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
This is a preview of subscription content, log in to check access.
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.
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.60.3.379Google Scholar
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.63.4.521PubMedCrossRefGoogle Scholar
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
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
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
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
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.2000.1052PubMedCrossRefGoogle Scholar
Poon RT, Fan ST, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225PubMedGoogle Scholar
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.1339PubMedCrossRefGoogle Scholar
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
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.6603677PubMedCrossRefGoogle Scholar
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
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/NEJMoa032691PubMedCrossRefGoogle Scholar