Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (Iressa)
Department of Surgery, Neurosurgery, Duke University Medical Center, Durham, North Carolina 27710, USA. Clinical Cancer Research
(Impact Factor: 8.72).
Iressa (ZD1839) is a p.o.-active, selective, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways implicated in cancer cell proliferation, survival, and host-dependent processes promoting cancer growth. EGFR is up-regulated in primary malignant tumors of the central nervous system (CNS) and in many systemic tumors that metastasize to the CNS. The purpose of our study was to evaluate the efficacy and toxicity of p.o.-administered ZD1839 for the treatment of established intracerebral (i.c.) tumors expressing EGFR or the tumorigenic mutated variant EGFRvIII, which is constitutively phosphorylated. Oral administration of ZD1839 at 50 or 100 mg/kg/day for 3 weeks in athymic mice with established i.c. A431 human epidermoid carcinoma expressing EGFR increased median survival by 88% (P = 0.009) and 105% (P < 0.001), respectively. Additionally, there was no evidence of systemic or CNS toxicity. However, ZD1839 failed to inhibit either s.c. or i.c. in vivo tumor growth when tumorigenicity was conferred by EGFRvIII. Western blotting revealed that treatment with ZD1839 virtually ablated phosphorylation of EGFR Tyr-1173 in A431 tumors. However, treatment of NR6M tumors with ZD1839 only partially decreased phosphorylation of EGFRvIII Tyr-1173 while up-regulating overall expression, suggesting that EGFRvIII may not be susceptible to the same molecular mechanisms of tyrosine kinase inhibition as EGFR. In conclusion, ZD1839 is active in a brain tumor model expressing EGFR, but not EGFRvIII, as EGFR mutations may lead to relative therapeutic resistance. On the basis of these observations, we believe that clinical trials of ZD1839 against brain tumors expressing EGFR are warranted, but that special consideration should be given to tumors that coexpress EGFRvIII.
Available from: ocean.kisti.re.kr
- "be effective and brought the median OS of 9-13.5 months to patients with BM from NSCLC (Heimberger et al., 2002; Ceresoli et al., 2004; Hotta, 2004; Namba et al., 2004; Takahashi et al., 2004; Shimato et al., 2006; Kim et al., 2009). With the concept of the disruption of blood brain barrier (BBB) by BM and radiation therapy, gefitinib with small molecular weight may have the ability to penetrate the BBB (Fidler et al., 2002; Van et al., 2002; Jackman et al., 2006). "
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ABSTRACT: Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities. This retrospective analysis was conducted to compare the efficacy of gefitinib alone with gefitinib plus concomitant WBRT in treatment of BM from NSCLC.
We retrospectively reviewed 90 patients with BM from NSCLC who received gefitinib alone (250 mg/day, gefitinib group) or with concomitant WBRT (40 Gy/20 f/4 w, gefitinib-WBRT group) between September 2005 and September 2009 at Sun Yat-Sen University Cancer Center. Forty-five patients were in each group.
The objective response rate of BM was significantly higher in gefitinib-WBRT group (64.4%) compared with gefitinib group (26.7%, P<0.001). The disease control rate of BM was 71.1% in gefitinib- WBRT group and 42.2% in gefitinib group (P=0.006). The median time to progression of BM was 10.6 months in gefitinib-WBRT group and 6.57 months in gefitinib group (P<0.001). The median overall survival (OS) of gefitinib-WBRT and gefitinib alone group was 23.40 months and 14.83 months, respectively (HR, 0.432, P=0.002).
Gefitinib plus concomitant WBRT had higher response rate of BM and significant improvement in OS compared with gefitinib alone in treatment of BM from NSCLC.
Asian Pacific journal of cancer prevention: APJCP 03/2012; 13(3):909-14. DOI:10.7314/APJCP.2012.13.3.909 · 2.51 Impact Factor
Available from: Suresh V Ambudkar
- "Along these lines, pre-clinical studies and clinical trials are currently ongoing to evaluate the combination of anticancer drugs with EGFR TKIs to improve therapeutic outcome in cancer patients (Milano et al., 2008). It should also be mentioned that several studies have shown that the brain concentrations of TKIs such as imatinib (Breedveld et al., 2005, 2006; Kun-Eek et al., 2007), gefitinib (Heimberger et al., 2002), and lapatinib (Lagas et al., 2009; Polli et al., 2008) were relatively low. This could now be explained by the fact that these are substrates of P-gp and ABCG2, which are present abundantly at the BBB. "
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ABSTRACT: Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells.
Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 02/2012; 15(1-2):70-80. DOI:10.1016/j.drup.2012.01.005 · 9.12 Impact Factor
Available from: Santosh Kesari
- "This result might be the reason why gefitinib is ineffective in treating malignant gliomas, including GBM, because these mutations have not been found in gliomas (Marie Y et al., 2005; Halatsch ME et al., 2006). In addition, preclinical data showed that gefitinib has very low or no activity against tumors that express EGFRvIII (Heimberger AB et al., 2002). Clinical data shows that gefitinib for glioma patients are generally well tolerated with few, minor side effects. "
Cancer Stem Cells - The Cutting Edge, 08/2011; , ISBN: 978-953-307-580-8
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