KEMTUB012-NI2, a novel potent tubulysin analog that selectively targets hypoxic cancer cells and is potentiated by cytochrome p450 reductase downregulation

References

• Mees G, Dierckx R, Vangestel C, Van De Wiele C. Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging. 2009;36(10):1674–1686.
   PubMed Web of Science ®Google Scholar
• Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996;56(5):941–943.
   PubMed Web of Science ®Google Scholar
• Höckel M, Vaupel P. Biological consequences of tumor hypoxia. Semin Oncol. 2001;28(2 suppl 8):36–41.
   PubMed Web of Science ®Google Scholar
• Fleming IN, Manavaki R, Blower PJ, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2015;112(2):238–250.
   PubMed Web of Science ®Google Scholar
• Milane L, Ganesh S, Shah S, Duan ZF, Amiji M. Multi-modal strategies for overcoming tumor drug resistance: hypoxia, the warburg effect, stem cells, and multifunctional nanotechnology. J Control Release. 2011;155(2):237–247.
   PubMed Web of Science ®Google Scholar
• Hay MP, Hicks KO, Wang J, editors. Hypoxia-directed drug strategies to target the tumor microenvironment. Adv Exp Med Biol. 2014;772:111–145.
   PubMed Web of Science ®Google Scholar
• McKeown SR, Cowen RL, Williams KJ. Bioreductive drugs: from concept to clinic. Clin Oncol. 2007;19(6):427–442.
   PubMed Web of Science ®Google Scholar
• Guise CP, Mowday AM, Ashoorzadeh A, et al. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin J Cancer. 2014;33(2):80–86.
   PubMed Web of Science ®Google Scholar
• Strese S, Fryknäs M, Larsson R, Gullbo J. Effects of hypoxia on human cancer cell line chemosensitivity. BMC Cancer. 2013;13:331.
   PubMed Web of Science ®Google Scholar
• Hunter FW, Young RJ, Shalev Z, et al. Identification of P450 oxidoreductase as a major determinant of sensitivity to hypoxia-activated prodrugs. Cancer Res. 2015;75(19):4211–4223.
   PubMed Web of Science ®Google Scholar
• Manley E, Waxman DJ. Impact of tumor blood flow modulation on tumor sensitivity to the bioreductive drug banoxantrones. J Pharmacol Exp Ther. 2013;344(2):368–377.
   PubMed Web of Science ®Google Scholar
• Lamidi OF, Sani M, Lazzari P, Zanda M, Fleming IN. The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, bim and bcl-2. J Cancer Res Clin Oncol. 2015;141(9):1575–1583.
   PubMed Web of Science ®Google Scholar
• Sasse F, Steinmetz H, Heil J, Hofle G, Reichenbach H. Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties. J Antibiot. 2000;53(9):879–885.
   PubMed Web of Science ®Google Scholar
• Herrmann J, Elnakady YA, Wiedmann RM, et al. Pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy. PLoS One. 2012;7(5):e37416.
   PubMed Web of Science ®Google Scholar
• Khalil MW, Sasse F, Lünsdorf H, Elnakady YA, Reichenbach H. Mechanism of action of tubulysin, an antimitotic peptide from myxobacteria. Chembiochem. 2006;7(4):678–683.
   PubMed Web of Science ®Google Scholar
• Schluep T, Gunawan P, Ling M, et al. Polymeric tubulysin-peptide nanoparticles with potent antitumor activity. Clin Cancer Res. 2009;15(1):181–189.
   PubMed Web of Science ®Google Scholar
• Cohen R, Vugts DJ, Visser GWM, et al. Development of novel ADCs: conjugation of tubulysin analogues to trastuzumab monitored by dual radiolabeling. Cancer Res. 2014;74(20):5700–5710.
   PubMed Web of Science ®Google Scholar
• Zanda M, Sani M, Lazzari P, Inventor; KemoTech s.r.l., assignee. Tubulysin with high cytotoxicity, pharmaceutical compositions thereof, and method of use thereof. United States patent 8,580,820. 2013 November 12.
   Google Scholar
• Zhaa Z, Zhu L, Liua Y, et al. Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging. Nucl Med Biol. 2011;38(4):501–508.
   PubMed Web of Science ®Google Scholar
• Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Nat Acad Sci U S A. 2001;98(19):10869–10874.
   PubMed Web of Science ®Google Scholar
• Smith TAD, Zanda M, Fleming IN. Hypoxia stimulates 18F-fluorodeoxyglucose uptake in breast cancer cells via hypoxia inducible factor-1 and AMP-activated protein kinase. Nucl Med Biol. 2013;40(6):858–864.
   PubMed Web of Science ®Google Scholar
• Green SR, Choudhary AK, Fleming IN. Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. Br J Cancer. 2010;103(9):1391–1399.
   PubMed Web of Science ®Google Scholar
• Blagosklonny MV, Robey R, Sheikh MS, Fojo T. Paclitaxel-induced fasl-independent apoptosis and slow (non-apoptotic) cell death. Cancer Biol Ther. 2002;1(2):113–117.
   PubMed Web of Science ®Google Scholar
• O’Donnell VB, Smith GCM, Jones OTG. Involvement of phenyl radicals in lodonium compound inhibition of flavoenzymes. Mol Pharmacol. 1994;46(4):778–785.
   PubMed Web of Science ®Google Scholar
• Wang J, Guise CP, Dachs GU, et al. Identification of one-electron reductases that activate both the hypoxia prodrug SN30000 and diagnostic probe EF5. Biochem Pharmacol. 2015;91(4):436–446.
   Web of Science ®Google Scholar
• Guise CP, Abbattista MR, Tipparaju SR, et al. Diflavin oxidoreductases activate the bioreductive prodrug PR-104A under hypoxia. Mol Pharmacol. 2012;81(1):31–40.
   PubMed Web of Science ®Google Scholar
• Rischin D, Hicks RJ, Fisher R, et al; Trans-Tasman Radiation Oncology Group Study 98.02. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of trans-tasman radiation oncology group study 98.02. J Clin Oncol. 2006;24(13):2098–2104.
   PubMed Web of Science ®Google Scholar
• Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck – a systematic review and meta-analysis. Radiother Oncol. 2011;100(1):22–32.
   PubMed Web of Science ®Google Scholar
• Nishida CR, Lee M, Ortiz De Montellano PR. Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1. Mol Pharmacol. 2010;78(3):497–502.
   PubMed Web of Science ®Google Scholar
• Mehibel M, Singh S, Chinje EC, Cowen RL, Stratford IJ. Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N). Mol Cancer Ther. 2009;8(5):1261–1269.
   PubMed Web of Science ®Google Scholar
• Pandey AV, Flück CE. NADPH P450 oxidoreductase: structure, function, and pathology of diseases. Pharmacol Ther. 2013;138(2):229–254.
   PubMed Web of Science ®Google Scholar