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ERLOTINIB (OSI-420) – AN HCL SALT

INTRODUCTION:
Erlotinib is commonly known as Erlotinib salt of HCl. It is a very small tyrosine kinase inhibitor molecule, works against the epidermal growth factor receptor. This EGFR usually gives high level of expression and most often gets mutated in different types of cancers, hence an attractive target for the anti-cancer therapy [1]. Researchers can purchase Erlotinib from supplier Erlotinib which sale it under the trading name of Tarceva. By paying Erlotinib prices around $65 for a 1000 mg vial one can buy OSI-420. Structure of Erlotinib reveals that it is having 2 rings of quinazoline. Erlotinib has found to inhibit the autophosphorylation of EGFR to render the downstreaming of stopped signaling pathway by binding to the ATP binding region of EGFR in a reversible manner causing a permanent conformational change in its structure. Erlotinib is poorly soluble in ethanol and water but gives a solution of 18 mg/ml upon heating in DMSO. For the inhibition of EGFR tyrosine kinase in human, Erlotinib IC50 is found to be near 20 nM [2]. Erlotinib must be stored far away from oxidizing agents to keep it safe and stable.


ERLOTINIB: BREAST, LUNG AND PANCREATIC CARCINOMA
Erlotinib as an oral and reversible EGFR inhibitor molecule was tested against different types of cancers like lung, pancreatic and breast cancer and it has exhibited very remarkable results there. According to an in vitro analysis of Erlotinib in case of clinical and preclinical trials of patients of lung carcinoma, it has proved itself quite suitable and minimum toxic in cellular system [3]. Erlotinib EGFR inhibitor was applied either alone or combined with Rapamycin or any other chemotherapeutic agent for lung carcinoma [4-6] and along with these agents it showed very good and synergistic results including high efficiency and lack of resistance development in case of lung, colon, breast and pancreatic cancers [6]. Erlotinib detailing dose according to its phamacokinetics, its toxicty profile and clearance rate were also assesed in breast carcinoma [7] and was further used for gliomas treatment [8]. Its effects on EGFR cascade were tested [8] and it was also tested alone and combined with Gemcitabine against pancreatic tumors [9-10]. Another study revealed the involvement of NF-B and Akt pathways as mechanism of Erlotinib to stimulate the regression in pancreatic carcinoma [11] hence throwing a new light on mode of action of Erlotinib and exploring a new avenue for its therapeutic potential.    


ERLOTINIB: CLINICAL TRIALS
Due to its successful role in phase II clinical studies against breast, pancreatic and lung cancers, OSI-420 Desmethyl Erlotinib has become a valuable drug for their treatment. After the failure of treatment by Gefitinib, Erlotinib was proved very successful against small cell lung carcinoma [12] as tumor cells are usually known to adapt evasion strategies for the ongoing therapeutic field hence shifting of paradigm from the Gefitinib to Erlotonib stimulated apoptotic cell death in cells resistant for Gefitinib. A phase 2 clinical trial of Erlotinib pancreatic cancer promised good results in case of patients of advanced metastatic hepatocellular carcinoma by stopping its progression [13]. Erlotinib was also found to have a good tolerance in elder lung cancer patients under phase 2 clinical trials [14] who were complaining of secondary complications produced by the side effects of induced medication. Erlotinib lung cancer clinical trial phase III has reported the improved overall survival and less toxicity level and side effects along the regression in tumor volume. Erlotinib has experienced valuable success in case of using against the patients of lung cancer having known smoking background [16]. Erlotinib has been also used in the phase III clinical studies of pancreatic cancers [17] and as a combinational therapy in case of breast cancer [18-19] hence now a great therapeutic regime for these all three 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.

 

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S2205 OSI-420 OSI-420 (DesMethyl Erlotinib, CP-473420) is the active metabolite of Erlotinib (EGFR inhibitor with IC50 of 2 nM). (14) (1)

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