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ERLOTINIB– INHIBITOR OF EGFR

by Selleckchem | Sep 03 2012

CHARACTERISTICS OF ERLOTINIB
Erlotinib is one of the tyrosine kinase inhibitors which is also referred OSI-420 EGFR inhibitor which is typically named as HCl salt. Epidermal growth factor tyrosine kinase receptor is sometimes seen abnormal in numerous kinds of cancers so that they are being utilized for the anti-cancer therapy. Plenty of new medicines are being created by using a similar approach [1]. Erlotinib structure revealed that it contained 2 quinazoline rings in its structures and it showed to inhibit the EGFR auto phosphorylation which eventually stops the pathway that is involved in the overexpression of genes. Around 18mg/ml in dimethyl sulfoxide (DMSO) is the Erlotinib solubility however it is scarcely soluble in water and ethanol. For inhibition of EGFR 20nM is Erlotinib IC50 [2]. It is readily oxidized therefore care should be taken to extend its shelf life. Approximately $65 per 1000mg is Erlotinib price and any one can get OSI-420 for any kind of purpose under this trade name.

MODE OF ATION OF ERLOTINIB
Oral administration of Erlotinib has shown to inhibit epidermal growth factor receptor in alterable manner. Lung, pancreatic and breast cancer are treated with Erlotinib and fruitful results were obtained. The drug was proved to be less toxic when in vitro studies were conducted on lung cancer [3]. For lung cancer therapy, Erlotinib alone or may be co-administered with different medicines like Rapamycin and alternative medicines [4-6] and it is revealed by the study that it has proved more practical when administered together and also no resistance was seen in patients affected by lung, breast, pancreatic and colon cancers [6]. The characteristics associated with the safety, rate of clearance from body and pharmacokinetics were studied patients of breast cancer [7] and those affected by gliomas [8]. When administered alone the action of Erlotinib on EGFR inhibition [8] or co-administered with different drugs like Gemcitabine for the treatment of pancreatic cancer patients have been analyzed [9-10]. Another a different way of inhibition by Eroltinib against pancreatic cancer was discovered in Akt and NF-kB pathways were found to be involved [11]. This has given new direction to researchers and scientists associated with the mechanism of action of Eroltinib.

ERLOTINIB: CLINICAL TRIALS
It has been shown that OSI-420 Desmethyl Erlotinib may be used as efficient drug against numerous sorts of cancers. When SCLC was found to be resistant against Gefitinib administration with Erlotinib showed outstanding results [12] where it acted as apoptotic agent. Erlotinib clinical trial of phase II was conducted and it had been shown to be efficient against pancreatic cancer patients and additionally in HCC of advanced stages tumor was found shrunk [13]. The tolerability of this medicine in elder patients of pulmonary cancer was outstanding [14] however these patients complained regarding the various complications that was the result of side effects. In phase III clinical trials improved survival, less toxic and side effects with marked tumor regression was seen when administered with OSI-420 in patients affected by lung cancer. Those lung cancer patients who were smokers too showed fruitful results when treated with OSI-420 [16]. Phase III trials additionally consisted of patients affected by pancreatic cancer [17]. For the therapy of breast cancer it was co-administered and shown positive results [18-19] therefore Erlotinib is currently being employed for the therapy of above mentioned 3 cancers.

REFERENCES:
1. Raymond, E.e.a., Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs, 2000. 60(1): p. 41-42.
2. Moyer, J.D.e.a., Induction of Apoptosis and Cell Cycle Arrest by erlotinib, an Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinase. Cancer Res, 1997. 57: p. 4838-4848.
3. Yauch, R.L.e.a., Epithelial versus Mesenchymal Phenotype Determines in vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients. Clin Cancer Res, 2005. 11: p. 8686.
4. Herbst, R.S.e.a., A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 2005. 23(25): p. 5892-5899.
5. Eberhard, D.A.e.a., Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non-Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib. Journal of Clinical Oncology, 2005. 23(25): p. 5900-5909.
6. Buck, E.e.a., Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther, 2006. 5(11): p. 2676-84.
7. Tan, A.R.e.a., Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. Journal of Clinical Oncology, 2004. 22(15): p. 3080-3090.
8. Haas, D.A.e.a., Epidermal Growth Factor Receptor, Protein Kinase B/Akt, and Glioma Response to Erlotinib. J Natl Cancer Inst. 97(12): p. 880-887.
9. Starling, N.e.a., Role of Erlotinib in the management of pancreatic cancer. Ther Clin Risk Manag., 2006. 2(4): p. 435-445.
10. Moore, M.J.e.a., Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 2007. 25(15): p. 1960-1966.
11. Rayes, B.F.e.a., Potentiation of the Effect of Erlotinib by Genistein in Pancreatic Cancer: The Role of Akt and Nuclear Factor-κB. Cancer Res, 2006. 66: p. 10553.
12. Lee, D.H.e.a., Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment. Annals of Oncology, 2008. 19(12): p. 2039-2042.
13. Philip, P.A.e.a., Phase II Study of Erlotinib (OSI-774) in Patients With Advanced Hepatocellular Cancer. Journal of Clinical Oncology, 2005. 23(27): p. 6657-6663.
14. Jackman, D.M.e.a., Phase II Clinical Trial of Chemotherapy-Naïve Patients ≥ 70 Years of Age Treated With Erlotinib for Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 2007 25(7): p. 760-766.
15. Bezjak, A., Symptom Improvement in Lung Cancer Patients Treated With Erlotinib: Quality of Life Analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. Journal of Clinical Oncology, 2006. 24(24): p. 3831-3837.
16. Clark, G.M.e.a., Smoking History and Epidermal Growth Factor Receptor Expression as Predictors of Survival Benefit from Erlotinib for Patients with Non-Small-Cell Lung Cancer in the National Cancer Institute of Canada Clinical Trials Group Study BR.21. Clinical Lung Cancer, 2006. 7(6): p. 389-394.
17. Cutsem, E.V.e.a., Phase III Trial of Bevacizumab in Combination With Gemcitabine and Erlotinib in Patients With Metastatic Pancreatic Cancer. Journal of Clinical Oncology, 2009. 27(13): p. 2231-2237.
18. Slamon, D.J.e.a., Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2. N Engl J Med, 2001. 344: p. 783-792.
19. Romond, E.H.e.a., Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. N Engl J Med, 2005. 353: p. 1673-1684.

Cat.No.	Product Name	Information
S2205	DesMethyl Erlotinib (OSI-420) HCl	DesMethyl Erlotinib (OSI-420) HCl is the active metabolite of Erlotinib (EGFR inhibitor with IC50 of 2 nM).
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.
S1149	Gemcitabine HCl	Gemcitabine HCl is a DNA synthesis inhibitor with IC50 of 50 nM, 40 nM, 18 nM and 12 nM in PANC1, MIAPaCa2, BxPC3 and Capan2 cells, respectively.
S1025	Gefitinib	Gefitinib is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively. Gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway.