Archives of Pharmacal Research

, Volume 37, Issue 1, pp 4–15 | Cite as

Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system

  • Golam Kibria
  • Hiroto Hatakeyama
  • Hideyoshi Harashima
Review

Abstract

Multidrug resistance (MDR), the principal mechanism by which many cancers develop resistance to chemotherapy, is one of the major obstacles to the successful clinical treatment of various types of cancer. Several key regulators are responsible for mediating MDR, a process that renders chemotherapeutic drugs ineffective in the internal organelles of target cells. A nanoparticulate drug delivery system (DDS) is a potentially promising tool for circumventing such MDR, which can be achieved by targeting tumor cells themselves or tumor endothelial cells that support the survival of MDR cancer cells. The present article discusses key factors that are responsible for MDR in cancer cells, with a specific focus on the application of DDS to overcome MDR via the use of chemotherapy or macromolecules.

Keywords

Cancer multidrug resistance (MDR) Key regulators Drug delivery system Reversal of MDR 

References

  1. Abu-Lila, A., T. Suzuki, Y. Doi, T. Ishida, and H. Kiwada. 2009. Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model. Journal of Controlled Release 134: 18–25.PubMedCrossRefGoogle Scholar
  2. Bai, F., C. Wang, Q. Lu, M. Zhao, F.Q. Ban, D.H. Yu, Y.Y. Guan, X. Luan, Y.R. Liu, H.Z. Chen, and C. Fang. 2013. Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer. Biomaterials 34: 6163–6174.PubMedCrossRefGoogle Scholar
  3. Bamias, A., and M.A. Dimopoulos. 2003. Angiogenesis in human cancer: Implications in cancer therapy. European Journal of Internal Medicine 14: 459–469.PubMedCrossRefGoogle Scholar
  4. Beck, A., M.C. Etienne, S. Cheradame, J.L. Fischel, P. Formento, N. Renee, and G. Milano. 1994. A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. European Journal of Cancer 30: 1517–1522.CrossRefGoogle Scholar
  5. Beck, W.T., M.K. Danks, J.S. Wolverton, R. Kim, and M. Chen. 1993. Drug resistance associated with altered DNA topoisomerase II. Advances in Enzyme Regulation 33: 113–127.PubMedCrossRefGoogle Scholar
  6. Borst, P., R. Evers, M. Kool, and J. Wijnholds. 2000. A family of drug transporters: The multidrug resistance-associated proteins. Journal of the National Cancer Institute 92: 1295–1302.PubMedCrossRefGoogle Scholar
  7. Boyle, P., and B. Levin. 2008. World Cancer Report 2008. Lyon: International Agency for Research on Cancer (IARC), 14–15.Google Scholar
  8. Chabner, B.A., and T.G. Roberts. 2005. Timeline: Chemotherapy and the war on cancer. Nature Reviews Cancer 5: 65–72.PubMedCrossRefGoogle Scholar
  9. Chaudhary, A., M.B. Hilton, S. Seaman, D.C. Haines, S. Stevenson, P.K. Lemotte, W.R. Tschantz, X.M. Zhang, S. Saha, T. Fleming, and B. St Croix. 2012. TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21: 212–226.PubMedCentralPubMedCrossRefGoogle Scholar
  10. Cherian, M.G., A. Jayasurya, and B.H. Bay. 2003. Metallothioneins in human tumors and potential roles in carcinogenesis. Mutation Research 533: 201–209.PubMedCrossRefGoogle Scholar
  11. Chin, J.L., D. Banerjee, S.A. Kadhim, T.E. Kontozoglou, P.J. Chauvin, and M.G. Cherian. 1993. Metallothionein in testicular germ cell tumors and drug resistance. Clinical correlation. Cancer 72: 3029–3035.PubMedCrossRefGoogle Scholar
  12. Choi, C.H. 2005. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell International 5: 30.PubMedCentralPubMedCrossRefGoogle Scholar
