Cancer Chemotherapy



The enhanced permeability and retention (EPR) effect is the first essential step for selective delivery of macromolecular drugs to tumor tissues. The EPR effect is based on the aberrant architecture of tumor blood vessels and the impaired lymphatic drainage system in tumor tissue. This effect is facilitated by overproduction of multiple vascular mediators such as bradykinin, nitric oxide, prostaglandins, vascular endothelial growth factor (VEGF), and other cytokines in tumor tissue, which may also affect surrounding normal tissues. The biocompatibility, molecular size, and surface charge of macromolecular drugs, i.e., nanomedicines, are critical determinants of tumor-targeted drug delivery based on the EPR effect. However, ineffective treatment can result from the heterogeneity of the EPR effect in tumor tissues, which impedes drug delivery to some tumors. In this chapter, we also discuss how to overcome this problem by using specific therapeutic methods, such as angiotensin (AT) II-induced high blood pressure, angiotensin-converting enzyme inhibitors, nitric oxide-releasing agents, tumor necrosis factor-α, transforming growth factor-β, and heme oxygenase-1 inducer, some of which were demonstrated to be effective in clinical settings.


Vascular Endothelial Growth Factor Vascular Permeability Interstitial Fluid Pressure Tumor Blood Vessel Kinin Level 
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.



