Cetuximab: From Biology To the Care of Colorectal Cancer Patients

Abstract

Cetuximab (IMC-C225, Erbitux ImClone Systems Inc., NY, USA) is a chimeric human:murine derivative IgG1 monoclonal antibody (mAb) that binds the extracellular domain of the EGF receptor (EGFR) [1–3]. Cetuximab has been approved by the US FDA, in combination with irinotecan, for use in the treatment of metastatic colorectal cancer, for locally/regionally advanced squamous cell carcinoma of the head and neck (SCCHN) in combination with radiation, and as a monotherapy for recurrent/metastatic SCCHN after failing platinum-based chemotherapy. The mechanisms through which cetuximab is thought to express its antitumor activity are numerous and not completely understood, as yet. They include the direct inhibition of EGFR tyrosine kinase activity [4], the inhibition of cell-cycle progression [5,6], angiogenesis, invasion and metastasization [3], the increase and activation of proapoptotic molecules [7,8], and synergic cytotoxicity with chemotherapy and radiotherapy [9]. Another mode of action is antibody-dependent cellular cytotoxicity. Cetuximab mediates cell-cycle arrest in various tumor cell lines, leading, in some cases, to apoptosis. Wu X et al. investigated the relationship between growth factor availability and the activation of the CDK kinases [10]. They demonstrated that blockage of EGFR mediated by cetuximab induces G1-phase cell-cycle arrest in DiFi human colon adenocarcinoma cells. Moreover, in an in vitro assay, immunodepletion of p27KIP1 removes the inhibitory activity of the lysates of mAb-treated cells, so that immunodepleted and heated lysates lose their capacity to inhibit cyclin E/CDK2 activity. The results suggest that G1 arrest in the cell cycle induced by EGFR blockade involves p27KIP1. Petit et al. were the first to describe the antiangiogenic effects of cetuximab [11]. They demonstrated that tumor xenografts of the human A431 squamouscell carcinoma exposed to mAb C225 resulted in a reduction in the release of angiogenic factors by tumor cells themselves. These results were confirmed by numerous studies on other tumor cell lines. Perrote et al. exposed in vitro human transitional cell carcinoma (TCC) of the bladder cell line 253J B-V to mAb C225 [12]. The effect observed was the inhibition of mRNA and protein production of VEGF, IL-8 and β-FGF by the cells. In vivo, mAb C225 therapy of nude mice with established TCCs growing orthotopically resulted in the downregulation of these angiogenic factors and, consequently, in the involution of blood vessels. Another study examined the impact of C225 exposition in human SCCHN using in vitro and in vivo model systems [13]. Regarding angiogenesis, in vitro treatment with C225 reduced cell-to-cell interaction of human umbilical vascular endothelial cells, resulting in disruption of tube formation. Using an in vivo tumor xenograft neovascularization model of angiogenesis, systemic treatment with C225 not only reduced tumor growth and the number of blood capillaries, but also inhibited the growth of established vessels toward the tumor. Taken together, these results provide evidence that C225 can suppress tumor-induced neovascularization in these tumor cell lines.