  13. Choi, H.S., W. Liu, F. Liu, K. Nasr, P. Misra, M.G. Bawendi, and J.V. Frangioni. 2010. Design considerations for tumour-targeted nanoparticles. Nature Nanotechnology 5: 42–47.PubMedCentralPubMedCrossRefGoogle Scholar
  14. Clapper, M.L., S.J. Hoffman, and K.D. Tew. 1990. Sensitization of human colon tumor xenografts to l-phenylalanine mustard using ethacrynic acid. Journal of Cellular Pharmacology 1: 71–78.Google Scholar
  15. Dalton, W.S. 1997. Mechanisms of drug resistance in hematologic malignancies. Seminars in Hematology 34: 3–8.PubMedGoogle Scholar
  16. Danenberg, P.V. 1977. Thymidylate synthetase: A target enzyme in cancer chemotherapy. Biochimica et Biophysica Acta 473: 73–92.PubMedGoogle Scholar
  17. Davis, M.E., Z.G. Chen, and D.M. Shin. 2008. Nanoparticle therapeutics: An emerging treatment modality for cancer. Nature Reviews Drug Discovery 7: 771–782.PubMedCrossRefGoogle Scholar
  18. Diestra, J.E., G.L. Scheffer, I. Català, M. Maliepaard, J.H. Schellens, R.J. Scheper, J.R. Germà-Lluch, and M.A. Izquierdo. 2002. Frequent expression of the multi-drug resistance associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. Journal of Pathology 198: 213–219.PubMedCrossRefGoogle Scholar
  19. Dietel, M., H. Arps, H. Lage, and A. Niendorf. 1990. Membrane vesicle formation due to acquired mitoxantrone resistance in human gastric carcinoma cell line EPG85–257. Cancer Research 50: 6100–6161.PubMedGoogle Scholar
  20. Di Paolo, D., C. Brignole, F. Pastorino, R. Carosio, A. Zorzoli, M. Rossi, M. Loi, G. Pagnan, L. Emionite, M. Cilli, S. Bruno, R. Chiarle, T.M. Allen, M. Ponzoni, and P. Perri. 2011. Neuroblastoma-targeted nanoparticles entrapping siRNA specifically knockdown ALK. Molecular Therapy 19: 1131–1140.PubMedCrossRefGoogle Scholar
  21. Doyle, L.A., W. Yang, L.V. Abruzzo, T. Krogmann, Y. Gao, A.K. Rishi, and D.D. Ross. 1998. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America 95: 15665–15670.PubMedCentralPubMedCrossRefGoogle Scholar
  22. Dziegiel, P., J. Forgacz, E. Suder, P. Surowiak, J. Kornafel, and M. Zabel. 2003. Prognostic significance of metallothionein expression in correlation with Ki-67 expression in adenocarcinomas of large intestine. Histology and Histopathology 18: 401–407.PubMedGoogle Scholar
  23. Filipowicz, W., L. Jaskiewicz, F.A. Kolb, and R.S. Pillai. 2005. Post-transcriptional gene silencing by siRNAs and miRNAs. Current Opinion in Structural Biology 15: 331–341.PubMedCrossRefGoogle Scholar
  24. Fischel, J.L., M.C. Etienne, T. Spector, P. Formento, N. Renee, and G. Milano. 1995. Dihydropyrimidine dehydrogenase: A tumoral target for fluorouracil modulation. Clinical Cancer Research 1: 991–996.PubMedGoogle Scholar
  25. Folkman, J. 1995. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine 1: 27–31.PubMedCrossRefGoogle Scholar
  26. Folkman, J. 2007. Angiogenesis: An organizing principle for drug discovery? Nature Reviews Drug Discovery 6: 273–286.PubMedCrossRefGoogle Scholar
  27. Gao, S., F. Dagnaes-Hansen, E.J. Nielsen, J. Wengel, F. Besenbacher, K.A. Howard, and J. Kjems. 2009. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Molecular Therapy 17: 1225–1233.PubMedCrossRefGoogle Scholar
  28. Gottesman, M.M., T. Fojo, and S.E. Bates. 2002. Multidrug resistance in cancer: Role of ATP dependent transporters. Nature Reviews Cancer 2: 48–58.PubMedCrossRefGoogle Scholar
  29. Gupta, A.K., and M. Gupta. 2005. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26: 3995–4021.PubMedCrossRefGoogle Scholar
  30. Haley, B., and E. Frenkel. 2008. Nanoparticles for drug delivery in cancer treatment. Urologic Oncology 26: 57–64.PubMedCrossRefGoogle Scholar