Angiotensin-converting enzyme


Angiotensin II


Bovine serum albumin


Carbon monoxide




Computer topography


Enhanced permeability and retention


Hypoxia-inducible factor 1 alpha


Heme oxygenase-1


Hydroxypropyl methacrylamide


Isosorbide dinitrate


Immunoglobulin G


Nicotinamide adenine dinucleotide phosphate






Nitric oxide


Nitric oxide synthase


Polyethylene glycol


Severe combined immune deficiency


Scanning electron microscopy


Sarcoplasmic/endoplasmic reticulum ATPase


Styrene maleic acid


Transforming growth factor beta


Tumor necrosis factor alpha


Vascular endothelial growth factor


  1. Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127PubMedCrossRefGoogle Scholar
  2. Akaike T, Ando M, Oda T et al (1990) Dependence on O2 generation by xanthine oxidase of pathogenesis of influenza virus infection in mice. J Clin Invest 85:739–745PubMedCrossRefGoogle Scholar
  3. Akaike T, Noguchi Y, Ijiri S et al (1996) Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci USA 93:2448–2453PubMedCrossRefGoogle Scholar
  4. Akaike T, Okamoto S, Sawa T et al (2003) 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis. Proc Natl Acad Sci USA 100:685–690PubMedCrossRefGoogle Scholar
  5. Blum MS, Toninelli E, Anderson JM et al (1997) Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines. Am J Physiol 273:H286–H294PubMedGoogle Scholar
  6. Cohen RA, Adachi T (2006) Nitric-oxide-induced vasodilatation: regulation by physiologic S-glutathiolation and pathologic oxidation of the sarcoplasmic endoplasmic reticulum calcium ATPase. Trends Cardiovasc Med 16:109–114PubMedCrossRefGoogle Scholar
  7. Daruwalla J, Nikfarjam M, Greish K et al (2010) In vitro and in vivo evaluation of tumor targeting styrene-maleic acid copolymer-pirarubicin micelles: survival improvement and inhibition of liver metastases. Cancer Sci 101:1866–1874PubMedCrossRefGoogle Scholar
  8. Dash PR, Read ML, Barrett LB, Wolfert MA, Seymour LW (1999) Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery. Gene Ther 6:643–650PubMedCrossRefGoogle Scholar
  9. Davis S, Abuchowski A, Park YK, Davis FF (1981) Alteration of the circulating life and antigenic properties of bovine adenosine deaminase in mice by attachment of polyethylene glycol. Clin Exp Immunol 46:649–652PubMedGoogle Scholar
  10. de Wilt JH, ten Hagen TL, de Boeck G et al (2000) Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer 82:1000–1003PubMedCrossRefGoogle Scholar
  11. Doi K, Akaike T, Horie H et al (1996) Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth. Cancer 77:1598–1604PubMedGoogle Scholar
  12. Doi K, Alaike T, Fujii S et al (1999) Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer 80:1945–1954PubMedCrossRefGoogle Scholar
  13. Editorial (2008) Welcome clinical leadership at NICE. Lancet 372:601CrossRefGoogle Scholar
  14. Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA (2002) Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res 62:5443–5450PubMedGoogle Scholar
  15. Fang J, Sawa T, Akaike T, Maeda H (2002) Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide. Cancer Res 62:3138–3143PubMedGoogle Scholar
  16. Fang J, Nakamura H, Maeda H (2011) The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63:136–151PubMedCrossRefGoogle Scholar
  17. Fang J, Qin H, Nakamura H, Tsukigawa K, Shin T, Maeda H (2012) Carbon monoxide, generated by heme oxygenase-1, mediates the enhanced permeability and retention effect in solid tumors. Cancer Sci 103:535–541PubMedCrossRefGoogle Scholar
  18. Fojo T, Grady C (2009) How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. J Natl Cancer Inst 101:1044–1048PubMedCrossRefGoogle Scholar
  19. Folli S, Pelegrin A, Chalandon Y et al (1993) Tumor-necrosis factor can enhance radio-antibody uptake in human colon carcinoma xenografts by increasing vascular permeability. Int J Cancer 53:829–836PubMedCrossRefGoogle Scholar
  20. From the Press Release material in Sankei Shinbun (2012). New beptile therapy for pancreatic cancer, March 3Google Scholar
  21. Greish K, Fang J, Inutsuka T, Nagamitsu A, Maeda H (2003) Macromolecular therapeutics: advantages and prospects with special emphasis on solid tumour targeting. Clin Pharmacokinet 42:1089–1105PubMedCrossRefGoogle Scholar
  22. Hagen TL, Eggermont AM (2004) Tumor vascular therapy with TNF: critical review on animal models. Methods Mol Med 98:227–246PubMedGoogle Scholar
  23. Hashizume H, Baluk P, Morikawa S et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156:1363–1380PubMedCrossRefGoogle Scholar
