Interfering with pH regulation in tumours as a therapeutic strategy (original) (raw)

• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  Article CAS PubMed Google Scholar
• Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273–286 (2007). This is a comprehensive review on angiogenesis.
  Article CAS Google Scholar
• Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004). This is an excellent review on the metabolism of cancer cells and the proposal of the somatic evolution theory of cancer.
  Article CAS Google Scholar
• Ebbesen, P. et al. Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies. J. Enzyme Inhib. Med. Chem. 24 (Suppl. 1), 1–39 (2009). This is an updated and comprehensive review on hypoxia and its role in tumorigenesis and how these phenomena can be used to design anticancer drugs.
  Article CAS PubMed Google Scholar
• Fang, J. S., Gillies, R. J. & Gatenby, R. A. Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Sem. Cancer Biol. 18, 330–337 (2008).
  Article CAS Google Scholar
• Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930–3942 (2008).
  CAS PubMed PubMed Central Google Scholar
• Huber, V. et al. Proton dynamics in cancer. J. Transl. Med. 8, 57 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Swietach, P. et al. Cancer-associated, hypoxia-inducible carbonic anhydrase IX facilitates CO2 diffusion. BJU Int. 101 (Suppl. 4), 22–24 (2008).
  Article CAS PubMed Google Scholar
• Swietach, P. et al. Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growth. J. Biol. Chem. 283, 20473–20483 (2008). This paper demonstrated the role of CA9 in the regulation of pH i in tumours.
  Article CAS PubMed Google Scholar
• Wykoff, C. C. et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 60, 7075–7083 (2000). This was the first report showing that CA9 is overexpressed as a consequence of the HIF1α activation pathway.
  CAS PubMed Google Scholar
• Borsi, L. et al. The alternative splicing pattern of the tenascin-C pre-mRNA is controlled by the extracellular pH. J. Biol. Chem. 270, 6243–6245 (1995).
  Article CAS PubMed Google Scholar
• Borsi, L., Allemanni, G., Gaggero, B. & Zardi, L. Extracellular pH controls pre-mRNA alternative splicing of tenascin-C in normal, but not in malignantly transformed, cells. Int. J. Cancer 66, 632–635 (1996).
  Article CAS PubMed Google Scholar
• Kremer, G. & Pouysségur, J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13, 472–482 (2008).
  Article CAS Google Scholar
• Pouysségur, J., Dayan, F. & Mazure, N. M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006). This is an excellent review on the role of various proteins that are involved in the control of pH in tumour cells.
  Article CAS PubMed Google Scholar
• Supuran, C. T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Rev. Drug Discov. 7, 168–181 (2008). This is a comprehensive review on carbonic anhydrases as drug targets.
  Article CAS Google Scholar
• Supuran, C. T. Carbonic anhydrase inhibitors. Bioorg. Med. Chem. Lett. 20, 3467–3474 (2010).
  Article CAS PubMed Google Scholar
• Pastorek, J. et al. Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and putative helix–loop–helix DNA binding segment. Oncogene 9, 2877–2888 (1994). This was a seminal paper reporting the discovery of the protein that would later be called CA9.
  CAS PubMed Google Scholar
• Pérez-Sayáns, M. et al. V-ATPase inhibitors and implication in cancer treatment. Cancer Treat. Rev. 35, 707–713 (2009).
  Article CAS PubMed Google Scholar
• Sterling, D., Brown, N. J. D., Supuran, C. T. & Casey, J. R. The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II. Am. J. Physiol. Cell. Physiol. 283, C1522–C1529 (2002).
  Article CAS PubMed Google Scholar
• Morgan, P. E., Supuran, C. T. & Casey, J. R. Carbonic anhydrase inhibitors that directly inhibit anion transport by the human Cl−/HCO3− exchanger, AE1. Mol. Membr. Biol. 21, 423–433 (2004).