  31. Hashizume, H., P. Baluk, S. Morikawa, J.W. McLean, G. Thurston, S. Roberge, R.K. Jain, and D.M. McDonald. 2000. Openings between defective endothelial cells explain tumor vessel leakiness. American Journal of Pathology 156: 1363–1380.PubMedCrossRefGoogle Scholar
  32. Hazlehurst, L.A., N.E. Foley, M.C. Gleason-Guzman, M.P. Hacker, A.E. Cress, L.W. Greenberger, M.C. De Jong, and W.S. Dalton. 1999. Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Research 59: 1021–1028.PubMedGoogle Scholar
  33. Hobbs, S.K., W.L. Monsky, F. Yuan, W.G. Roberts, L. Griffith, V.P. Torchilin, and R.K. Jain. 1998. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proceedings of the National Academy of Sciences of the United States of America 95: 4607–4612.PubMedCentralPubMedCrossRefGoogle Scholar
  34. Huwyler, J., A. Cerletti, G. Fricker, A.N. Eberle, and J. Drewe. 2002. By-passing of P-glycoprotein using immunoliposomes. Journal of Drug Targets 10: 73–79.CrossRefGoogle Scholar
  35. Izquierdo, M.A., A.G. van der Zee, J.B. Vermorken, P. van der Valk, J.A. Belien, G. Giaccone, et al. 1995. Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. Journal of the National Cancer Institute 87: 1230–1237.PubMedCrossRefGoogle Scholar
  36. Jain, R.K. 2005. Antiangiogenic therapy for cancer: Current and emerging concepts. Oncology 19: 7–16.PubMedGoogle Scholar
  37. Jiang, J., S.J. Yang, J.C. Wang, L.J. Yang, Z.Z. Xu, T. Yang, X.Y. Liu, and Q. Zhang. 2010. Sequential treatment of drug-resistant tumors with RGD-modified liposomes containing siRNA or doxorubicin. European Journal of Pharmaceutics and Biopharmaceutics 76: 170–178.PubMedCrossRefGoogle Scholar
  38. Jonston, P.G., H.J. Lenz, and C.G. Leichman. 1995. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumor. Cancer Research 55: 1407–1412.Google Scholar
  39. Kanwar, J.R., S.K. Kamalapuram, and R.K. Kanwar. 2011. Targeting survivin in cancer: The cell-signalling perspective. Drug Discovery Today 16: 485–494.PubMedCrossRefGoogle Scholar
  40. Kasahara, K., Y. Fujiwara, K. Nishio, T. Ohmori, Y. Sugimoto, K. Komiya, T. Matsuda, and N. Saijo. 1991. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Research 51: 3237–3242.PubMedGoogle Scholar
  41. Kibria, G., H. Hatakeyama, N. Ohga, K. Hida, and H. Harashima. 2013. The effect of liposomal size on the targeted delivery of doxorubicin to Integrin αvβ3-expressing tumor endothelial cells. Biomaterials 34: 5617–5627.PubMedCrossRefGoogle Scholar
  42. Kickhoefer, V.A., K.S. Rajavel, G.L. Scheffer, W.S. Dalton, R.J. Scheper, and L.H. Rome. 1998. Vaults are up-regulated in multidrug-resistant cancer cell lines. Journal of Biological Chemistry 273: 8971–8974.PubMedCrossRefGoogle Scholar
  43. Kitazono, M., T. Sumizawa, Y. Takebayashi, Z.S. Chen, T. Furukawa, S. Nagayama, A. Tani, S. Takao, T. Aikou, and S. Akiyama. 1999. Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells. Journal of the National Cancer Institute 91: 1647–1653.PubMedCrossRefGoogle Scholar
  44. Kondo, Y., E.S. Woo, A.E. Michalska, K.H. Choo, and J.S. Lazo. 1995. Metallothionein null cells have increased sensitivity to anticancer drugs. Cancer Research 55: 2021–2023.PubMedGoogle Scholar
  45. Kunjachan, S., A. Blauz, D. Mockel, B. Theek, F. Kiessling, T. Etrych, K. Ulbrich, L.V. Bloois, G. Storm, G. Bartosz, B. Rychlik, and T. Lammers. 2012. Overcoming cellular multidrug resistance using classical nanomedicine formulations. European Journal of Pharmaceutical Sciences 45: 421–428.PubMedCrossRefGoogle Scholar
