Disease relevance of Iressa

• Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib [1].
• Clinical efficacy and toxiciy of gefitinib in patients with lung cancer [2].
• Severe acute interstitial pneumonia and gefitinib [3].
• Gefitinib induces myeloid differentiation of acute myeloid leukemia [4].
• This phase II study sought to explore the activity, toxicity, and pharmacodynamics of ZD1839 in SCCHN [5].
• Fifty-eight patients with pretreated advanced non-small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses) [6].
• Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients [7].
• Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non-small cell lung cancer patients with EGFR mutations [8].

Psychiatry related information on Iressa

• CONCLUSIONS: Individual differences in CYP3A expression do not explain all the interindividual variability in gefitinib exposure [9].
• NCI-CTC grade 1/2 drug-related adverse events were observed in seven volunteers, including loose stools and skin events associated with gefitinib, and lethargy and headache, flushing, and dizziness associated with tamoxifen [10].

High impact information on Iressa

• Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1(-/-) mice [11].
• Carcinogen-induced tumors displayed by Errfi1(-/-) mice were highly sensitive to gefitinib [11].
• We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib [3].
• Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272 [12].
• Therapies that target the EGF receptor (EGFR), such as gefitinib (IRESSA), are effective in a subset of patients with advanced non-small cell lung cancer (NSCLC) [13].

Chemical compound and disease context of Iressa

• The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC) [12].
• Inhibition of ErbB2 by either the HSP (heat shock protein) 90 inhibitor geldanamycin or the ErbB inhibitor ZD1839 in SKBR3 cells, a human breast cancer cell line overexpressing ErbB2 protein, induces a rapid and dramatic decrease in AKT activity [14].
• Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF [15].
• The threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene has been reported in progressing lesions after gefitinib treatment in non-small cell lung cancer (NSCLC) that causes sensitive tumors to become resistant to gefitinib [16].
• The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer [17].

Biological context of Iressa

• Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor [18].
• Down-regulation of ErbB-3 by means of short hairpin RNA leads to decreased phospho-Akt levels in the gefitinib-sensitive NSCLC cell lines, Calu-3 (WT EGFR) and H3255 (L858R EGFR), but has no effect on Akt activation in the gefitinib-resistant cell lines, A549 and H522 [13].
• We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples [19].
• Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib [19].
• Concomitantly, ZD1839 increased the expression of p27(KIP1) (P <.001) and maturation markers (P <.001) and increased apoptosis (P <.001) [20].

Anatomical context of Iressa

• In this study, we observe that gefitinib reduces phospho-Akt levels only in NSCLC cell lines in which it inhibits growth [13].
• To examine antiangiogenic effects, we studied the impact of ZD1839 on human umbilical vascular endothelial cells (HUVECs) [21].
• In vitro studies also demonstrated that the addition of ZD1839 at a concentration of < or =1 microM suppressed the proliferation of type II-like epithelial cells (A549) but not that of lung fibroblasts (IMR90) [22].
• In addition, ZD1839 inhibited MAPK activation (P <.001) and reduced keratinocyte proliferation index (P <.001) [20].
• In a panel of human breast cancer and other epithelial tumor cell lines, HER2-overexpressing tumors were particularly sensitive to ZD1839 [23].

Associations of Iressa with other chemical compounds

• We have developed a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa(2) ) [24].
• Epidermal growth factor receptor kinase inhibitor, gefitinib (ZD1839) inhibited growth of LTLT-Ca cells (IC(50) approximately 10 micromol/L) and restored their sensitivity to tamoxifen and anastrozole [25].
• We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells [26].
• The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of an ATP-binding site (exon 19) in the EGFR was detected (delE746-A750-type deletion) [27].
• We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions [28].
• Gefitinib did interact with recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce high levels of apoptosis in gefitinib-responsive but not gefitinib-unresponsive lines [29].
• Results from all four DNA damage repair analyses in cultured A549 and H1299 cells showed that gefitinib had a strong inhibitory effect on the repair of DSBs after ionizing radiation [30].
• In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients [31].
• The primary endpoint of progression-free survival was longer with gefitinib than docetaxel, and the secondary endpoints showed superior objective response rate, good tolerability, and similar quality of life improvement rates for gefitinib than docetaxel [32].
• In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy [33].
• Simvastatin may improve the efficacy of gefitinib in that subgroup of gefitinib-resistant NSCLC patients [34].

Gene context of Iressa

• Gefitinib dissociates this complex, thereby linking EGFR inhibition to decreased Akt activity [13].
• Although gefitinib inhibited BCRP more potently than MDR1 (10-fold), the inhibition of both transporters occurred at clinically relevant concentrations (e.g., 1-5 micromol/L) [35].
• Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression [36].
• These effects of gefitinib on VEGF promoter activity and DNA binding were both reversed by Akt expression [37].
• Gefitinib inhibited Akt phosphorylation in all three cell lines, but it was about five times less effective in AD3 cells [38].
• The balance of expression levels between gefitinib-sensitive or gefitinib-resistant EGFR may govern the response to gefitinib in lung cancer [39].
• EGFR exon 20 mutations of NSCLC patients result in poorer responsiveness to gefitinib treatment, but variability exists between different individuals [40].
• Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR [41].
• Gefitinib abolished the prognostic discriminative power of high IGF1R expression; patients with elevated IGF1R expression benefited from gefitinib whereas those with low IGF1R fared worse [42].

Analytical, diagnostic and therapeutic context of Iressa

• These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted [4].
• To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy [43].
• The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers [44].
• However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration [45].
• However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method [46].

References