  Article CAS PubMed Google Scholar
• Halestrap, A. P. & Price, N. T. The proton-linked mono-carboxylate transporter (MCT) family: structure, function and regulation. Biochem. J. 343, 281–299 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Enerson, B. E. & Drewes, L. R. Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery. J. Pharm. Sci. 92, 1531–1544 (2003).
  Article CAS PubMed Google Scholar
• Parks, S. K., Chiche, J. & Pouysségur, J. pH control mechanisms of tumor survival and growth. J. Cell. Physiol. 226, 299–308 (2010).
  Article CAS Google Scholar
• Scozzafava, A., Mastrolorenzo, A. & Supuran, C. T. Modulation of carbonic anhydrase activity and its applications in therapy. Expert Opin. Ther. Pat. 14, 667–702 (2004).
  Article CAS Google Scholar
• Scozzafava, A., Mastrolorenzo, A. & Supuran, C. T. Carbonic anhydrase inhibitors and activators and their use in therapy. Expert Opin. Ther. Pat. 16, 1627–1664 (2006).
  Article CAS Google Scholar
• Supuran, C. T. Carbonic anhydrase inhibition/activation: trip of a scientist around the world in the search of novel chemotypes and drug targets. Curr. Pharm. Des. 16, 3233–3245 (2010).
  Article CAS PubMed Google Scholar
• Tureci, O. et al. Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc. Natl Acad. Sci. USA 95, 7608–7613 (1998). This paper reported the discovery of the second tumour-associated carbonic anhydrase, CA12.
  Article CAS PubMed PubMed Central Google Scholar
• Švastová, E. et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 577, 439–445 (2004). This was a proof-of-concept study on the role of CA9 in the acidification of tumours. It suggested that CA9 might be useful as a therapeutic target and for imaging hypoxic tumours.
  Article CAS PubMed Google Scholar
• Hilvo, M. et al. Biochemical characterization of CA IX: one of the most active carbonic anhydrase isozymes. J. Biol. Chem. 283, 27799–27809 (2008).
  Article CAS PubMed Google Scholar
• Scheurer, S. B. et al. Modulation of gene expression by hypoxia in umbilical vein endothelial cells: a transcriptomic and proteomic study. Proteomics 4, 1737–1760 (2004).
  Article CAS PubMed Google Scholar
• Innocenti, A. et al. The proteoglycan region of the tumor-associated carbonic anhydrase isoform IX acts as an intrinsic buffer optimizing CO2 hydration at acidic pH values characteristic of solid tumors. Bioorg. Med. Chem. Lett. 19, 5825–5828 (2009).
  Article CAS PubMed Google Scholar
• Alterio, V. et al. Crystal structure of the extracellular catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc. Natl Acad. Sci. USA 106, 16233–16238 (2009). This was a report of the three-dimensional structure of CA9, which was determined using X-ray crystallography.
  Article PubMed PubMed Central Google Scholar
• Vullo, D. et al. Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides — a new target for the design of antitumor and antiglaucoma drugs? Bioorg. Med. Chem. Lett. 15, 963–969 (2005).
  Article CAS PubMed Google Scholar
• Pastorekova, S. et al. Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX. Bioorg. Med. Chem. Lett. 14, 869–873 (2004).
  Article CAS PubMed Google Scholar
• Pastorekova, S., Parkkila, S., Pastorek, J. & Supuran, C. T. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J. Enzyme Inhib. Med. Chem. 19, 199–229 (2004).
  Article CAS PubMed Google Scholar
• Cecchi, A. et al. Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors. J. Med. Chem. 48, 4834–4841 (2005).
  Article CAS PubMed Google Scholar
• Thiry, A., Dogné, J.-M., Masereel, B. & Supuran, C. T. Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends Pharmacol. Sci. 27, 566–573 (2006).
  Article CAS PubMed Google Scholar
• Guler, O. O., De Simone, G. & Supuran, C. T. Drug design studies of the novel antitumor targets carbonic anhydrase IX and XII. Curr. Med. Chem. 17, 1516–1526 (2010).
