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Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

The Pharmacogenomics Journal volume 6, pages 388–396 (2006)Cite this article

Abstract

TZT-1027 is an antimicrotubule agent targeting beta-tubulin that is undergoing clinical development. The genomic response of cancer cells to TZT-1027 was profiled to evaluate its biochemical activity. A lung cancer cell line, PC-14, was exposed to antimicrotubule agents including dolastatins, Vinca alkaloids and taxanes at an equivalent toxicity level. Alterations in the TZT-1027-induced gene expression of ∼600 genes were then examined using microarray technology and the resulting gene profiles were compared with those for cells exposed to the other antimicrotubule agents. A principle component analysis using the whole gene set demonstrated that TZT-1027 produced similar gene profiles to those produced by dolastatin 10, but that these gene profiles differed from those produced by other agents. The agents were classified according to their induced genomic response in a molecular structure-dependent manner. Genes whose expression profiles differed according to drug class included intermediate filaments, extracellular matrix protein and Rho regulatory genes that may be involved in cytoskeletal and angiogenesis processes that are regulated by microtubule dynamics. TZT-1027 produces a unique genomic response profile distinct from that of Vinca alkaloids and taxanes, suggesting that this agent has a different mechanism of action. The selected genes may act as pharmacodynamic biomarkers allowing the unique mode of action of TZT-1027 to be discriminated from those of other antimicrotubule agents.

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References

  1. Pettit G, Kamano Y, Herald C, Tuinman A, Boettner F, Kizu H et al. The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. J Am Chem Soc 1987; 109: 6883–6885.

    Article  CAS  Google Scholar 

  2. Saad ED, Kraut EH, Hoff PM, Moore Jr DF, Jones D, Pazdur R et al. Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer. Am J Clin Oncol 2002; 25: 451–453.

    Article  PubMed  Google Scholar 

  3. Vaishampayan U, Glode M, Du W, Kraft A, Hudes G, Wright J et al. Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma. Clin Cancer Res 2000; 6: 4205–4208.

    CAS  PubMed  Google Scholar 

  4. Krug LM, Miller VA, Kalemkerian GP, Kraut MJ, Ng KK, Heelan RT et al. Phase II study of dolastatin-10 in patients with advanced non-small-cell lung cancer. Ann Oncol 2000; 11: 227–228.

    Article  CAS  PubMed  Google Scholar 

  5. Margolin K, Longmate J, Synold TW, Gandara DR, Weber J, Gonzalez R et al. Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium. Invest New Drugs 2001; 19: 335–340.

    Article  CAS  PubMed  Google Scholar 

  6. Miyazaki K, Kobayashi M, Natsume T, Gondo M, Mikami T, Sakakibara K et al. Synthesis and antitumor activity of novel dolastatin 10 analogs. Chem Pharm Bull (Tokyo) 1995; 43: 1706–1718.

    Article  CAS  Google Scholar 

  7. Kobayashi M, Natsume T, Tamaoki S, Watanabe J, Asano H, Mikami T et al. Antitumor activity of TZT-1027, a novel dolastatin 10 derivative. Jpn J Cancer Res 1997; 88: 316–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chaplin DJ, Pettit GR, Parkins CS, Hill SA . Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents. Br J Cancer Suppl 1996; 27: S86–S88.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Otani M, Natsume T, Watanabe JI, Kobayashi M, Murakoshi M, Mikami T et al. TZT-1027, an antimicrotubule agent, attacks tumor vasculature and induces tumor cell death. Jpn J Cancer Res 2000; 91: 837–844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Natsume T, Watanabe J, Koh Y, Fujio N, Ohe Y, Horiuchi T et al. Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo. Cancer Sci 2003; 94: 826–833.

    Article  CAS  PubMed  Google Scholar 

  11. Niitani H, Hasegawa K . Phase I studies of TZT-1027, a novel inhibitor of tubulin polymerization. Ann Oncol 1998; 9 (Suppl 2): 360.

    Google Scholar 

  12. de Jonge MJ, van der Gaast A, Planting AS, van Doorn L, Lems A, Boot I et al. Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027, given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors. Clin Cancer Res 2005; 11: 3806–3813.

    Article  CAS  PubMed  Google Scholar 

  13. Schoffski P, Thate B, Beutel G, Bolte O, Otto D, Hofmann M et al. Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer. Ann Oncol 2004; 15: 671–679.

    Article  CAS  PubMed  Google Scholar 

  14. Natsume T, Watanabe J, Tamaoki S, Fujio N, Miyasaka K, Kobayashi M . Characterization of the interaction of TZT-1027, a potent antitumor agent, with tubulin. Jpn J Cancer Res 2000; 91: 737–747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fujita F, Koike M, Fujita M, Sakamoto Y, Tsukagoshi S . Antitumor effects of TZT-1027, a novel dolastatin 10 derivative, on human tumor xenografts in nude mice. Gan To Kagaku Ryoho 2000; 27: 451–458.

    CAS  PubMed  Google Scholar 

  16. Watanabe J, Natsume T, Fujio N, Miyasaka K, Kobayashi M . Induction of apoptosis in human cancer cells by TZT-1027, an antimicrotubule agent. Apoptosis 2000; 5: 345–353.

    Article  CAS  PubMed  Google Scholar 

  17. Natsume T, Kobayashi M, Fujimoto S . Association of p53 gene mutations with sensitivity to TZT-1027 in patients with clinical lung and renal carcinoma. Cancer 2001; 92: 386–394.

