 42.
    Wang YC, Juric D, Francisco B, Yu RX, Duran GE, Chen GK, Chen X, Sikic BI (2006) Regional activation of chromosomal arm 7q with and without gene amplification in taxane-selected human ovarian cancer cell lines. Genes Chromosomes Cancer 45(4):365–374.  https://doi.org/10.1002/gcc.20300 PubMedCrossRefGoogle Scholar
  43. 43.
    Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang T, Nephew KP (2012) Epigenetic resensitization to platinum in ovarian cancer. Cancer Res 72(9):2197–2205.  https://doi.org/10.1158/0008-5472.CAN-11-3909 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Balch C, Nephew KP (2013) Epigenetic targeting therapies to overcome chemotherapy resistance. Adv Exp Med Biol 754:285–311.  https://doi.org/10.1007/978-1-4419-9967-2_14 PubMedCrossRefGoogle Scholar
  45. 45.
    Wilting RH, Dannenberg JH (2012) Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist Updates 15 (1–2):21–38.  https://doi.org/10.1016/j.drup.2012.01.008 CrossRefGoogle Scholar
  46. 46.
    Zeller C, Dai W, Steele NL, Siddiq A, Walley AJ, Wilhelm-Benartzi CS, Rizzo S, van der Zee A, Plumb JA, Brown R (2012) Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. Oncogene 31(42):4567–4576.  https://doi.org/10.1038/onc.2011.611 PubMedCrossRefGoogle Scholar
  47. 47.
    Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25(10):1010–1022.  https://doi.org/10.1101/gad.2037511 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P, Carroll WL (2012) Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 119(22):5201–5210.  https://doi.org/10.1182/blood-2012-01-401687 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Issa ME, Takhsha FS, Chirumamilla CS, Perez-Novo C, Vanden Berghe W, Cuendet M (2017) Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clin Epigenetics 9:17.  https://doi.org/10.1186/s13148-017-0319-5 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Huang Y (2007) Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy. Cancer Metastasis Rev 26(1):183–201.  https://doi.org/10.1007/s10555-007-9050-6 PubMedCrossRefGoogle Scholar
  51. 51.
    Gottesman MM, Ambudkar SV (2001) Overview: ABC transporters and human disease. J Bioenerg Biomembr 33(6):453–458PubMedCrossRefGoogle Scholar
  52. 52.
    Glavinas H, Krajcsi P, Cserepes J, Sarkadi B (2004) The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv 1(1):27–42CrossRefGoogle Scholar
  53. 53.
    Campos L, Guyotat D, Archimbaud E, Calmard-Oriol P, Tsuruo T, Troncy J, Treille D, Fiere D (1992) Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79(2):473–476PubMedGoogle Scholar
  54. 54.
    Dalton WS, Grogan TM, Meltzer PS, Scheper RJ, Durie BG, Taylor CW, Miller TP, Salmon SE (1989) 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 7(4):415–424.  https://doi.org/10.1200/JCO.1989.7.4.415 PubMedCrossRefGoogle Scholar
  55. 55.
    Marie JP, Zittoun R, Sikic BI (1991) Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78(3):586–592PubMedGoogle Scholar
  56. 56.
    Miller TP, Grogan TM, Dalton WS, Spier CM, Scheper RJ, Salmon SE (1991) P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. J Clin Oncol 9(1):17–24.  https://doi.org/10.1200/JCO.1991.9.1.17 PubMedCrossRefGoogle Scholar
  57. 57.
    Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22(47):7468–7485.  https://doi.org/10.1038/sj.onc.1206948 PubMedCrossRefGoogle Scholar
  58. 58.
    Bradshaw DM, Arceci RJ (1998) Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J Clin Oncol 16(11):3674–3690.  https://doi.org/10.1200/JCO.1998.16.11.3674 PubMedCrossRefGoogle Scholar
  59. 59.
    Clarke R, Leonessa F, Trock B (2005) Multidrug resistance/P-glycoprotein and breast cancer: review and meta-analysis. Semin Oncol 32(6 Suppl 7):S9–S15.  https://doi.org/10.1053/j.seminoncol.2005.09.009 CrossRefGoogle Scholar
  60. 60.
    Mahadevan D, List AF (2004) Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood 104(7):1940–1951.  https://doi.org/10.1182/blood-2003-07-2490 PubMedCrossRefGoogle Scholar
  61. 61.
    Fisher GA, Sikic BI (1995) Clinical studies with modulators of multidrug resistance. Hematol/Oncol Clin N Am 9(2):363–382CrossRefGoogle Scholar
  62. 62.
    Sikic BI (1993) Modulation of multidrug resistance: at the threshold. J Clin Oncol 11(9):1629–1635.  https://doi.org/10.1200/JCO.1993.11.9.1629 PubMedCrossRefGoogle Scholar
  63. 63.