  Article CAS PubMed Google Scholar
• Alterio, V. et al. Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX. J. Am. Chem. Soc. 128, 8329–8335 (2006).
  Article CAS PubMed Google Scholar
• De Simone, G. et al. Carbonic anhydrase inhibitors: hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX. J. Med. Chem. 49, 5544–5551 (2006).
  Article CAS PubMed Google Scholar
• Ahlskog, J. K. J. et al. In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives. Bioorg. Med. Chem. Lett. 19, 4851–4856 (2009). This was a proof-of-concept study regarding the the anticancer effects of in vivo inhibition of CA9 in tumour-bearing animals.
  Article CAS PubMed Google Scholar
• Maresca, A. et al. Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors. J. Am. Chem. Soc. 131, 3057–3062 (2009). This paper reported the discovery of a new class of carbonic anhydrase inhibitors.
  Article CAS PubMed Google Scholar
• Maresca, A. et al. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J. Med. Chem. 53, 335–344 (2010).
  Article CAS PubMed Google Scholar
• Stiti, M. et al. Carbonic anhydrase inhibitor coated gold nanoparticles selectively inhibit the tumor-associated isoform IX over the cytosolic ubiquitous isozymes I and II. J. Am. Chem. Soc. 130, 16130–16131 (2008).
  Article CAS PubMed Google Scholar
• Dubois, L. et al. Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. Radiother. Oncol. 83, 367–373 (2007).
  Article CAS PubMed Google Scholar
• Dubois, L. et al. Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model. Radiother. Oncol. 92, 423–428 (2009). This was a proof-of-concept study for the in vivo imaging of hypoxic tumours with sulphonamide-based CA9 inhibitors.
  Article CAS PubMed Google Scholar
• Chiche, J. et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 69, 358–368 (2009). This paper reported the discovery that genetic silencing of CA9 and CA12 has potent antitumour effects.
  Article CAS PubMed Google Scholar
• Lou, Y. et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 71, 3364–3376 (2011). This was the first report to show that sulphonamide and/or coumarin inhibitors potently inhibit the growth of primary tumours and metastases by inhibiting CA9.
  Article CAS PubMed Google Scholar
• Buller, F. et al. Selection of carbonic anhydrase IX inhibitors from one million DNA-encoded compounds. ACS Chem. Biol. 6, 336–344 (2011).
  Article CAS PubMed Google Scholar
• Pacchiano, F. et al. Ureido-substituted benzenesulfon-amides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 54, 1896–1902 (2011).
  Article CAS PubMed Google Scholar
• Dubois, L. et al. Specific inhibition of CA IX activity enhances the therapeutic effect of tumor irradiation. Radiother. Oncol. 99, 424–431 (2011).
  Article CAS PubMed Google Scholar
• Maresca, A., Scozzafava, A. & Supuran, C. T. 7,8-Disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range. Bioorg. Med. Chem. Lett. 20, 7255–7258 (2010).
  Article CAS PubMed Google Scholar
• Pearson, M. A. & Fabbro, D. Targeting protein kinases in cancer therapy: a success? Expert. Rev. Anticancer Ther. 4, 1113–1124 (2004).
  Article CAS PubMed Google Scholar
• Parkkila, S. et al. The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian α-carbonic anhydrase isoforms. Bioorg. Med. Chem. Lett. 19, 4102–4106 (2009). This paper reported the discovery that imatinib and nilotinib exert potent inhibitory effects on carbonic anhydrase, and that this may be an additional antitumour mechanism of these drugs.
  Article CAS PubMed Google Scholar
• Parkkila, S. et al. Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Mod. Pathol. 23, 743–750 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Battke, C. et al. Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII. Cancer Immunol. Immunother. 60, 649–658 (2011).
  Article CAS PubMed Google Scholar
• Stillebroer, A. B. et al. Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy. Eur. Urol. 58, 75–83 (2010).
  Article CAS PubMed Google Scholar
• Winter, G. & Milstein, C. Man-made antibodies. Nature 349, 293–299 (1991).