  24. He C, Hu Y, Yin L, Tang C, Yin C (2010) Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31:3657–3666PubMedCrossRefGoogle Scholar
  25. Hirano T, Todoroki T, Kato S et al (1994) Synthesis of the conjugate of superoxide dismutase with the copolymer of divinylether and maleic anhydride retaining enzymatic activity. J Control Release 28:203–209CrossRefGoogle Scholar
  26. Hoffman RM (2009) Tumor-targeting amino acid auxotrophic Salmonella typhimurium. Amino Acids 37:509–521PubMedCrossRefGoogle Scholar
  27. Hori K, Suzuki M, Tanda S (1991) Fluctuations in tumor blood flow under normotension and the effect of angiotensin II-induced hypertension. Cancer Sci 82:1309–1316CrossRefGoogle Scholar
  28. Iwai K, Maeda H, Konno T (1984) Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Res 44:2115–2121PubMedGoogle Scholar
  29. Jain RK (1990) Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res 50:814s–819sPubMedGoogle Scholar
  30. Janssens MY, Van den Berge DL, Verovski VN et al (1998) Activation of inducible nitric oxide synthase results in nitric oxide-mediated radiosensitization of hypoxic EMT-6 tumor cells. Cancer Res 58:5646–5648PubMedGoogle Scholar
  31. Jordan BF, Misson P, Demeure R, Baudelet C, Beghein N, Gallez B (2000) Changes in tumor oxygenation/perfusion induced by the NO donor, isosorbide dinitrate, in comparison with carbogen: monitoring by EPR and MRI. Int J Radiat Oncol Biol Phys 48:565–570PubMedCrossRefGoogle Scholar
  32. Kamata R, Yamamoto T, Matsumoto K, Maeda H (1985) A serratial protease causes vascular permeability reaction by activation of the Hageman factor-dependent pathway in guinea pigs. Infect Immun 48:747–753PubMedGoogle Scholar
  33. Kano MR, Bae Y, Iwata C et al (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci USA 104:3460–3465PubMedCrossRefGoogle Scholar
  34. Kimura NT, Taniguchi S, Aoki K, Baba T (1980) Selective localization and growth of Bifidobacterium bifidum in mouse tumors following intravenous administration. Cancer Res 40:2061–2068PubMedGoogle Scholar
  35. Kimura M, Matsumura Y, Miyauchi Y, Maeda H (1988) A new tactic for the treatment of jaundice: an injectable polymer-conjugated bilirubin oxidase. Proc Soc Exp Biol Med 188:364–369PubMedCrossRefGoogle Scholar
  36. Kimura M, Matsumura Y, Konno T, Miyauchi Y, Maeda H (1990) Enzymatic removal of bilirubin toxicity by bilirubin oxidase in vitro and excretion of degradation products in vivo. Proc Soc Exp Biol Med 195:64–69PubMedCrossRefGoogle Scholar
  37. Kohmoto J, Nakao A, Kaizu T et al (2006) Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery 140:179–185PubMedCrossRefGoogle Scholar
  38. Kojima Y, Haruta A, Imai T, Otagiri M, Maeda H (1993) Conjugation of Cu, Zn-superoxide dismutase with succinylated gelatin: pharmacological activity and cell-lubricating function. Bioconjug Chem 4:490–498PubMedCrossRefGoogle Scholar
  39. Konerding MA, Miodonski AJ, Lametschwandtner A (1995) Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc 9:1233–1243; discussion 1243–1244Google Scholar
  40. Konno T, Maeda H, Iwai K et al (1983) Effect of arterial administration of high-molecular-weight anticancer agent SMANCS with lipid lymphographic agent on hepatoma: a preliminary report. Eur J Cancer Clin Oncol 19:1053–1065PubMedCrossRefGoogle Scholar
  41. Konno T, Maeda H, Iwai K et al (1984) Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium. Cancer 54:2367–2374PubMedCrossRefGoogle Scholar
  42. Kuwahara H, Kariu T, Fang J, Maeda H (2009) Generation of drug-resistant mutants of Helicobacter pylori in the presence of peroxynitrite, a derivative of nitric oxide, at pathophysiological concentration. Microbiol Immunol 53:1–7PubMedCrossRefGoogle Scholar
  43. Kwoh DY, Coffin CC, Lollo CP et al (1999) Stabilization of poly-L-lysine/DNA polyplexes for in vivo gene delivery to the liver. Biochim Biophys Acta 1444:171–190PubMedCrossRefGoogle Scholar
  44. Lampugnani MG, Resnati M, Raiteri M et al (1992) A novel endothelial-specific membrane protein is a marker of cell-cell contacts. J Cell Biol 118:1511–1522PubMedCrossRefGoogle Scholar
  45. Li CJ, Miyamoto Y, Kojima Y, Maeda H (1993) Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure. Br J Cancer 67:975–980PubMedCrossRefGoogle Scholar
  46. Li CY, Shan S, Huang Q et al (2000) Initial stage of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92:143–147PubMedCrossRefGoogle Scholar
  47. Lincoln TM (1989) Cyclic GMP and mechanisms of vasodilation. Pharmacol Ther 41:479–502PubMedCrossRefGoogle Scholar
  48. Maeda H (2001a) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41:189–207PubMedCrossRefGoogle Scholar
