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

Springer Science and Business Media LLC - Tập 35 - Trang 309-318 - 2018
Michail Nikolaou1, Athanasia Pavlopoulou2, Alexandros G. Georgakilas3, Efthymios Kyrodimos4
1Department of Internal Medicine, Oncology Unit, Hippokrateio Hospital, University of Athens, Athens, Greece
2İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
3DNA Damage Laboratory, Department of Physics, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Athens, Greece
41st Department of Otolaryngology Head and Neck Surgery, Hippokrateio Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece

Tóm tắt

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.

Tài liệu tham khảo

Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627. https://doi.org/10.1146/annurev.med.53.082901.103929 Clynes M (1998) Multiple drug resistance in cancer 2: molecular, cellular and clinical aspects. Kluwer Academic Publishers, Dodrecht 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 Sherlach KS, Roepe PD (2014) Drug resistance associated membrane proteins. Front Physiol 5:108. https://doi.org/10.3389/fphys.2014.00108 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 Gottesman MM, Ludwig J, Xia D, Szakacs G (2006) Defeating drug resistance in cancer. Discov Med 6(31):18–23 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 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 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 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 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 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 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 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 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 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 Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74(6):957–967 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 Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481(7381):306–313. https://doi.org/10.1038/nature10762 Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194(4260):23–28 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):1727–1733 Goldie JH, Coldman AJ (1985) Genetic instability in the development of drug resistance. Semin Oncol 12(3):222–230 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):279–292 Woodhouse JR, Ferry DR (1995) The genetic basis of resistance to cancer chemotherapy. Ann Med 27(2):157–167 Angerer WP (2001) An explicit representation of the Luria-Delbruck distribution. J Math Biol 42(2):145–174 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 Frank SA (2003) Somatic mosaicism and cancer: inference based on a conditional Luria-Delbruck distribution. J Theor Biol 223(4):405–412 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 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 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 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 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):1593–1602 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):4980–4987 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):1091–1097 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):1152–1158 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 Matsumoto Y, Takano H, Fojo T (1997) Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype. Cancer Res 57(22):5086–5092 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 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 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 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 24:397–410 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 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 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 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 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 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 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 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 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 Gottesman MM, Ambudkar SV (2001) Overview: ABC transporters and human disease. J Bioenerg Biomembr 33(6):453–458 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):27–42 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):473–476 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 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):586–592 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 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 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 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 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 Fisher GA, Sikic BI (1995) Clinical studies with modulators of multidrug resistance. Hematol/Oncol Clin N Am 9(2):363–382 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 Sikic BI (1997) Pharmacologic approaches to reversing multidrug resistance. Semin Hematol 34(4 Suppl 5):40–47 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):682–685 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 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 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):1160–1166 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):10073–10080 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 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):503–511 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):429–433 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 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 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 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 Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV (2003) Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 3(1):1–19 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 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 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):5565–5569 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):58–62 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):1848–1854 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 Xu Y, Villalona-Calero MA (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 13(12):1841–1851 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 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 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 Kaina B, Christmann M (2002) DNA repair in resistance to alkylating anticancer drugs. Int J Clin Pharmacol Ther 40(8):354–367 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 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 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 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 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 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):5824–5830 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 Tannock I (1978) Cell kinetics and chemotherapy: a critical review. Cancer Treat Rep 62(8):1117–1133 Tannock IF (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22(2):258–273 Hirst DG, Denekamp J (1979) Tumour cell proliferation in relation to the vasculature. Cell Tissue Kinetics 12(1):31–42 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):215–228 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 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):69–78 Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270(3):1230–1237 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 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):5978–5982 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):9261–9264 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):3387–3394 Kennedy KA (1987) Hypoxic cells as specific drug targets for chemotherapy. Anti-Cancer Drug Des 2(2):181–194 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 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):1219–1229 Cowan DS, Tannock IF (2001) Factors that influence the penetration of methotrexate through solid tissue. Intl J Cancer 91(1):120–125 Cooper GM (2000) The cell: a molecular approach, 2nd edn. Sinauer Associates, Boston University, Sunderland (MA) Spears CP (1995) Clinical resistance to antimetabolites. Hematol/Oncol Clin N Am 9(2):397–413 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):8971–8974 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):2464–2469 Steuart CD, Burke PJ (1971) Cytidine deaminase and the development of resistance to arabinosyl cytosine. Nature 233(38):109–110 Carlson RW, Sikic BI (1983) Continuous infusion or bolus injection in cancer chemotherapy. Ann Internal Med 99(6):823–833 Cassidy J (1994) Chemotherapy administration: doses, infusions and choice of schedule. Ann Oncol 5(Suppl 4):25–29 (discussion 29–30) 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):233–248 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 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 Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592. https://doi.org/10.1038/nrc1893 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 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):695–698 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):491–502 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 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 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 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