    Sikic BI (1997) Pharmacologic approaches to reversing multidrug resistance. Semin Hematol 34(4 Suppl 5):40–47PubMedGoogle Scholar
  64. 64.
    Capranico G, De Isabella P, Castelli C, Supino R, Parmiani G, Zunino F (1989) P-glycoprotein gene amplification and expression in multidrug-resistant murine P388 and B16 cell lines. Br J Cancer 59(5):682–685PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Shukla S, Chen ZS, Ambudkar SV (2012) Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist Updates 15 (1–2):70–80.  https://doi.org/10.1016/j.drup.2012.01.005 CrossRefGoogle Scholar
  66. 66.
    Chang XB (2007) A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. Cancer Metastasis Rev 26(1):15–37.  https://doi.org/10.1007/s10555-007-9041-7 PubMedCrossRefGoogle Scholar
  67. 67.
    Burg D, Wielinga P, Zelcer N, Saeki T, Mulder GJ, Borst P (2002) Inhibition of the multidrug resistance protein 1 (MRP1) by peptidomimetic glutathione-conjugate analogs. Mol Pharmacol 62(5):1160–1166PubMedCrossRefGoogle Scholar
  68. 68.
    Chen YN, Mickley LA, Schwartz AM, Acton EM, Hwang JL, Fojo AT (1990) Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein. J Biol Chem 265(17):10073–10080PubMedGoogle Scholar
  69. 69.
    Robey RW, Polgar O, Deeken J, To KW, Bates SE (2007) ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26(1):39–57.  https://doi.org/10.1007/s10555-007-9042-6 PubMedCrossRefGoogle Scholar
  70. 70.
    Bates SE, Robey R, Miyake K, Rao K, Ross DD, Litman T (2001) The role of half-transporters in multidrug resistance. J Bioenerg Biomembr 33(6):503–511PubMedCrossRefGoogle Scholar
  71. 71.
    Ross DD, Yang W, Abruzzo LV, Dalton WS, Schneider E, Lage H, Dietel M, Greenberger L, Cole SP, Doyle LA (1999) Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst 91(5):429–433PubMedCrossRefGoogle Scholar
  72. 72.
    Westover D, Ling X, Lam H, Welch J, Jin C, Gongora C, Del Rio M, Wani M, Li F (2015) FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance. Mol Cancer 14:92.  https://doi.org/10.1186/s12943-015-0362-9 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Dumontet C, Sikic BI (1999) Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J Clin Oncol 17(3):1061–1070.  https://doi.org/10.1200/JCO.1999.17.3.1061 PubMedCrossRefGoogle Scholar
  74. 74.
    Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22(47):7280–7295.  https://doi.org/10.1038/sj.onc.1206934 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Seve P, Mackey J, Isaac S, Tredan O, Souquet PJ, Perol M, Lai R, Voloch A, Dumontet C (2005) Class III beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther 4(12):2001–2007.  https://doi.org/10.1158/1535-7163.MCT-05-0244 PubMedCrossRefGoogle Scholar
  76. 76.
    Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV (2003) Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 3(1):1–19PubMedCrossRefGoogle Scholar
  77. 77.
    Rouzier R, Rajan R, Wagner P, Hess KR, Gold DL, Stec J, Ayers M, Ross JS, Zhang P, Buchholz TA, Kuerer H, Green M, Arun B, Hortobagyi GN, Symmans WF, Pusztai L (2005) Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci USA 102(23):8315–8320.  https://doi.org/10.1073/pnas.0408974102 PubMedCrossRefGoogle Scholar
  78. 78.
    Wagner P, Wang B, Clark E, Lee H, Rouzier R, Pusztai L (2005) Microtubule Associated Protein (MAP)-Tau: a novel mediator of paclitaxel sensitivity in vitro and in vivo. Cell Cycle 4(9):1149–1152.  https://doi.org/10.4161/cc.4.9.2038 PubMedCrossRefGoogle Scholar
  79. 79.
    Andoh T, Ishii K, Suzuki Y, Ikegami Y, Kusunoki Y, Takemoto Y, Okada K (1987) Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I. Proc Natl Acad Sci USA 84(16):5565–5569PubMedCrossRefGoogle Scholar
  80. 80.
    Deffie AM, Batra JK, Goldenberg GJ (1989) Direct correlation between DNA topoisomerase II activity and cytotoxicity in adriamycin-sensitive and -resistant P388 leukemia cell lines. Cancer Res 49(1):58–62PubMedGoogle Scholar
  81. 81.
    Tanizawa A, Pommier Y (1992) Topoisomerase I alteration in a camptothecin-resistant cell line derived from Chinese hamster DC3F cells in culture. Cancer Res 52(7):1848–1854PubMedGoogle Scholar
  82. 82.
