Erlotinib
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Erlotinib
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| Systematic (IUPAC) name | |
| N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine |
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| Identifiers | |
| CAS number | 183321-74-6 |
| ATC code | L01XX34 |
| PubChem | 176870 |
| DrugBank | APRD00951 |
| Chemical data | |
| Formula | C22H23N3O4 |
| Mol. weight | 393.436 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | Oral |
Erlotinib hydrochloride (trade name Tarceva®, Genentech/OSIP) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.
Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the Adenosine Triphosphate binding site of the receptor[1]. For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change in their intracellular structure, exposing a further binding site for binding proteins which cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped.
Like gefitinib, erlotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. It has been approved for the treatment of locally advanced or metastatic non small cell lung cancer that has failed at least one prior chemotherapy regimen. In November 2005, the FDA approved the use of erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.
A test for the EGFR mutation in cancer patients has been developed by Genzyme. This may predict who will respond to erlotinib and other tyrosine kinase inhibitors. It is reported that responses among patients with lung cancer are seen most often in females never-smokers, particularly asian women and those with adenocarcinoma cell type.
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[edit] Administration
Oral tablets
[edit] Side effects
Common side effects include:
- Diarrhea
- Rash occurs in the majority of patients. This resembles acne and primarily involves the face and neck. It is self-limited and resolves in the majority of cases, even with continued use. Interestingly, some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantatively assessed.
- Loss of appetite
- Fatigue
- Rarely, interstitial pneumonitis, which is characterized by cough & increased dyspnea. This may be severe and must be considered among those patients whose breathing acutely worsens.
[edit] Resistance to treatment
A key issue with EGFR-directed treatments is that after a period of 8-12 months, the cancer cells become resistant to the treatment, most commonly by recruiting a mutated IGF-1 Receptor to act as one of the EGFR partners in the homodimer, so forming a heterodimer[2]. This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538[3] or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541[4].
[edit] References
- 1. Raymond, E., Faivre, S., and Armand, J.P.; Epidermal Growth Factro Receptor Tyrosine Kinase as a Target for Anticancer Therapy, Drugs, 2000; 60(Suppl.1): p.15-23
- 2. H.E. Jones, L. Goddard, J.M. Gee et al; Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocrine-Related Cancer,2004. 11(4): p.793-814
- 3. Alexander Levitzki, Galia Blum, Aviv Gazit; Substrate Competitive Inhibitors of IGF-1 Receptor Kinase; Biochemistry, 2000; 39: p.15705-15712
- 4. Warshamana-Greene, G.S., Litz, J., Buchdunger, E., et al; The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy, Clinical Cancer Research, 2005; 11: p. 1563-1571
- Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-7. PMID 15284455.
- Genzyme "Genzyme Launches Exclusive Lung Cancer Test" Press Release September 27, 2005