  49. Maeda H (2001b) SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev 46:169–185PubMedCrossRefGoogle Scholar
  50. Maeda H (2010a) Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjug Chem 21:797–802PubMedCrossRefGoogle Scholar
  51. Maeda H (2010b) Nitroglycerin enhances vascular blood flow and drug delivery in hypoxic tumor tissues: analogy between angina pectoris and solid tumors and enhancement of the EPR effect. J Control Release 142:296–298PubMedCrossRefGoogle Scholar
  52. Maeda H (2012a) Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting. Proc Jpn Acad Ser B 88:53–71CrossRefGoogle Scholar
  53. Maeda H (2012) Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 164:138–144Google Scholar
  54. Maeda H, Matsumura Y (1989) Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst 6:193–210PubMedGoogle Scholar
  55. Maeda H, Takeshita J, Kanamaru R (1979) A lipophilic derivative of neocarzinostatin. A polymer conjugation of an antitumor protein antibiotic. Int J Pept Protein Res 14:81–87PubMedCrossRefGoogle Scholar
  56. Maeda H, Matsumura Y, Oda T, Sasamoto K (1986) Cancer selective macromolecular therapeusis; tailoring of an antitumor protein drug. In: Feeney RE, Whitaker JR (eds) Protein tailoring for food and medical uses. Marcel Dekker, New YorkGoogle Scholar
  57. Maeda H, Matsumura Y, Kato H (1988) Purification and identification of [hydroxyprolyl3]bradykinin in ascitic fluid from a patient with gastric cancer. J Biol Chem 263:16051–16054PubMedGoogle Scholar
  58. Maeda H, Kimura I, Sasaki Y et al (1992) Toxicity of bilirubin and detoxification by PEG-bilirubin oxidase conjugate: a new tactic for treatment of jaundice. In: Harris JM (ed) Poly(ethylene glycol) chemistry: biotech biomed applications. Plenum Press, New York, pp 153–169CrossRefGoogle Scholar
  59. Maeda H, Fang J, Inutsuka T, Kitamoto Y (2003) Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol 3:319–328PubMedCrossRefGoogle Scholar
  60. Maeda H, Bharate GY, Daruwalla J (2009) Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur J Pharm Biopharm 71:409–419PubMedCrossRefGoogle Scholar
  61. Maki S, Konno T, Maeda H (1985) Image enhancement in computerized tomography for sensitive diagnosis of liver cancer and semiquantitation of tumor selective drug targeting with oily contrast medium. Cancer 56:751–757PubMedCrossRefGoogle Scholar
  62. Matsumoto K, Yamamoto T, Kamata R, Maeda H (1984) Pathogenesis of serratial infection: activation of the Hageman factor-prekallikrein cascade by serratial protease. J Biochem 96:739–749PubMedGoogle Scholar
  63. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392PubMedGoogle Scholar
  64. Matsumura Y, Kimura M, Yamamoto T, Maeda H (1988) Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn J Cancer Res 79:1327–1334PubMedCrossRefGoogle Scholar
  65. Matsumura Y, Maruo K, Kimura M, Yamamoto T, Konno T, Maeda H (1991) Kinin-generating cascade in advanced cancer patients and in vitro study. Jpn J Cancer Res 82:732–741PubMedCrossRefGoogle Scholar
  66. Mayer RJ (2009) Targeted therapy for advanced colorectal cancer—more is not always better. N Engl J Med 360:623–625PubMedCrossRefGoogle Scholar
  67. Minowa T, Kawano K, Kuribayashi H et al (2009) Increase in tumour permeability following TGF-β type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI. Br J Cancer 101:1884–1890PubMedCrossRefGoogle Scholar
  68. Nagamitsu A, Greish K, Maeda H (2009) Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors. Jpn J Clin Oncol 39:756–766PubMedCrossRefGoogle Scholar
  69. Nakao A, Neto JS, Kanno S et al (2005) Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both. Am J Transplant 5:282–291PubMedCrossRefGoogle Scholar
  70. Noguchi A, Takahashi T, Yamaguchi T et al (1992) Enhanced tumor localization of monoclonal antibody by treatment with kininase II inhibitor and angiotensin II. Jpn J Cancer Res 83:240–243PubMedCrossRefGoogle Scholar
  71. Noguchi Y, Wu J, Duncan R et al (1998) Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer Res 89:307–314PubMedCrossRefGoogle Scholar
  72. Oda T, Akaike T, Hamamoto T et al (1989) Oxygen radicals in influenza-induced pathogenesis and treatment with pyran polymer-conjugated SOD. Science 244:974–976PubMedCrossRefGoogle Scholar
  73. Ogino T, Inoue M, Ando Y, Awai M, Maeda H, Morino Y (1988) Chemical modification of superoxide dismutase. Extension of plasma half life of the enzyme through its reversible binding to the circulating albumin. Int J Pept Protein Res 32:153–159PubMedCrossRefGoogle Scholar