  Article CAS PubMed Google Scholar
• Winter, G., Griffiths, A. D., Hawkins, R. E. & Hoogenboom, H. R. Making antibodies by phage display technology. Annu. Rev. Immunol. 12, 433–455 (1994).
  Article CAS PubMed Google Scholar
• Carter, P. J. Potent antibody therapeutics by design. Nature Rev. Immunol. 6, 343–357 (2010).
  Article CAS Google Scholar
• Chrastina, A. et al. Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma. Int. J. Cancer 105, 873–881 (2003).
  Article CAS PubMed Google Scholar
• Siebels, M. et al. A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX®) and interferon-α-2a in metastatic renal cell carcinoma patients. World J. Urol. 29, 121–126 (2011). These preliminary data reported the successful use of a CA9-specific monoclonal antibody as an anticancer drug in patients with renal carcinoma.
  Article CAS PubMed Google Scholar
• Steffens, M. G. et al. In vivo and in vitro characterizations of three 99mTc-labeled monoclonal antibody G250 preparations. J. Nucl. Med. 40, 829–836 (1999).
  CAS PubMed Google Scholar
• van Schaijk, F. G. et al. Pretargeting with bispecific anti-renal cell carcinoma x anti-DTPA(In) antibody in 3 RCC models. J. Nucl. Med. 46, 495–501 (2005).
  CAS PubMed Google Scholar
• Low, P. & Kularatne, S. A. Folate-targeted therapeutic and imaging agents for cancer. Curr. Opin. Chem. Biol. 13, 256–262 (2009).
  Article CAS PubMed Google Scholar
• Fais, S. Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J. Intern. Med. 267, 515–525 (2010). This paper described an unorthodox way of managing tumour acidification with a class of drugs that were originally designed for the treatment of peptic ulcers.
  Article CAS PubMed Google Scholar
• Spugnini, E., Citro, G. & Fais, S. Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J. Exp. Clin. Cancer Res. 29, 44 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ohta, T. et al. Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1. J. Pathol. 185, 324–330 (1998).
  Article CAS PubMed Google Scholar
• De Milito, A. et al. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int. J. Cancer 127, 207–219 (2010).
  Article CAS PubMed Google Scholar
• Horn, J. The proton-pump inhibitors: similarities and differences. Clin. Ther. 22, 266–280 (2000).
  Article CAS PubMed Google Scholar
• Denny, W. A. & Wilson, W. R. Considerations for the design of nitrophenyl mustards as agents with selective toxicity for hypoxic tumor cells. J. Med. Chem. 29, 879–887 (1986).
  Article CAS PubMed Google Scholar
• Johnson, D. E. & Casey, J. R. in Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications (eds Supuran, C. T. & Winum, J. Y.) 415–437 (Wiley, Hoboken, New Jersey, 2009). This book provides an updated review on HCO 3 − transporters and the metabolons in which they are involved.
  Book Google Scholar
• Sowah, D. & Casey, J. R. An intramolecular transport metabolon: fusion of carbonic anhydrase II to the COOH terminus of the Cl−/HCO3− exchanger, AE1. Am. J. Physiol. Cell Physiol. 301, C336–C346 (2011).
  Article CAS PubMed Google Scholar
• Morgan, P. E. et al. Interactions of transmembrane carbonic anhydrase, CA IX, with bicarbonate transporters. Am. J. Physiol. Cell. Physiol. 293, C738–C748 (2007).
  Article CAS PubMed Google Scholar
• Jessen, F., Sjøholm, C. & Hoffmann, E. K. Identification of the anion exchange protein of ehrlich cells: a kinetic analysis of the inhibitory effects of 4, 4′-diisothiocyano-2,2′-stilbene-disulfonic acid (DIDS) and labeling of membrane proteins with 3H-DIDS. J. Membr. Biol. 92, 195–205 (1986).
  Article CAS PubMed Google Scholar
• Liu, C. J. et al. Anion exchanger inhibitor DIDS induces human poorly-differentiated malignant hepatocellular carcinoma HA22T cell apoptosis. Mol. Cell. Biochem. 308, 117–125 (2008).
