Gefitinib hydrochloride

The EGFR is a Mr 170,000 transmembrane glycoprotein with an external binding domain and an intracellular tyrosine kinase domain. Gefitinib (ZD-1839, Iressa) is an Epidermal Growth Factor Receptor-selective Tyrosine Kinase Inhibitor.

In vitro: Gefitinib inhibited colony formation in soft agar in a dose dependent manner in all cancer cell lines. However, treatment with higher doses resulted in a 2–4-fold increases in apoptosis. Dose-dependent supra-additive increase in growth inhibition was observed when cancer cells were treated with totoxic drugs and Gefitinib. The combined treatment markedly enhanced apoptotic cell death induced by single agent treatment [1].

In vivo: Gefitinib treatment of nude mice bearing established human GEO colon cancer xenografts revealed a reversible dose-dependent inhibition of tumor growth because GEO tumors resumed the growth rate of controls at the end of the treatment [1].

Clinical trial: Administration of a 250-mg dose of gefitinib as a dispersion preparation by drink or nasogastric tube achieved a systemic exposure to gefitinib that was consistent with that achieved when gefitinib was administered as a whole tablet. No evidence of tolerability problems associated with the routes of administration studied was observed in these healthy volunteers [2].

References:
[1] Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S, Bianco AR, Tortora G.  Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000;6(5):2053-63.
[2] Cantarini MV, McFarquhar T, Smith RP, Bailey C, Marshall AL.  Relative bioavailability and safety profile of gefitinib administered as a tablet or as a dispersion preparation via drink or nasogastric tube: results of a randomized, open-label, three-period crossover study in healthy volunteers. Clin Ther. 2004;26(10):1630-6.

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non-small-cell lung cancer.[Pubmed:28714370]

Tumour Biol. 2017 Jul;39(7):1010428317709639.

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small-cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor-resistant non-small-cell lung cancer.

Cytochrome P450 3A selectively affects the pharmacokinetic interaction between erlotinib and docetaxel in rats.[Pubmed:28716728]

Biochem Pharmacol. 2017 Nov 1;143:129-139.

Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes. In whole animal studies, erlotinib and docetaxel were given to WT and KO rats individually or jointly, and the pharmacokinetic profiles of these two drugs were analyzed and compared among different groups. The results showed that docetaxel not only inhibited the CYP3A-mediated biotransformation of erlotinib in vitro, but also significantly increased the maximum concentration and systemic exposure of erlotinib in vivo in WT rats. In contrast, the DDI was significantly attenuated in KO rats. On the other hand, erlotinib did not influence docetaxel either in vitro biotransformation or in vivo pharmacokinetic behaviors. These results exhibited the potentials of erlotinib-docetaxel interaction and indicated that the CYP3A played the perpetrating role of docetaxel on erlotinib in rats. A better understanding of this DDI with CYP3A may help the regulation of the use of these two drugs, avoid potential problems, and adjust dose carefully and early in clinic.

Effects of an Alkaline Diet on EGFR-TKI Therapy in EGFR Mutation-positive NSCLC.[Pubmed:28870946]

Anticancer Res. 2017 Sep;37(9):5141-5145.

BACKGROUND: The acidic tumor microenvironment is associated with progression of cancers. The purpose of this study was to investigate the association between an alkaline diet and the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eleven advanced or recurrent NSCLC patients with EGFR mutations treated with EGFR-TKI after being instructed to follow an alkaline diet were retrospectively evaluated. RESULTS: The median progression-free survival (PFS) and overall survival (OS) were 19.5 (range=3.1-33.8) and 28.5 (range=15.4-46.6) months. The average dosage of EGFR-TKI was 56+/-22% of the standard dosage. Urine pH was significantly increased after the alkaline diet (6.00+/-0.38 vs. 6.95+/-0.55; p<0.05). CONCLUSION: An alkaline diet may enhance the effect of EGFR-TKI treatment in NSCLC patients with EGFR mutations.

Impact of Small Molecules on beta-Catenin and E-Cadherin Expression in HPV16-positive and -negative Squamous Cell Carcinomas.[Pubmed:28551620]

Anticancer Res. 2017 Jun;37(6):2845-2852.

BACKGROUND: The validation of potential molecular targets in head and neck squamous cell carcinoma (SCC) is mandatory. beta-Catenin and E-cadherin are crucial for cancer progression through epithelial-mesenchymal transition. We analyzed the effect of the tyrosine kinase inhibitors nilotinib, dasatinib, erlotinib and gefitinib on beta-catenin and E-cadherin expression in SCC with respect to human papillomavirus (HPV) status. MATERIALS AND METHODS: Expression of beta-catenin and E-cadherin in cell lines UMSCC 11A, UMSCC 14C and CERV196 under the influence of tyrosine kinase inhibitors were analyzed by enzyme-linked immunosorbent assay. RESULTS: All agents reduced beta-catenin and E-cadherin expression of HPV16-negative cells. Increased E-cadherin expression was observed after treatment with gefitinib and dasatinib in HPV16-positive cells. CONCLUSION: All substances, nilotinib, dasatinib, erlotinib and gefitinib have a significant impact on beta-catenin and E-cadherin expression in both HPV16-positive and HPV16-negative cells in vitro. Alterations of beta-catenin and E-cadherin could provide novel insights for future targeted therapies of head and neck SCC.

Treatment in EGFR-mutated non-small cell lung cancer: how to block the receptor and overcome resistance mechanisms.[Pubmed:28708233]

Tumori. 2017 Jul 31;103(4):325-337.

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

Gefitinib hydrochloride (ZD1839 hydrochloride) is a potent, selective and orally active EGFR tyrosine kinase inhibitor with an IC50 of 33 nM. Gefitinib hydrochloride selectively inhibits EGF-stimulated tumor cell growth (IC50 of 54 nM) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. Gefitinib hydrochloride also induces autophagy. Gefitinib hydrochloride has antitumour activity.

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