    Beck WT, Morgan SE, Mo YY, Bhat UG (1999) Tumor cell resistance to DNA topoisomerase II inhibitors: new developments. Drug Resist Updates 2(6):382–389.  https://doi.org/10.1054/drup.1999.0110 CrossRefGoogle Scholar
  83. 83.
    Xu Y, Villalona-Calero MA (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 13(12):1841–1851PubMedCrossRefGoogle Scholar
  84. 84.
    Lackner MR, Wilson TR, Settleman J (2012) Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol 8(8):999–1014.  https://doi.org/10.2217/fon.12.86 PubMedCrossRefGoogle Scholar
  85. 85.
    O’Hare T, Eide CA, Deininger MW (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110(7):2242–2249.  https://doi.org/10.1182/blood-2007-03-066936 PubMedCrossRefGoogle Scholar
  86. 86.
    Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4(4):307–320.  https://doi.org/10.1038/nrd1691 PubMedCrossRefGoogle Scholar
  87. 87.
    Kaina B, Christmann M (2002) DNA repair in resistance to alkylating anticancer drugs. Int J Clin Pharmacol Ther 40(8):354–367PubMedCrossRefGoogle Scholar
  88. 88.
    Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, Cambieri A, Selvaggi G, Saviozzi S, Calogero R, Papotti M, Scagliotti GV (2006) ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 17(12):1818–1825.  https://doi.org/10.1093/annonc/mdl300 PubMedCrossRefGoogle Scholar
  89. 89.
    Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22(47):7265–7279.  https://doi.org/10.1038/sj.onc.1206933 PubMedCrossRefGoogle Scholar
  90. 90.
    Gerson SL (2004) MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 4(4):296–307.  https://doi.org/10.1038/nrc1319 PubMedCrossRefGoogle Scholar
  91. 91.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362(6423):847–849.  https://doi.org/10.1038/362847a0 PubMedCrossRefGoogle Scholar
  92. 92.
    Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362(6423):849–852.  https://doi.org/10.1038/362849a0 PubMedCrossRefGoogle Scholar
  93. 93.
    Fan S, el-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ Jr, Magrath I, Kohn KW, O’Connor PM (1994) p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res 54(22):5824–5830PubMedGoogle Scholar
  94. 94.
    Carnero A, Garcia-Mayea Y, Mir C, Lorente J, Rubio IT, LLeonart ME (2016) The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev 49:25–36.  https://doi.org/10.1016/j.ctrv.2016.07.001 PubMedCrossRefGoogle Scholar
  95. 95.
    Tannock I (1978) Cell kinetics and chemotherapy: a critical review. Cancer Treat Rep 62(8):1117–1133PubMedGoogle Scholar
  96. 96.
    Tannock IF (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22(2):258–273PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hirst DG, Denekamp J (1979) Tumour cell proliferation in relation to the vasculature. Cell Tissue Kinetics 12(1):31–42PubMedGoogle Scholar
  98. 98.
    Ljungkvist AS, Bussink J, Rijken PF, Kaanders JH, van der Kogel AJ, Denekamp J (2002) Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 54(1):215–228PubMedCrossRefGoogle Scholar
  99. 99.
    Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS (2000) Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19(38):4319–4327.  https://doi.org/10.1038/sj.onc.1203782 PubMedCrossRefGoogle Scholar
  100. 100.
    Shain KH, Dalton WS (2001) Cell adhesion is a key determinant in de novo multidrug resistance (MDR): new targets for the prevention of acquired MDR. Mol Cancer Ther 1(1):69–78PubMedGoogle Scholar
  101. 101.
    Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270(3):1230–1237PubMedCrossRefGoogle Scholar
  102. 102.
    Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441(7092):437–443.  https://doi.org/10.1038/nature04871 PubMedCrossRefGoogle Scholar
  103. 103.
    Rice GC, Hoy C, Schimke RT (1986) Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci USA 83(16):5978–5982PubMedCrossRefGoogle Scholar
  104. 104.
    Rice GC, Ling V, Schimke RT (1987) Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (adriamycin) resistance. Proc Natl Acad Sci USA 84(24):9261–9264PubMedCrossRefGoogle Scholar
  105. 105.
    Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62(12):3387–3394PubMedGoogle Scholar
  106. 106.
    Kennedy KA (1987) Hypoxic cells as specific drug targets for chemotherapy. Anti-Cancer Drug Des 2(2):181–194Google Scholar
  107. 107.
    Raghunand N, He X, van Sluis R, Mahoney B, Baggett B, Taylor CW, Paine-Murrieta G, Roe D, Bhujwalla ZM, Gillies RJ (1999) Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 80(7):1005–1011.  https://doi.org/10.1038/sj.bjc.6690455 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Raghunand N, Mahoney BP, Gillies RJ (2003) Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol 66(7):1219–1229PubMedCrossRefGoogle Scholar
  109. 109.