    Article  CAS  PubMed  Google Scholar 

  18. Natsume T, Nakamura T, Koh Y, Kobayashi M, Saijo N, Nishio K . Gene expression profiling of exposure to TZT-1027, a novel microtubule-interfering agent, in non-small cell lung cancer PC-14 cells and astrocytes. Invest New Drugs 2001; 19: 293–302.

    Article  CAS  PubMed  Google Scholar 

  19. DeRisi JL, Iyer VR, Brown PO . Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 1997; 278: 680–686.

    Article  CAS  PubMed  Google Scholar 

  20. Parsons AB, Brost RL, Ding H, Li Z, Zhang C, Sheikh B et al. Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nat Biotechnol 2004; 22: 62–69.

    Article  CAS  PubMed  Google Scholar 

  21. Baetz K, McHardy L, Gable K, Tarling T, Reberioux D, Bryan J et al. Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action. Proc Natl Acad Sci USA 2004; 101: 4525–4530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kung C, Kenski DM, Dickerson SH, Howson RW, Kuyper LF, Madhani HD et al. Chemical genomic profiling to identify intracellular targets of a multiplex kinase inhibitor. Proc Natl Acad Sci USA 2005; 102: 3587–3592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gunther EC, Stone DJ, Gerwien RW, Bento P, Heyes MP . Prediction of clinical drug efficacy by classification of drug-induced genomic expression profiles in vitro. Proc Natl Acad Sci USA 2003; 100: 9608–9613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. DeVita VT, Hellman S, Rosenberg SA . Cancer: Principles and Practice of Oncology, 7th edn, Lippincott Williams & Wilkins (LWW): Philadelphia, 2004.

    Google Scholar 

  25. Jordan MA, Wilson L . Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004; 4: 253–265.

    Article  CAS  PubMed  Google Scholar 

  26. Diaz JF, Andreu JM . Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition. Biochemistry 1993; 32: 2747–2755.

    Article  CAS  PubMed  Google Scholar 

  27. Jordan A, Hadfield JA, Lawrence NJ, McGown AT . Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med Res Rev 1998; 18: 259–296.

    Article  CAS  PubMed  Google Scholar 

  28. Gupta S, Bhattacharyya B . Antimicrotubular drugs binding to Vincadomain of tubulin. Mol Cell Biochem 2003; 253: 41–47.

    Article  CAS  PubMed  Google Scholar 

  29. Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E . Halichondrin B and homohalichondrin B, marine natural products binding in the Vincadomain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem 1991; 266: 15882–15889.

    CAS  PubMed  Google Scholar 

  30. Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature 2002; 420: 629–635.

    Article  CAS  PubMed  Google Scholar 

  31. Sahai E, Marshall CJ . RHO-GTPases and cancer. Nat Rev Cancer 2002; 2: 133–142.

    Article  PubMed  Google Scholar 

  32. Board PG, Coggan M, Chelvanayagam G, Easteal S, Jermiin LS, Schulte GK et al. Identification, characterization, and crystal structure of the Omega class glutathione transferases. J Biol Chem 2000; 275: 24798–24806.

    Article  CAS  PubMed  Google Scholar 

  33. Schisselbauer JC, Silber R, Papadopoulos E, Abrams K, LaCreta FP, Tew KD . Characterization of glutathione S-transferase expression in lymphocytes from chronic lymphocytic leukemia patients. Cancer Res 1990; 50: 3562–3568.

    CAS  PubMed  Google Scholar 

  34. Ban N, Takahashi Y, Takayama T, Kura T, Katahira T, Sakamaki S et al. Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide. Cancer Res 1996; 56: 3577–3582.

    CAS  PubMed  Google Scholar 

  35. Anand-Apte B, Bao L, Smith R, Iwata K, Olsen BR, Zetter B et al. A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol 1996; 74: 853–862.

    Article  CAS  PubMed  Google Scholar 

  36. Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ . Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 1998; 95: 365–377.

    Article  CAS  PubMed  Google Scholar 

  37. Anand-Apte B, Pepper MS, Voest E, Montesano R, Olsen B, Murphy G et al. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci 1997; 38: 817–823.

    CAS  PubMed  Google Scholar 

  38. Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407–415.

    Article  CAS  PubMed  Google Scholar 

  39. Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.

    Article  CAS  PubMed  Google Scholar 

  40. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  PubMed  Google Scholar 

  41. Hosack DA, Dennis Jr G, Sherman BT, Lane HC, Lempicki RA . Identifying biological themes within lists of genes with EASE. Genome Biol 2003; 4: R70.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dennis Jr G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 2003; 4: P3.

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by a Grant-in-Aid for Cancer Research and the 3rd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare, Tokyo, Japan. K Nishio and T Shimoyama designed the study. T Shimoyama and K Nishio prepared the manuscript. Y Koh and T Natsume undertook the study. T Shimoyama and T Hamano performed the statistical analysis. T Shimoyama is the recipient of a Research Resident Fellowship from the Foundation of Promotion of Cancer Research in Japan.

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Authors and Affiliations

  1. Shien-Lab and Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

    T Shimoyama, T Hamano, T Natsume, F Koizumi & K Nishio

  2. Department of Medicine II, Okayama University Medical School, Shikata-cho, Okayama, Japan

    T Shimoyama, K Kiura & M Tanimoto

  3. Pharmacology Division, National Cancer Center Research Institution, Chuo-ku, Tokyo, Japan

    K Nishio

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  1. T Shimoyama
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Correspondence to K Nishio.

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Supplementary Information accompanies the paper on The Pharmacogenomics Journal website (http://www.nature.com/tpj).

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Shimoyama, T., Hamano, T., Natsume, T. et al. Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro. Pharmacogenomics J 6, 388–396 (2006). https://doi.org/10.1038/sj.tpj.6500386

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