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Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy

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Abstract

We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of 131I-A7, an IgG1 anti-colorectal monoclonal antibody, or 131I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation (n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice (n=8) (P<0.05). 131I-A7 RIT displayed a marked therapeutic effect (n=8) (P<0.001); however, all animals eventually died due to metastases by 99 days. The combined regimen of 131I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy (n=10) (P<0.05); three mice survived the entire 160-day observation period. The combination of antiangiogenic therapy and 131I-HPMS-1 RIT failed to provide an appreciable benefit (n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases.

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References

  1. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med 1995; 1:27–31.

    CAS  PubMed  Google Scholar 

  2. Kuwano M, Uchiumi T, Hayakawa H, et al. The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignancies. Cancer Sci 2003; 94:9–14.

    CAS  PubMed  Google Scholar 

  3. Yano S, Nishioka Y, Goto H, Sone S. Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules. Cancer Sci 2003; 94:479–485.

    CAS  PubMed  Google Scholar 

  4. Hall EJ. Radiobiology for the radiologist, 5th edn. Philadelphia: Lippincott Williams & Wilkins, 2000.

  5. Sharkey RM, Weadock KS, Natale A, et al. Successful radioimmunotherapy for lung metastasis of human colonic cancer in nude mice. J Natl Cancer Inst 1991; 83:627–632.

    CAS  PubMed  Google Scholar 

  6. Blumenthal RD, Sharkey RM, Haywood L, et al. Targeted therapy of athymic mice bearing GW-39 human colonic cancer micrometastases with131I-labeled monoclonal antibodies. Cancer Res 1992; 52:6036–6044.

    CAS  PubMed  Google Scholar 

  7. Dunn RM, Juweid M, Sharkey RM, Behr TM, Goldenberg DM. Can occult metastases be treated by radioimmunotherapy? Cancer (Suppl) 1997; 80:2656–2659.

    Google Scholar 

  8. Vogel C-A, Galmiche MC, Buchegger F. Radioimmunotherapy and fractionated radiotherapy of human colon cancer liver metastases in nude mice. Cancer Res 1997; 57:447–453.

    CAS  PubMed  Google Scholar 

  9. Behr TM, Blumenthal RD, Memtsoudis S, et al. Cure of metastatic human colonic cancer in mice with radiolabeled monoclonal antibody fragments. Clin Cancer Res 2000; 6:4900–4907.

    CAS  PubMed  Google Scholar 

  10. Saga T, Sakahara H, Nakamoto Y, et al. Radioimmunotherapy for liver micrometastases in mice: pharmacokinetics, dose estimation, and long-term effect. Jpn J Cancer Res 1999; 90:342–348.

    CAS  PubMed  Google Scholar 

  11. Sato N, Saga T, Sakahara H, et al. Intratumoral distribution of radiolabeled antibody and radioimmunotherapy in experimental liver metastases model of nude mouse. J Nucl Med 1999; 40:685–692.

    Google Scholar 

  12. Kinuya S, Yokoyama K, Kawashima A, et al. Radioimmunotherapy with186Re-labeled monoclonal antibody to treat liver metastases of colon cancer cells in nude mice. Cancer Biother Radiopharm 2002; 17:681–687.

    Article  CAS  PubMed  Google Scholar 

  13. Kinuya S, Li X-F, Yokoyama K, et al. Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy. Cancer Sci 2003; 94:650–654.

    PubMed  Google Scholar 

  14. Imam SK. Status of radioimmunotherapy in the new millennium. Cancer Biother Radiopharm 2001; 16:237–256.

    CAS  PubMed  Google Scholar 

  15. Kinuya S, Kawashima A, Yokoyama K, et al. Anti-angiogenic therapy and radioimmunotherapy in colon cancer xenografts. Eur J Nucl Med 2001; 28:1306–1312.

    Google Scholar 

  16. Kinuya S, Kawashima A, Yokoyama K, et al. Cooperative effect of radioimmunotherapy and anti-angiogenic therapy with thalidomide in human cancer xenografts. J Nucl Med 2002; 43:1084–1089.

    Google Scholar 

  17. Li X-F, Kinuya S, Yokoyama K, et al. Benefits of combined radioimmunotherapy and anti-angiogenic therapy in a liver metastasis model of human colon cancer cells. Eur J Nucl Med Mol Imaging 2002; 29:1669–1674.

    Article  CAS  PubMed  Google Scholar 

  18. Klauber N, Parangi S, Flynn E, Hamel E, D’Amato RJ. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 1997; 57:81–86.

    CAS  Google Scholar 

  19. Tsukamoto A, Kaneko Y, Yoshida T, Han K, Ichinose M, Kimura S. 2-Methoxyestradiol, an endogenous metabolite of estrogen, enhances apoptosis and beta-galactosidase expression in vascular endothelial cells. Biochem Biophys Res Commun 1998; 248:9–12.

    CAS  PubMed  Google Scholar 

  20. Reiser F, Way D, Bernas M, Witte M, Witte C. Inhibition of normal and experimental angiotumor endothelial cell proliferation and cell cycle progression by 2-methoxyestradiol. Proc Soc Exp Biol Med 1998; 219:211–216.