    Cowan DS, Tannock IF (2001) Factors that influence the penetration of methotrexate through solid tissue. Intl J Cancer 91(1):120–125CrossRefGoogle Scholar
  110. 110.
    Cooper GM (2000) The cell: a molecular approach, 2nd edn. Sinauer Associates, Boston University, Sunderland (MA)Google Scholar
  111. 111.
    Spears CP (1995) Clinical resistance to antimetabolites. Hematol/Oncol Clin N Am 9(2):397–413CrossRefGoogle Scholar
  112. 112.
    Kickhoefer VA, Rajavel KS, Scheffer GL, Dalton WS, Scheper RJ, Rome LH (1998) Vaults are up-regulated in multidrug-resistant cancer cell lines. J Biol Chem 273(15):8971–8974PubMedCrossRefGoogle Scholar
  113. 113.
    List AF, Spier CS, Grogan TM, Johnson C, Roe DJ, Greer JP, Wolff SN, Broxterman HJ, Scheffer GL, Scheper RJ, Dalton WS (1996) Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood 87(6):2464–2469PubMedGoogle Scholar
  114. 114.
    Steuart CD, Burke PJ (1971) Cytidine deaminase and the development of resistance to arabinosyl cytosine. Nature 233(38):109–110Google Scholar
  115. 115.
    Carlson RW, Sikic BI (1983) Continuous infusion or bolus injection in cancer chemotherapy. Ann Internal Med 99(6):823–833CrossRefGoogle Scholar
  116. 116.
    Cassidy J (1994) Chemotherapy administration: doses, infusions and choice of schedule. Ann Oncol 5(Suppl 4):25–29 (discussion 29–30)PubMedCrossRefGoogle Scholar
  117. 117.
    Marangolo M, Bengala C, Conte PF, Danova M, Pronzato P, Rosti G, Sagrada P (2006) Dose and outcome: the hurdle of neutropenia (Review). Oncol Rep 16(2):233–248PubMedGoogle Scholar
  118. 118.
    Ribatti D (2008) Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis 11(1):3–10.  https://doi.org/10.1007/s10456-008-9092-6 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kyle AH, Huxham LA, Yeoman DM, Minchinton AI (2007) Limited tissue penetration of taxanes: a mechanism for resistance in solid tumors. Clin Cancer Res 13(9):2804–2810.  https://doi.org/10.1158/1078-0432.CCR-06-1941 PubMedCrossRefGoogle Scholar
  120. 120.
    Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592.  https://doi.org/10.1038/nrc1893 PubMedCrossRefGoogle Scholar
  121. 121.
    Matsumoto S, Batra S, Saito K, Yasui H, Choudhuri R, Gadisetti C, Subramanian S, Devasahayam N, Munasinghe JP, Mitchell JB, Krishna MC (2011) Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res 71(20):6350–6359.  https://doi.org/10.1158/0008-5472.CAN-11-2025 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86(2):695–698PubMedCrossRefGoogle Scholar
  123. 123.
    Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP et al (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77(4):491–502PubMedCrossRefGoogle Scholar
  124. 124.
    Benzekry S, Pasquier E, Barbolosi D, Lacarelle B, Barlesi F, Andre N, Ciccolini J (2015) Metronomic reloaded: theoretical models bringing chemotherapy into the era of precision medicine. Semin Cancer Biol 35:53–61.  https://doi.org/10.1016/j.semcancer.2015.09.002 PubMedCrossRefGoogle Scholar
  125. 125.
    Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7(8):455–465.  https://doi.org/10.1038/nrclinonc.2010.82 PubMedCrossRefGoogle Scholar
  126. 126.
    Callaghan R, Luk F, Bebawy M (2014) Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy? Drug Metabol Dispos 42(4):623–631.  https://doi.org/10.1124/dmd.113.056176 CrossRefGoogle Scholar
  127. 127.
    Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ, von Mering C (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45(D1):D362–D368.  https://doi.org/10.1093/nar/gkw937 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Internal Medicine, Oncology Unit, Hippokrateio HospitalUniversity of AthensAthensGreece
  2. 2.Izmir International Biomedicine and Genome InstituteDokuz Eylül UniversityIzmirTurkey
  3. 3.DNA Damage Laboratory, Department of Physics, School of Applied Mathematical and Physical SciencesNational Technical University of Athens (NTUA)AthensGreece
  4. 4.1st Department of Otolaryngology Head and Neck Surgery, Hippokrateio HospitalNational and Kapodistrian University of Athens11527 AthensGreece

Personalised recommendations