  46. Laborde, E. 2010. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death and Differentiation 17: 1373–1380.PubMedCrossRefGoogle Scholar
  47. Lenz, H.J., C.G. Leichman, and K.D. Danenberg. 1995. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: A predictor for primary tumor response and overall survival. Journal of Clinical Oncology 14: 176–182.Google Scholar
  48. Linton, K.J. 2007. Structure and function of ABC transporters. Physiology (Bethesda) 22: 122–130.CrossRefGoogle Scholar
  49. List, A.F., C.S. Spier, T.M. Grogan, C. Johnson, D.J. Roe, J.P. Greer, S.N. Wolff, H.J. Broxterman, G.L. Scheffer, R.J. Scheper, and W.S. Dalton. 1996. Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood 87: 2464–2469.PubMedGoogle Scholar
  50. Liu, C., G. Zhao, J. Liu, N. Ma, P. Chivukula, L. Perelman, K. Okada, Z. Chen, D. Gough, and L. Yu. 2009. Novel biodegradable lipid nano complex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel. Journal of Controlled Release 140: 277–283.PubMedCrossRefGoogle Scholar
  51. Liu, L.F. 1989. DNA topoisomerase poisons as antitumor drugs. Annual Review of Biochemistry 58: 351–375.PubMedCrossRefGoogle Scholar
  52. Luqmani, Y.A. 2005. Mechanisms of drug resistance in cancer chemotherapy. Medical Principles and Practice 14: 35–48.PubMedCrossRefGoogle Scholar
  53. MacDiarmid, J.A., N.B. Amaro-Mugridge, J. Madrid-Weiss, I. Sedliarou, S. Wetzel, K. Kochar, V.N. Brahmbhatt, L. Phillips, S.T. Pattison, C. Petti, B. Stillman, R.M. Graham, and H. Brahmbhatt. 2009. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nature Biotechnology 27: 643–651.PubMedCrossRefGoogle Scholar
  54. Maeda, H., J. Wu, T. Sawa, Y. Matsumura, and K. Hori. 2000. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. Journal of Controlled Release 65: 271–284.PubMedCrossRefGoogle Scholar
  55. Meng, H., M. Liong, T. Xia, Z. Li, Z. Ji, J.I. Zink, and A.E. Nel. 2010. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano 4: 4539–4550.PubMedCrossRefGoogle Scholar
  56. Murakami, M., H. Cabral, Y. Matsumoto, S. Wu, M.R. Kano, T. Yamori, N. Nishiyama, and K. Kataoka. 2011. Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting. Science Translational Medicine 3: 64ra2.PubMedCrossRefGoogle Scholar
  57. Murphy, E.A., B.K. Majeti, L.A. Barnes, M. Makale, S.M. Weis, K. Lutu-Fuga, W. Wrasidlo, and D.A. Cheresh. 2008. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proceedings of the National Academy of Sciences of the United States of America 105: 9343–9348.PubMedCentralPubMedCrossRefGoogle Scholar
  58. Nakamura, K., A.S. Abu Lila, M. Matsunaga, Y. Doi, T. Ishida, and H. Kiwada. 2011. A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA. Molecular Therapy 19: 2040–2047.PubMedCrossRefGoogle Scholar
  59. Pastorino, F., C. Brignole, D. Marimpietri, M. Cilli, C. Gambini, D. Ribatti, R. Longhi, T.M. Allen, A. Corti, and M. Ponzoni. 2003. Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Research 63: 7400–7409.PubMedGoogle Scholar
  60. Patil, Y., and J. Panyam. 2009. Polymeric nanoparticles for siRNA delivery and gene silencing. International Journal of Pharmaceutics 367: 195–203.PubMedCentralPubMedCrossRefGoogle Scholar
  61. Patil, Y.B., S.K. Swaminathan, T. Sadhukha, L. Ma, and J. Panyam. 2010. The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials 31: 358–365.PubMedCentralPubMedCrossRefGoogle Scholar
  62. Patil, Y., T. Sadhukha, L. Ma, and J. Panyam. 2009. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. Journal of Controlled Release 136: 21–29.PubMedCrossRefGoogle Scholar