  Article CAS PubMed Google Scholar
• Supuran, C. T., Scozzafava, A. & Casini, A. Carbonic anhydrase inhibitors. Med. Res. Rev. 23, 146–189 (2003).
  Article CAS PubMed Google Scholar
• Supuran, C. T., Casini, A., Mastrolorenzo, A. & Scozzafava, A. COX-2 selective inhibitors, carbonic anhydrase inhibition and anticancer properties of sulfonamides belonging to this class of pharmacological agents. Mini Rev. Med. Chem. 4, 625–632 (2004).
  Article CAS PubMed Google Scholar
• Yamagata, M. & Tannock, I. F. The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects. Br. J. Cancer 73, 1328–1334 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Di Sario, A. et al. Selective inhibition of ion transport mechanisms regulating intracellular pH reduces proliferation and induces apoptosis in cholangiocarcinoma cells. Dig. Liver Dis. 39, 60–69 (2007).
  Article CAS PubMed Google Scholar
• Wong, P., Lee, C. & Tannock, I. F. Reduction of intracellular pH as a strategy to enhance the pH-dependent cytotoxic effects of melphalan for human breast cancer cells. Clin. Cancer Res. 11, 3553–3557 (2005).
  Article CAS PubMed Google Scholar
• Lagarde, A. E., Franchi, A. J., Paris, S. & Pouysségur, J. M. Effect of mutations affecting Na+:H+ antiport activity on tumorigenic potential of hamster lung fibroblasts. J. Cell. Biochem. 36, 249–260 (1988).
  Article CAS PubMed Google Scholar
• Harley, W. et al. Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas. Brain Res. 1363, 159–169 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Masereel, B., Pochet, L. & Laeckmann, D. An overview of inhibitors of Na+/H+ exchanger. Eur. J. Med. Chem. 38, 547–554 (2003).
  Article CAS PubMed Google Scholar
• Theroux, P. et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Circulation 102, 3032–3038 (2000).
  Article CAS PubMed Google Scholar
• Feron, O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother. Oncol. 92, 329–333 (2009).
  Article CAS PubMed Google Scholar
• Ullah, M. S., Davies, A. J. & Halestrap, A. P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J. Biol. Chem. 281, 9030–9037 (2006).
  Article CAS PubMed Google Scholar
• Chiche, J. et al. In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. Int. J. Cancer 30 May 2011 (doi:10.1002/ijc.26125).
• Khandoudi, N. et al. Inhibition of the cardiac electrogenic sodium bicarbonate cotransporter reduces ischemic injury. Cardiovasc. Res. 52, 387–396 (2001).
  Article CAS PubMed Google Scholar
• De Giusti, V. et al. Antibodies against the cardiac sodium/bicarbonate cotransporter (NBCe1) as a pharmacological tool. Br. J. Pharmacol. 19 May 2011 (doi: 10.1111/j.1476-5381.2011.01496).
• Chiappe de Cingolani, G. E. et al. Involvement of AE3 isoform of Na+-independent Cl−/HCO3− exchanger in myocardial pHi recovery from intracellular alkalinization. Life Sci. 78, 3018–3026 (2006).
  Article CAS PubMed Google Scholar
• Brack, S. S., Silacci, M., Birchler, M. & Neri, D. Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C. Clin. Cancer Res. 12, 3200–3208 (2006).
  Article CAS PubMed Google Scholar
• Trachsel, E. et al. A human mAb specific to oncofetal fibronectin selectively targets chronic skin inflammation in vivo. J. Invest. Dermatol. 127, 881–886 (2007).
  Article CAS PubMed Google Scholar
• Schwager, K. et al. Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immuno-cytokine which inhibits the progression of collagen-induced arthritis. Arthritis Res. Ther. 11, R142 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Schwager, K. et al. The antibody-mediated targeted delivery of interleukin-10 inhibits endometriosis in a syngeneic mouse model. Human Reprod. 26, 2344–2352 (2011).