    Google Scholar 

  21. D’Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci USA 1994; 91:3964–3968.

    CAS  PubMed  Google Scholar 

  22. Hamel E, Lin CM, Fglynn E, D’amato RJ. Interaction of 2-methoxyestradiol, an endogenous mammalian metabolite, with unpolymerized tubulin and with tubulin polymers. Biochemistry 1996; 35:1304–1310.

    Google Scholar 

  23. Mukhopadhyay T, Roth JA. Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis. Oncogene 1998; 17:241–246.

    CAS  PubMed  Google Scholar 

  24. Asano M, Yukita A, Suzuki H. Wide spectrum of antitumor activity of a neutralizing monoclonal antibody to human vascular endothelial growth factor. Jpn J Cancer Res 1999; 90:93–100.

    CAS  PubMed  Google Scholar 

  25. Kotanagi H, Takahashi T, Masuko T, Hashimoto Y, Koyama K. A monoclonal antibody against human colon cancers. Tohoku J Exp Med 1986; 148:353–360.

    CAS  PubMed  Google Scholar 

  26. Hirano K, Iiizumi Y, Hayashi Y, et al. A highly sensitive assay method for human placental alkaline phosphatase involving a monoclonal antibody bound to a paper disk. Anal Biochem 1986; 154:624–631.

    CAS  PubMed  Google Scholar 

  27. Lakhani NJ, Sarkar MA, Venitz J, Figg WD. 2-Methoxyestradiol, a promising anticancer agent. Pharmacotherapy 2003; 23:165–172.

    CAS  PubMed  Google Scholar 

  28. Schlom J, Molinolo A, Simpson JF, et al. Advantage of dose fractionation in monoclonal antibody-targeted radioimmunotherapy. J Natl Cancer Inst 1990; 82:763–771.

    CAS  PubMed  Google Scholar 

  29. Buchsbaum D, Khazaeli MB, Liu T, et al. Fractionated radioimmunotherapy of human colon carcinoma xenografts with131I-labeled monoclonal antibody CC49. Cancer Res 1995; 55:5881s–5887s.

    CAS  PubMed  Google Scholar 

  30. Peterson JA, Blank EW, Ceriani RL. Effect of multiple, repeated doses of radioimmunotherapy on target antigen expression (breast MUC-1 mucin) in breast carcinomas. Cancer Res 1997; 57:1103–1108.

    CAS  PubMed  Google Scholar 

  31. Roberson PL, Dudek S, Buchsbaum DJ. Dosimetric comparison of bolus and continuous injections of CC49 monoclonal antibody in a colon cancer xenograft model. Cancer 1997; 80:2567–2575.

    Article  CAS  PubMed  Google Scholar 

  32. Borchardt PE, Quadri SM, Freedman RS, Vriesendorp HM. Intraperitoneal radioimmunotherapy with human monoclonal IGM in nude mice with peritoneal carcinomatosis. Cancer Biother Radiopharm 2000; 15:53–64.

    CAS  PubMed  Google Scholar 

  33. Goel A, Augustine S, Baranowska-Kortylewicz J, et al. Single-dose versus fractionated radioimmunotherapy of human colon carcinoma xenografts using131I-labeled multivalent CC49 single-chain fvs. Clin Cancer Res 2001; 7:175–184.

    CAS  PubMed  Google Scholar 

  34. DeNardo GL, Schlom J, Buchsbaum DJ, et al. Rationales, evidence, and design considerations for fractionated radioimmunotherapy. Cancer 2002; 94:1332–1348.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank former Professor Toshio Takahashi and Dr. Toshiharu Yamaguchi, First Department of Surgery, Kyoto Prefectural University of Medicine, for providing A7 MAb. This study was supported in part by grants-in-aid from the Ministry of Education, Science, Sports, and Culture, Japan.

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Authors and Affiliations

  1. Department of Biotracer Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan

    Seigo Kinuya, Kunihiko Yokoyama, Jingming Bai, Takatoshi Michigishi & Norihisa Tonami

  2. Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan

    Kiyoshi Koshida

  3. Radioisotope Center, Kanazawa University, Kanazawa, Ishikawa, Japan

    Hirofumi Mori & Kazuhiro Shiba

  4. Department of Radiology, Toyama Medical and Pharmaceutical University, Toyama, Japan

    Naoto Watanabe

  5. Department of Radiology, Asahikawa Medical College, Asahikawa, Hokkaido, Japan

    Noriyuki Shuke

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  1. Seigo Kinuya
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  2. Kunihiko Yokoyama
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  4. Hirofumi Mori
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Correspondence to Seigo Kinuya.

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Kinuya, S., Yokoyama, K., Koshida, K. et al. Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy. Eur J Nucl Med Mol Imaging 31, 981–985 (2004). https://doi.org/10.1007/s00259-004-1497-x

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  • DOI: https://doi.org/10.1007/s00259-004-1497-x

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