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ERLOTINIB– THE HCL SALT

ERLOTINIB AND ITS PROPERTIES
Erlotinib comes under the category of tyrosine kinase inhibitorswhich is also called OSI-420 EGFR inhibitor and usually named as HCl salt. Epidermal growth factor tyrosine kinase receptor is usually seen abnormal in various types of cancers so they are being employed for the anti-cancer therapy. A lot of new medicines are being produced by using the same approach [1]. Erlotinib structure revealed that it contained two quinazoline rings in its structures and it showed to inhibit the EGFR auto phosphorylationwhich eventually stops the pathway which 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 easily oxidize able so care must be taken to increase its shelf life. Approximately $65 per 1000mg is Erlotinib price and buy OSI-420 for any kind of purpose under this trade name.


ERLOTINIB STUDIES IN VARIOUS KINDS OF CANCERS
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 medicine was proved to be less toxic when in vitro studies were conducted on lung cancer [3]. For lung cancer therapy, Erlotinib alone or can be co-administered with other medicines such as Rapamycin and other medicines [4-6] and it is revealed by the study that it has proved more effective when administered in combination and also no resistance was seen in patients suffering from lung, breast, pancreatic and colon cancers [6]. The characteristics related to the safety, rate of clearance from body and pharmacokinetics were studied patients of breast cancer [7] and those suffering from gliomas [8]. When administered alone the action of Erlotinib on EGFR inhibition [8] or co-administered with other medicine like Gemcitabine for the treatment of pancreatic cancer patients have been analyzed [9-10]. Another way of inhibition by Eroltinib against pancreatic cancer was discovered in which Akt and NF-kB pathways were found to be involved [11]. This has given new direction to researchers and scientists related to the mechanism of action of Eroltinib.


ERLOTINIB AND ITS CLINICAL TRIALS
It has been shown that OSI-420 Desmethyl Erlotinib can be used as efficient drug against various types 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 was proved to be efficient against pancreatic cancer patients and also in HCC of advanced stages tumor was found shrunk [13]. The tolerability of this medicine in elder patients of pulmonary cancer was outstanding [14] but these patients complained about the various complications that was the result of it side effects. In phase III clinical trials improved survival, less toxic and side effects with marked tumor regression was seen when administered with OSI-420in patients suffering from lung cancer. Those lung cancer patients who were smokers too showed fruitful results when treated with OSI-420 [16]. Phase III trials also consisted of patients suffering from pancreatic cancer [17]. For the therapy of breast cancer it was co-administered and shown positive results [18-19] so therefore Erlotinib is now being used for the therapy of above mentioned 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.
 

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S1023 Erlotinib HCl (OSI-744) Erlotinib HCl (OSI-744, CP358774, NSC 718781) is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl. (450) (17)

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