  63. Peer, D., J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, and R. Langer. 2007. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2: 751–760.PubMedCrossRefGoogle Scholar
  64. Persidis, A. 1999. Cancer multidrug resistance. Nature Biotechnology 17: 94–95.PubMedCrossRefGoogle Scholar
  65. Raaijmakers, H.G., M.A. Izquierdo, H.M. Lokhorst, C. de Leeuw, J.A. Belien, A.C. Bloem, A.W. Dekker, R.J. Scheper, and P. Sonneveld. 1998. Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 91: 1029–1036.PubMedGoogle Scholar
  66. Rajagopal, A., and S.M. Simon. 2003. Subcellular localization and activity of multidrug resistance proteins. Molecular Biology of the Cell 14: 3389–3399.PubMedCentralPubMedCrossRefGoogle Scholar
  67. Rejman, J., V. Oberle, I.S. Zuhorn, and D. Hoekstra. 2004. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochemical Journal 377: 159–169.PubMedCrossRefGoogle Scholar
  68. Rezzani, R. 2004. Cyclosporine A and adverse effects on organs: Histochemical studies. Progress in Histochemistry and Cytochemistry 39: 85–128.PubMedCrossRefGoogle Scholar
  69. Ruoslahti, E. 2002. Specialization of tumour vasculature. Nature Reviews Cancer 2: 83–90.PubMedCrossRefGoogle Scholar
  70. Saad, M., O.B. Garbuzenko, and T. Minko. 2008. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (London) 3: 761–776.CrossRefGoogle Scholar
  71. Salonga, D., K.D. Danenberg, M. Johnson, R. Metzger, S. Groshen, D.D. Tsao-Wei, H.J. Lenz, C.G. Leichman, L. Leichman, R.B. Diasio, and P.V. Danenberg. 2000. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clinical Cancer Research 6: 1322–1327.PubMedGoogle Scholar
  72. Scheffer, G.L., A.B. Schroeijers, M.A. Izquierdo, E.A. Wiemer, and R.J. Scheper. 2000. Lung resistance-related protein/major vault protein and vaults in multidrug-resistant cancer. Current Opinion in Oncology 12: 550–556.PubMedCrossRefGoogle Scholar
  73. Sharma, A., E. Mayhew, and R.M. Straubinger. 1993. Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor model. Cancer Research 53: 5877–5881.PubMedGoogle Scholar
  74. Shen, F., S. Chu, A.K. Bence, B. Bailey, X. Xue, P.A. Erickson, M.H. Montrose, W.T. Beck, and L.C. Erickson. 2008. Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. Journal of Pharmacology and Experimental Therapeutics 324: 95–102.PubMedCrossRefGoogle Scholar
  75. Shimoda, R., W.E. Achanzar, W. Qu, T. Nagamine, H. Takagi, M. Mori, and M.P. Waalkes. 2003. Metallothionein is a potential negative regulator of apoptosis. Toxicological Sciences 73: 294–300.PubMedCrossRefGoogle Scholar
  76. Shintani, Y., M. Ohta, H. Hirabayashi, H. Tanaka, K. Iuchi, K. Nakagawa, H. Maeda, T. Kido, S. Miyoshi, and H. Matsuda. 2003. New prognostic indicator for non-small-cell lung cancer, quantitation of thymidylate synthase by real-time reverse transcription polymerase chain reaction. International Journal of Cancer 104: 790–795.CrossRefGoogle Scholar
  77. Siwak, D.R., A.M. Tari, and G. Lopez-Berestein. 2002. The potential of drug-carrying immunoliposomes as anticancer agents. Clinical Cancer Research 8: 955–956.PubMedGoogle Scholar
  78. Smith, K., S. Houlbrook, M. Greenall, J. Carmichael, and A.L. Harris. 1993. Topoisomerase IIα coamplification with erbB2 in human primary breast cancer and breast cancer cell lines -relationship to m-AMSA and mitoxantrone sensitivity. Oncogene 8: 933–938.PubMedGoogle Scholar
  79. Soma, C.E., C. Dubernet, D. Bentolila, S. Benita, and P. Couvreur. 2000. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Biomaterials 21: 1–7.PubMedCrossRefGoogle Scholar
