Investigational New Drugs

, Volume 27, Issue 2, pp 159–165 | Cite as

A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer

  • Elaina M. GartnerEmail author
  • Kent A. Griffith
  • Quintin Pan
  • George J. Brewer
  • Gwen F. Henja
  • Sofia D. Merajver
  • Mark M. Zalupski
Phase II Studies


Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8–46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7–7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.


Colorectal cancer Anti-angiogenesis Tetrathiomolybdate Copper chelation Vascular endothelial growth factor 



Dr. Sofia Merajver received partial funding for this research from grants CA77612, the Burroughs Wellcome Fund, the Breast Cancer Research Foundation, and Tempting Tables. The conduction of the clinical trial was supported by a National Cancer Institute General Cancer Research Center Grant to the University of Michigan Cancer Center.


  1. 1.
    Brewer GJ, Hedera P, Kluin KJ, Carlson MD, Askari F, Dick RB et al (2003) Treatment of Wilson’s disease with tetrathiomolybdate III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 60:378–385, doi: 10.1001/archneur.60.3.379 Google Scholar
  2. 2.
    Brewer GJ, Askari F, Lorincz MT, Carlson MD, Schilsky M, Kluin KJ et al (2006) Treatment of Wilson’s disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double blind study of treatment of the neurologic presentation of Wilson’s disease. Arch Neurol 63:521–527, doi: 10.1001/archneur.63.4.521 PubMedCrossRefGoogle Scholar
  3. 3.
    Cox C, Teknos TN, Barrios M, Brewer GJ, Dick RD, Merajver SD (2002) The role of copper suppression as an antiangiogenic strategy in head and neck squamous cell carcinoma. Laryngoscope 111:696–701, doi: 10.1097/00005537–200104000–00024 CrossRefGoogle Scholar
  4. 4.
    Goodman VL, Brewer GJ, Merajver SD (2004) Copper deficiency as an anti-cancer strategy. Endocr Relat Cancer 11:255–263, doi: 10.1677/erc.0.0110255 PubMedCrossRefGoogle Scholar
  5. 5.
    Pan Q, Bao LW, Kleer CG, Brewer GJ, Merajver SD (2003) Antiangiogenic tetrathiomolybdate enhances the efficacy of doxorubicin against breast carcinoma. Mol Cancer Ther 2:617–622PubMedGoogle Scholar
  6. 6.
    Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C et al (2002) Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 62:4854–4859PubMedGoogle Scholar
  7. 7.
    Redman BG, Esper P, Pan Q, Dunn RL, Hussain HK, Chenevert T et al (2003) Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clin Cancer Res 9:1666–1672PubMedGoogle Scholar
  8. 8.
    Pan Q, Bao LW, Merajver SD (2003) Tetrathiomolybdate inhibits angiogenesis and metastasis through suppression of the NFκB signaling cascade. Mol Cancer Res 1:701–706PubMedGoogle Scholar
  9. 9.
    Ellis LM, Takahashi Y, Liu W, Shaheen RM (2000) Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 5(suppl 1):11–15, doi: 10.1634/theoncologist.5-suppl_1–11 PubMedCrossRefGoogle Scholar
  10. 10.
    Broll R, Erdmann H, Duchrow M, Oevermann E, Schwandner O, Markert U et al (2001) Vascular endothelial growth factor (VEGF)—a valuable serum tumour marker in patients with colorectal cancer? Eur J Surg Oncol 27:37–42, doi: 10.1053/ejso.2000.1052 PubMedCrossRefGoogle Scholar
  11. 11.
    Poon RT, Fan ST, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225PubMedGoogle Scholar
  12. 12.
    George ML, Dzik-Jurasz A, Padhani AR, Brown G, Tait DM, Eccles SA et al (2001) Non-invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer. Br J Surg 88:1628–1636, doi: 10.1046/j.0007–1323.2001.01947.x PubMedCrossRefGoogle Scholar
  13. 13.
    Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PAE, Robinson BA et al (2003) The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma–carcinoma sequence during colorectal cancer progression. J Pathol 200:183–194, doi: 10.1002/path.1339 PubMedCrossRefGoogle Scholar
  14. 14.
    Saclarides TJ, Speziale NJ, Drab E, Szeluga DJ, Rubin DB (1994) Tumor angiogenesis and rectal carcinoma. Dis Colon Rectum 37:921–926, doi: 10.1007/BF02052599 PubMedCrossRefGoogle Scholar
  15. 15.
    Tanigawa N, Amaya H, Matsumura M, Lu C, Kitaoka A, Matsuyama K et al (1997) Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res 57:1043–1046PubMedGoogle Scholar
  16. 16.
    Rajaganeshan R, Prasad R, Guillou PJ, Chalmers CR, Scott N, Sarkar R et al (2007) The influence of invasive growth pattern and microvessel density on prognosis in colorectal cancer and colorectal liver metastases. Br J Cancer 96:1112–1117, doi: 10.1038/sj.bjc.6603677 PubMedCrossRefGoogle Scholar
  17. 17.
    Brewer GJ, Dick RD, Grover DK, LeClaire B, Tseng M, Wicha M et al (2000) Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clin Cancer Res 6:1–10PubMedGoogle Scholar
  18. 18.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342, doi: 10.1056/NEJMoa032691 PubMedCrossRefGoogle Scholar
  19. 19.
    Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352:476–487, doi: 10.1056/NEJMra040958 PubMedCrossRefGoogle Scholar
  20. 20.
    Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914, doi: 10.1056/NEJM200009283431302 PubMedCrossRefGoogle Scholar
  21. 21.
    Lissoni P, Rovelli F, Malugani F, Brivio F, Fumagalli L, Gardani GS (2003) Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer. Int J Biol Markers 18:152–155PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Elaina M. Gartner
    • 1
    Email author
  • Kent A. Griffith
    • 2
  • Quintin Pan
    • 2
  • George J. Brewer
    • 2
  • Gwen F. Henja
    • 2
  • Sofia D. Merajver
    • 2
  • Mark M. Zalupski
    • 2
  1. 1.Wayne State UniversityDetroitUSA
  2. 2.The University of MichiganAnn ArborUSA

Personalised recommendations