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Human Epidermal growth factor Receptors are located on the surface of cells, which stimulate cell proliferation by signal communication. HER2 is one type of receptors, overexpressing in 20-30% of breast cancer cells. Trastuzumab is a humanized monoclonal antibody, which has been widely used in the clinic by directly against HER2 (Kute, et al., 2004). Trastuzumab is also called heclon or herceptin in the market. Designed by Genentech Company, it was the first targeted cancer drug and has become one of the biggest sellers to treat breast cancer, which was reported to be worth $1.66 billion in 2011. Herceptin is licensed by the Food and Drug Administration (FDA) to treat patients with HER2-positive metastatic (advanced) breast cancer and early breast cancer. In addition to breast cancer, herceptin also has significant effects on other cancers such as salivary gland carcinomas which over expresses HER2 in tumor cells as well (Haddad, et al., 2003). This article will briefly introduce herceptin in terms of breast cancer treatment.
HER2 was identified as a target for treatment of human breast cancer due to the discovery of inhibitory effects on cell growth by binding antibodies to HER2 extracellular domain. The 4D5 murine monoclonal antibody was detected to inhibit the proliferation of breast cancer cells by directly against HER2 with high risk of generation of a human anti-mouse immune response (Carter, et al., 1992). Light (VL) and heavy chain (VH) V regions gene from the 4D5 murine monoclonal antibodies (mumAb4D5) were cloned by PCR and humanized using gene conversion mutagenesis (Carter, et al., 1992). The identified gene encoding antigen binding loops was further cloned into an expression vector that contains a human k light chain and a consensus human IgG1 (Dokmanovic & Wu, 2011). The antibody was produced by trasducting the vectors into Chinese hamster ovary (CHO) cells and then purified by affinity chromatography and buffer exchanged. The humanized version of mumAb4D5 derived from above expression system was known as Herceptin, which showed a higher efficacy on breast cancer therapy.
The high costs on producing herceptin by this system prompt researchers to explore other methods. Generation of herceptin in plant cells by a Agrobacterium-mediated transient expression system is a good way, which proved to be more effective in inhibition of tumor growth (Komarova, et al., 2011).
Mechanisms of action
Though herceptin has been approved for treatment of HER2 positive breast cancer, the mechanisms by which herceptin induces have not been fully understood. Several hypotheses have been proposed, including reduction of signaling pathways, G1 arrest, induction of apoptosis, induction of immune response and prevention of HER2 cleavage (Nahta & Esteva, 2006) (Fig. 1).
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Fig. 1. Proposed action mechanisms of Herceptin. (Nahta R & Esteva FJ (2006) Herceptin: mechanisms of action and resistance. Cancer letters. [Accessed on 24/02/2013])
Inhibition of HER2 shedding
Overexpression of HER2 results in the proteolytic cleavage in breast cancer cells, releasing the extracellular domain (ECD)in serum and generating a truncated highly active fragment, p95 (Molina, et al., 2001). The high level of HER2 ECD in serum is associated with increased risk of metastasis. The shedding of Her2 can be blocked by herceptin via inhibition of 4-aminophenylmercuric acetate (APMA) activity. A decrease of HER2 extracellular domain in serum in response to trastuzumab treatment was detected, providing supports to this hypothesis of action mechanisms (Molina, et al., 2001) (Fig. 2).
(Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J & Baselga J (2001) Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer research. [Accessed on 24/02/2013])
Induction of Immune response
Preclinical models have demonstrated that Herceptin can activate antibody-dependent cellular cytotoxicity (ADCC) by recruiting immune effector cells such as natural killer cells (NK). The binding of the Fc portion of herceptin to the Fc gamma receptor in NK leads to activation of death of bound tumor cells (Valabrega, et al., 2007). The experiments were conducted to test the effects of herceptin on cytotoxic activity against HER2. The percentage of target cells of Peripheral blood mononuclear cells (PBMC) lysis with herceptin treatment was obviously higher than that without treatment (Gennari, et al., 2004), supporting the immune-mediate response mechanism (Fig. 3). However, patients with metastatic breast cancer may not follow this immune-mediated mechanism due to damage to the immune system.
(Gennari, Gennari R, Menard S, Fagnoni F, et al. (2004) Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clinical Cancer Research. [Accessed on 24/02/2013])
Other proposed mechanisms
Many signaling pathways including the PI3 kinase (PI3K) cascades are initially activated by HER2, leading to transmitting signals of cell proliferation. Herceptin is able to diminish signaling probably through downregulation of HER2 receptor, thus preventing homo and heterodimerization with other HER receptors (Harries & Smith, 2002). These events take place as a result of cell cycle arrest and apoptosis (Nahta & Esteva, 2006). However, the hypothesis has not been confirmed yet due to the observation of unchanged receptor level with herceptin treatment. Recent research on demonstration how herceptin blocks PI3K signaling pathway indicated that herceptin reduces signaling by disrupting the interaction between HER2 and the Src tyrosine kinase. The events trigger the activation of PI3K inhibitor PTEN and inhibition of cell proliferation (Nahta & Esteva, 2006).
It is obvious that Herceptin has become one of the powerful drug for early breast cancer that over expresses HER2 oncogene. Unfortunately, this adjuvant therapy has unexpected but serious side effect, causing a decrease in cardiac function or heart failure to patients. The incidence of cardiac dysfunction depends on levels and phases of exposure to anthracycline (Chien, 2006). It has been reported that the risk of cardiac dysfunction increased from 1% to 7% when patients with trastuzumab monotherapy suffered from more extensive prior anthracycline exposure. The risk of cardiac dysfunction increased to 29% if patients were treated with anthracycline and trastuzumab concurrently (Sparano, 2001). Apart from cardiotoxicity, herceptin administration can result in embryo-fetal toxicity and pulmonary toxicity. In addition, the most common adverse side effects such as infusion-related reactions also occur, which however, were mild and well tolerated. The symptoms including fever and chills were primarily seen during or within 24 hours of first Herceptin infusion only (Baselga, 2001).
Conclusions and further directions
While herceptin has been approved to treat HER2 positive breast cancer, the resistance is a significant challenge for herceptin therapy. It is of importance to understand the mechanism of herceptin resistance as well as the mechanisms of action of herceptin. Combination with chemotherapy has been put forward to increase the chance of survival. On the other hand, predicting the cancer status of each patient offers the possibility for more accurate drug administration and a higher rate of survival.