Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2000 Aug;91(8):837–844. doi: 10.1111/j.1349-7006.2000.tb01022.x

TZT‐1027, an Antimicrotubule Agent, Attacks Tumor Vasculature and Induces Tumor Cell Death

Masashi Otani 1,✉, Tsugitaka Natsume 2, Jun‐ichi Watanabe 2, Motohiro Kobayashi 2, Masanori Murakoshi 1, Takashi Mikami 1, Takaharu Nakayama 1
PMCID: PMC5926421  PMID: 10965026

Abstract

TZT‐1027, a dolastatin 10 derivative, is an antimicrotubule agent with potent antitumor activity both in vitro and in vivo. In this study, we performed biochemical and histopathological examinations, and evaluated TZT‐1027‐induced tumoral vascular collapse and tumor cell death in an advanced tumor model, murine colon 26 adenocarcinoma. In addition, we studied the effects of TZT‐1027 on cultured human umbilical vein endothelial cells (HUVEC). Tolerable doses of TZT‐1027 induced tumor‐selective hemorrhage within 1 h. This hemorrhage occurred mainly in the peripheral area of the tumor mass. Measurements of tumoral hemoglobin content and dye permeation revealed that the hemorrhage occurred firstly and tumor blood flow stopped secondarily. The vascular damage was followed by continuous induction of apoptosis of the tumor cells, tumor tissue necrosis, and tumor regression. In cultured HUVEC, TZT‐1027 induced marked cell contraction with membrane blebbing in 30 min. These cell changes were completely inhibited by K252a, a broad‐spectrum inhibitor of protein kinases. These effects of TZT‐1027 on both tumor vasculature and HUVEC were greater than those of vincristine. In conclusion, TZT‐1027 quickly attacked the well‐developed vascular system of advanced tumors by a putative protein kinase‐dependent mechanism, and then blocked tumor blood flow. Therefore, TZT‐1027 has both a conventional antitumor activity and a unique anti‐tumoral vascular activity, making it a potentially powerful tool for clinical cancer therapy.

Keywords: TZT‐1027, Antimicrotubule agent, Tumoral vascular collapse, Tumor cell death, Advanced tumor