  74. Papillon J, Dargent M, Chassard JL (1963) [Ultra-fluid lipiodol lymphography in cancerology (apropos of 62 cases)]. J Radiol Electrol Med Nucl 44:397–406PubMedGoogle Scholar
  75. Riganti C, Miraglia E, Viarisio D et al (2005) Nitric oxide reverts the resistance to doxorubicin in human colon cancer cells by inhibiting the drug efflux. Cancer Res 65:516–525PubMedGoogle Scholar
  76. Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100:8621–8623PubMedCrossRefGoogle Scholar
  77. Romer LH, McLean NV, Yan HC et al (1995) IFN-gamma and TNF-alpha induce redistribution of PECAM-1 (CD31) on human endothelial cells. J Immunol 154:6582–6592PubMedGoogle Scholar
  78. Rutter DA, Wade HE (1971) The influence of the iso-electric point of L-asparaginase upon its persistence in the blood. Br J Exp Pathol 52:610–614PubMedGoogle Scholar
  79. Sahoo SK, Sawa T, Fang J et al (2002) Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity. Bioconjug Chem 13:1031–1038PubMedCrossRefGoogle Scholar
  80. Seki T, Fang J, Maeda H (2009) Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application. Cancer Sci 100:2426–2430PubMedCrossRefGoogle Scholar
  81. Seki T, Carroll F, Illingworth S et al (2011) Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway. J Control Release 156:381–389PubMedCrossRefGoogle Scholar
  82. Seymour LW, Miyamoto Y, Maeda H et al (1995) Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier. Eur J Cancer 31A:766–770PubMedCrossRefGoogle Scholar
  83. Sinha G (2008) Expensive cancer drugs with modest benefit ignite debate over solutions. J Natl Cancer Inst 100:1347–1349PubMedCrossRefGoogle Scholar
  84. Sjöblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedCrossRefGoogle Scholar
  85. Sofuni A, Iijima H, Moriyasu F et al (2005) Differential diagnosis of pancreatic tumors using ultrasound contrast imaging. J Gastroenterol 40:518–525PubMedCrossRefGoogle Scholar
  86. Suzuki M, Hori K, Abe I, Saito S, Sato H (1981) A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II. J Natl Cancer Inst 67:663–669PubMedGoogle Scholar
  87. Suzuki M, Hori K, Abe I et al (1984) Functional characterization of the microcirculation in tumors. Cancer Metastasis Rev 3:115–126PubMedCrossRefGoogle Scholar
  88. Takahashi Y, Cleary KR, Mai M et al (1996) Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res 2:1679–1684PubMedGoogle Scholar
  89. Tol J, Koopman M, Cats A et al (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360:563–572PubMedCrossRefGoogle Scholar
  90. van der Veen AH, de Wilt JH, Eggermont AM et al (2000) TNF-α augments intratumoural concentrations of doxorubicin in TNF-α-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects. Br J Cancer 82:973–980PubMedCrossRefGoogle Scholar
  91. van Nieuw Amerongen GP, Vermeer MA, Negre-Aminou P et al (2000) Simvastatin improves disturbed endothelial barrier function. Circulation 102:2803–2809PubMedCrossRefGoogle Scholar
  92. Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discov Today 10:1451–1458PubMedCrossRefGoogle Scholar
  93. Wood LD, Parsons W, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113PubMedCrossRefGoogle Scholar
  94. Wu J, Akaike T, Maeda H (1998) Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger. Cancer Res 58:159–165PubMedGoogle Scholar
  95. Yasuda H, Nakayama K, Watanabe M et al (2006a) Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma. Clin Cancer Res 12:6748–6757PubMedCrossRefGoogle Scholar
  96. Yasuda H, Yamaya M, Nakayama K et al (2006b) Randomized phase II trial comparing nitroglycerin plus vinorelbine and cisplatin with vinorelbine and cisplatin alone in previously untreated stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 24:688–694PubMedCrossRefGoogle Scholar
  97. Yoshitake J, Akaike T, Akuta T et al (2004) Nitric oxide as an endogenous mutagen for Sendai virus without antiviral activity. J Virol 78:8709–8719PubMedCrossRefGoogle Scholar
  98. Zhang JS, Liu F, Huang L (2005) Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv Drug Deliv Rev 57:689–698PubMedCrossRefGoogle Scholar
  99. Zhao M, Yang M, Li XM et al (2005) Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc Natl Acad Sci USA 102:755–760PubMedCrossRefGoogle Scholar
  100. Zhao W, Zhuang S, Qi XR (2011) Comparative study of the in vitro and in vivo characteristics of cationic and neutral liposomes. Int J Nanomed 6:3087–3098Google Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Research Institute for Drug Delivery System and Faculty of Pharmaceutical SciencesSojo UniversityKumamotoJapan

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