  Article CAS Google Scholar
• Pedretti, M. et al. Comparative immunohistochemistry of L19 and F16 in non-small cell lung cancer and mesothelioma: two human antibodies investigated in clinical trials in patients with cancer. Lung Cancer 64, 28–33 (2009).
  Article PubMed Google Scholar
• Fiechter, M. et al. Comparative in vivo analysis of the atherosclerotic plaque targeting properties of eight human monoclonal antibodies. Atherosclerosis 214, 325–330 (2011).
  Article CAS PubMed Google Scholar
• Chiquet-Ehrismann, R. & Tucker, R. P. Tenascins and the importance of adhesion modulation. Cold Spring Harb. Perspect. Biol. 3, a004960 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Neri, D. & Bicknell, R. Tumour vascular targeting. Nature Rev. Cancer 5, 436–446 (2005). This is a comprehensive review on targeting the tumour vasculature.
  Article CAS Google Scholar
• Carnemolla, B. et al. Identification of a glioblastoma-associated tenascin-C isoform by a high affinity recombinant antibody. Am. J. Pathol. 154, 1345–1352 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Silacci, M. et al. Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo. Protein Eng. Des. Sel. 19, 471–478 (2006).
  Article CAS PubMed Google Scholar
• Berndt, A. et al. A comparative analysis of oncofetal fibronectin and tenascin-C incorporation in tumour vessels using human recombinant SIP format antibodies. Histochem. Cell. Biol. 133, 467–475 (2010).
  Article CAS PubMed Google Scholar
• Castellani, P. et al. The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis. Int. J. Cancer 59, 612–618 (1994).
  Article CAS PubMed Google Scholar
• Kaczmarek, J. et al. Distribution of oncofetal fibronectin isoforms in normal, hyperplastic and neoplastic human breast tissues. Int. J. Cancer 59, 11–16 (1994).
  Article CAS PubMed Google Scholar
• Carnemolla, B. et al. Phage antibodies with pan-species recognition of the oncofoetal angiogenesis marker fibronectin ED-B domain. Int. J. Cancer 68, 397–405 (1996).
  Article CAS PubMed Google Scholar
• Castellani, P. et al. Differentiation between high- and low-grade astrocytoma using a human recombinant antibody to the extra domain-B of fibronectin. Am. J. Pathol. 161, 1695–1700 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Rybak, J. N. et al. The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Res. 67, 10948–10957 (2007).
  Article CAS PubMed Google Scholar
• Sauer, S. et al. Expression of the oncofetal ED-B-containing fibronectin isoform in hematologic tumors enables ED-B-targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients. Blood 113, 2265–2274 (2009).
  Article CAS PubMed Google Scholar
• Schliemann, C. et al. Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood 113, 2275–2283 (2009).
  Article CAS PubMed Google Scholar
• Schliemann, C. et al. Three clinical-stage tumor targeting antibodies reveal differential expression of oncofetal fibronectin and tenascin-C isoforms in human lymphoma. Leuk. Res. 33, 1718–1722 (2009).
  Article CAS PubMed Google Scholar
• Castronovo, V. et al. A chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer. Mol. Cell. Proteomics 5, 2083–2091 (2006).
  Article CAS PubMed Google Scholar
• Borgia, B. et al. A proteomic approach for the identification of vascular markers of liver metastasis. Cancer Res. 70, 309–318 (2010).
  Article CAS PubMed Google Scholar
• Schliemann, C. et al. In vivo biotinylation of the vasculature in B-cell lymphoma identifies BST-2 as a target for antibody-based therapy. Blood 115, 736–744 (2010).
  Article CAS PubMed Google Scholar
• Soltermann, A. et al. Prognostic significance of epithelial–mesenchymal and mesenchymal–epithelial transition protein expression in non-small cell lung cancer. Clin. Cancer Res. 14, 7430–7437 (2008).
  Article CAS PubMed Google Scholar