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

REFERENCES

  • 1. ) Miyazaki , K. , Kobayashi , M. , Natsume , T. , Gondo , M. , Mikami , T. , Sakakibara , K. and Tsukagoshi , S.Synthesis and antitumor activity of novel dolastatin 10 analogs . Chem. Pharm. Bull. , 43 , 1706 – 1718 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Kobayashi , M. , Natsume , T. , Tamaoki , S. , Watanabe , J. , Asano , H. , Mikami , T. , Miyasaka , K. , Miyazaki , K. , Gondo , M. , Sakakibara , K. and Tsukagoshi , S.Antitumor activity of TZT‐1027, a novel dolastatin 10 derivative . Jpn. J. Cancer Res. , 88 , 316 – 327 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Mohammad , R. M. , Pettit , G. R. , Almatchy , V. P. , Wall , N. , Varterasian , M. and Al‐Katib , A.Synergistic interaction of selected marine animal anticancer drugs against human diffuse large cell lymphoma . Anticancer Drugs , 9 , 149 – 156 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Mohammad , R. M. , Al‐Katib , A. , Pettit , G. R. , Vaitkevicius , V. K. , Joshi , U. , Adsay , V. , Majumdar , A. P. and Sarkar , F. H.An orthotropic model of human pancreatic cancer in severe combined immunodeficient mice: potential application for preclinical studies . Clin. Cancer Res. , 4 , 887 – 894 ( 1998. ). [PubMed] [Google Scholar]
  • 5. ) Mohammad , R. M. , Varterasian , M. L. , Almatchy , V. P. , Hannoudi , G. N. , Pettit , G. R. and Al‐Katib , A.Successful treatment of human chronic lymphocytic leukemia xenografts with combination biological agents auristatin PE and bryostatin 1 . Clin. Cancer Res. , 4 , 1337 – 1343 ( 1998. ). [PubMed] [Google Scholar]
  • 6. ) Li , Y. , Singh , B. , Ali , N. and Sarkar , F. H.Induction of growth inhibition and apoptosis in pancreatic cancer cells by auristatin‐PE and gemcitabine . Int. J. Mol. Med. , 3 , 647 – 653 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Mohammad , R. M. , Limvarapuss , C. , Wall , N. R. , Hamdy , N. , Beck , F. W. , Pettit , G. R. and Al‐Katib , A.A new tubulin polymerization inhibitor, auristatin PE, induces tumor regression in a human Waldenstorm's macroglobulinemia xenograft model . Int. J. Oncol. , 15 , 367 – 372 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Natsume , T. , Watanabe , J. , Tamaoki , S. , Fujio , N. , Miyasaka , K. and Kobayashi , M.Characterization of the interaction of TZT‐1027, a potent antitumor agent, with tubulin . Jpn. J. Cancer Res. , 91 ( 2000. ). in press . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Watanabe , J. , Natsume , T. , Fujio , N. , Miyasaka , K. and Kobayashi , M.Induction of apoptosis in human cancer cells by TZT‐1027, an antimicrotubule agent . Apoptosis , 5 ( 2000. ). in press . [DOI] [PubMed] [Google Scholar]
  • 10. ) Hill , S. A. , Lonergan , S. J. , Denekamp , J. and Chaplin , D. J.Vinca alkaloids: anti‐vascular effects in a murine tumour . Eur. J. Cancer , 29A , 1320 – 1324 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Baguley , B. C. , Holdaway , K. M. , Thomsen , L. L. , Zhuang , L. and Zwi , L. J.Inhibition of growth of colon 38 adenocarcinoma by vinblastine and colchicine: evidence for a vascular mechanism . Eur. J. Cancer , 27 , 482 – 487 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Chaplin , D. J. , Pettit , G. R. , Parkins , C. S. and Hill , S. A.Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents . Br. J. Cancer Suppl. , 27 , S86 – S88 ( 1996. ). [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Dark , G. G. , Hill , S. A. , Prise , V. E. , Tozer , G. M. , Pettit , G. R. and Chaplin , D. J.Combretastatin A‐4, an agent that displays potent and selective toxicity toward tumor vasculature . Cancer Res. , 57 , 1829 – 1834 ( 1997. ). [PubMed] [Google Scholar]
  • 14. ) Hori , K. , Saito , S. , Nihei , Y , Suzuki , M. and Sato , Y.Antitumor effects due to irreversible stoppage of tumor tissue blood flow: evaluation of a novel combretastatin A‐4 derivative, AC7700 . Jpn. J. Cancer Res. , 90 , 1026 – 1038 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Nihei , Y. , Suzuki , M. , Okano , A. , Tsuji , T. , Akiyama , Y. , Tsuruo , T. , Saito , S. , Hori , K. and Sato , Y.Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumor therapy . Jpn. J. Cancer Res. , 90 , 1387 – 1395 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Geran , R. I. , Greenberg , N. H. , Macdonald , M. M. , Schumacher , A. M. and Abott , B. J.Protocols for screening chemical agents and natural products against animal tumor and other biochemical systems (3rd ed.) . Cancer Chemother. Rep. [3] , 3 , 1 – 103 ( 1972. ). [Google Scholar]
  • 17. ) Matsumura , Y. and Maeda , H.A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs . Cancer Res. , 46 , 6387 – 6392 ( 1986. ). [PubMed] [Google Scholar]
  • 18. ) Crosby , W. H. , Munn , J. I. and Furth , F. W.Standardizing a method for clinical hemoglobinometry . US Armed Forces Med. J. , 5 , 693 – 703 ( 1954. ). [PubMed] [Google Scholar]
  • 19. ) Compton , M. M. and Cidlowsky , J. A.Rapid in vivo effects of glucocorticoids on the integrity of rat lymphocyte genomic deoxyribonucleic acid . Endocrinology , 118 , 38 – 45 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Senger , D. R. , Van de Water , L. , Brown , L. F. , Nagy , J. A. , Yeo , T. K. , Berse , B. , Jackman , R. W. , Dvorak , A. M. and Dvorak , H. F.Vascular permeability factor (VPF, VEGF) in tumor biology . Cancer Metastasis Rev. , 12 , 303 – 324 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Dvorak , H. F. , Brown , L. F. , Detmar , M. and Dvorak , A. M.Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis . Am. J. Pathol. , 146 , 1029 – 1039 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Blood , C. H. and Zetter , B. R.Tumor interactions with the vasculature: angiogenesis and tumor metastasis . Biochim. Biophys. Acta , 1032 , 89 – 118 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Dvorak , H. F. , Nagy , J. A. and Dvorak , A. M.Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies . Cancer Cells , 3 , 77 – 85 ( 1991. ). [PubMed] [Google Scholar]
  • 24. ) Molema , G. , de Leij , L. F. and Meijer , D. K.Tumor vascular endothelium: barrier or target in tumor directed drug delivery and immunotherapy . Pharm. Res. , 14 , 2 – 10 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Gores , G. J. , Herman , B. and Lemasters , J. J.Plasma membrane bleb formation and rupture: common feature of hepatocellular injury . Hepatology , 11 , 690 – 698 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Becker , L. C. and Ambrosio , G.Myocardial consequences of reperfusion . Prog. Cardiovasc. Dis. , 30 , 23 – 44 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Johnson , K. J. , Wilson , B. S. , Till , G. O. and Ward , P. A.Acute lung injury in rat caused by immunogloblin A immune complexes . J. Clin. Invest. , 74 , 358 – 369 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Folkman , J.Tumor angiogenesis: therapeutic implications . N. Engl. J. Med. , 285 , 1182 – 1186 ( 1971. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Folkman , J.The role of angiogenesis in tumor growth . Semin. Cancer Biol. , 3 , 65 – 71 ( 1992. ). [PubMed] [Google Scholar]
  • 30. ) Folkman , J. and Ingber , D.Inhibition of angiogenesis . Semin. Cancer Biol. , 3 , 89 – 96 ( 1992. ). [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES