International Journal of Radiation Oncology*Biology*Physics
EGFR INHIBITORSRationale and clinical basis for combining gefitinib (IRESSA, ZD1839) with radiation therapy for solid tumors☆
Introduction
Radiation therapy plays a major role in the treatment of most common solid tumors. However, response to radiation therapy varies by individual tumor, and local control is often limited by tumor radiation resistance and the rapid proliferation of cells after radiation, resulting in tumor repopulation 1, 2. Research has led to considerable advances in understanding the molecular and cellular mechanisms underlying the resistance of solid tumors to ionizing radiation. Novel therapies have been designed to specifically inhibit the key molecules in these processes, including the epidermal growth factor receptor–tyrosine kinase (EGFR-TK) 1, 2. It is hoped that these new agents will enhance tumor sensitivity to radiation therapy and will lead to better therapeutic outcomes for patients with solid tumors.
The EGFR-TK is a particularly attractive drug target for treatment of solid tumors 1, 3. The expression of epidermal growth factor receptor (EGFR) has been linked to more aggressive tumor behavior and a worse clinical prognosis (3), and the tyrosine kinase (TK) enzyme activity of the EGFR protein is increased in many solid tumors. Signal transduction pathways turned on by EGFR-TK contribute to tumor processes such as cellular proliferation, decreased apoptosis, angiogenesis, and invasion and metastasis (3). Abnormal activity of the EGFR-TK may allow tumor cells to escape the lethality of radiation treatment and contribute to radiation resistance. Agents that inhibit EGFR-TK signaling may block this mechanism and enhance the tumor cell killing effectiveness of radiation therapy or serve as radiation sensitizers (4). Gefitinib (IRESSA, ZD1839; AstraZeneca Pharmaceuticals, LP, Wilmington, DE) is an inhibitor of EGFR-TK activity with proven antitumor efficacy as monotherapy for advanced non–small-cell lung cancer (NSCLC). Evidence will be reviewed indicating that gefitinib may act as a radiation sensitizer in a variety of solid tumors and thereby enhance the antitumor efficacy of radiation therapy.
Section snippets
EGFR-TK in solid tumors
The EGFR/ErbB1 is a member of the ErbB family of receptor TKs (5). The binding of extracellular ligands such as epidermal growth factor or transforming growth factor-α (TGF-α) causes EGFR to associate with another EGFR molecule or ErbB family member. This dimerization leads to a conformational change that activates the TK domain on the intracellular portion of the receptor, resulting in autophosphorylation of specific tyrosine residues. These phosphorylated tyrosines then bind with and activate
Advanced solid tumors
The safety and tolerability of gefitinib were investigated in several Phase I trials involving patients with tumors that are known to frequently overexpress EGFR, including NSCLC, head and neck, breast, and colorectal, among others 33, 34, 35. Almost all patients had received prior treatment with radiation therapy and/or chemotherapy. In these trials, gefitinib was found to be generally well tolerated. The most common adverse events were diarrhea, acneiform rash, nausea, asthenia, and vomiting,
Conclusions
The effectiveness of radiation therapy is limited by tumor resistance, both inherent and that induced by radiation therapy. Considerable evidence exists to suggest that EGFR plays a key role in tumor resistance to ionizing radiation itself. Agents that inhibit EGFR have been shown to counteract this resistance, thereby increasing the antitumor activity of radiation therapy.
One such agent is gefitinib (IRESSA, ZD1839), a selective EGFR-TKI. Gefitinib has been shown to inhibit tumor growth in a
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Synthesis and evaluation of tryptanthrins as antitumor agents
2021, TetrahedronInduction of apoptosis, cytotoxicity and radiosensitization by novel 3,4-dihydroquinazolinone derivatives
2021, Bioorganic and Medicinal Chemistry LettersLung cancer epidermal growth factor receptor mutations and radiotherapy response: A multicentre clinical study
2021, Clinical and Translational Radiation OncologyCitation Excerpt :In this study distant recurrence and relapse free survival were no different. The better clinical response to radiotherapy in EGFR+ patients observed in these studies are discrepant with laboratory studies reporting that EGFR over-expression confers radioresistance [3–7]. One explanation for the more favorable finding in clinical studies could be from the concurrent use of systemic therapy and its radiosensitizing and anti-tumor effects, which may be enhanced in EGFR mutants [4,16].
Development of a novel acetyl glucose-modified gefitinib derivative to enhance the radiosensitizing effect
2021, Bioorganic and Medicinal ChemistryCitation Excerpt :Gefitinib suppresses the proliferation of cancer cells by inhibiting autophosphorylation of the epidermal growth factor receptor (EGFR) and is currently known as an anticancer drug for non-small cell lung cancer. Recently, it has been reported that gefitinib has a radiosensitizing effect, and it could serve as a radiosensitizer.14–16 Therefore, in this study, we aimed to develop a radiosensitizer that has a higher radiosensitizing activity while maintaining the EGFR autophosphorylation inhibitory activity by conjugating acetyl glucose to gefitinib.
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Dr. Ochs has received financial or material support from AstraZeneca Pharmaceuticals LP.