  80. Sugahara, S., M. Kajiki, H. Kuriyama, and T.R. Kobayashi. 2007. Complete regression of xenografted human carcinomas by a paclitaxel-carboxymethyl dextran conjugate (AZ10992). Journal of Controlled Release 117: 40–50.PubMedCrossRefGoogle Scholar
  81. Takara, K., H. Hatakeyama, G. Kibria, N. Ohga, K. Hida, and H. Harashima. 2012. Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy. Journal of Controlled Release 162: 225–232.PubMedCrossRefGoogle Scholar
  82. Tewey, K.M., T.C. Rowe, L. Yang, B.D. Halligan, and L.F. Liu. 1984. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226: 466–468.PubMedCrossRefGoogle Scholar
  83. Toyoda, Y., Y. Hagiya, T. Adachi, K. Hoshijima, M.T. Kuo, and T. Ishikawa. 2008. MRP class of human ATP binding cassette (ABC) transporters: Historical background and new research directions. Xenobiotica 38: 833–862.PubMedCrossRefGoogle Scholar
  84. Walther, W., U. Stein, and H. Lage. 2010. Jet-injection of short hairpin RNA-encoding vectors into tumor cells. Methods in Molecular Biology 629: 123–139.PubMedGoogle Scholar
  85. Wang, R.B., C.L. Kuo, L.L. Lien, and E.J. Lien. 2003. Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors. Journal of Clinical Pharmacy and Therapeutic 28: 203–228.CrossRefGoogle Scholar
  86. Wang, Y., S. Gao, W.H. Ye, H.S. Yoon, and Y.Y. Yang. 2006. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nature Materials 5: 791–796.PubMedCrossRefGoogle Scholar
  87. Wang, Z., Y. Li, A. Ahmad, A.S. Azmi, D. Kong, S. Banerjee, and F.H. Sarkar. 2010. Targeting mirnas involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resistance Updates 13: 109–118.PubMedCentralPubMedCrossRefGoogle Scholar
  88. Wright, J.A., H.S. Smith, F.M. Watt, M.C. Hancock, D.L. Hudson, and G.R. Stark. 1990. DNA amplification is rare in normal human cells. Proceedings of the National Academy of Sciences of the United States of America 87: 1791–1795.PubMedCentralPubMedCrossRefGoogle Scholar
  89. Wu, J., Y. Lu, A. Lee, X. Pan, X. Yang, X. Zhao, and R.J. Lee. 2007. Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. Journal of Pharmacy and Pharmaceutical Sciences 10: 350–357.PubMedGoogle Scholar
  90. Yamachika, T., H. Nakanishi, K. Inada, T. Tsukamoto, T. Kato, M. Fukushima, M. Inoue, and M. Tatematsu. 1998. A new prognostic factor for colorectal carcinoma, thymidylate synthase, and its therapeutic significance. Cancer 82: 70–77.PubMedCrossRefGoogle Scholar
  91. Yuan, F., M. Leunig, S.K. Huang, D.A. Berk, D. Papahadjopoulos, and R.K. Jain. 1994. Microvascular permeability and interstitial penetration of sterically stabilized (Stealth®) liposomes in a human tumor xenografts. Cancer Research 54: 3352–3356.PubMedGoogle Scholar
  92. Zhang, B., M. Liu, H.K. Tang, H.B. Ma, C. Wang, X. Chen, and H.Z. Huang. 2012. The expression and significance of MRP1, LRP, TOPOIIβ, and BCL2 in tongue squamous cell carcinoma. Journal of Oral Pathology and Medicine 41: 141–148.PubMedCrossRefGoogle Scholar
  93. Zhang, L., F.X. Gu, J.M. Chan, A.Z. Wang, R.S. Langer, and O.C. Farokhzad. 2008. Nanoparticles in medicine: therapeutic applications and developments. Clinical Pharmacology and Therapeutics 83: 761–769.PubMedCrossRefGoogle Scholar
  94. Zhou, S.F. 2008. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38: 802–832.PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2013

Authors and Affiliations

  • Golam Kibria
    • 1
  • Hiroto Hatakeyama
    • 1
  • Hideyoshi Harashima
    • 1
  1. 1.Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical SciencesHokkaido UniversitySapporoJapan

Personalised recommendations