Gefitinib
N-(3-chloro-4-fluorophenyl)-7-methoxy- 6-(3-morpholinopropoxy)quinazolin-4-amine
Empirical formula	C22H24ClFN4O3
Molecular weight	446.9
Bioavailability (Oral)	59%
Metabolism	hepatic, mainly CYP3A4
Half life	41 hours
Excretion	hepatic
Pregnancy category	C (Australia)

Gefitinib is a new drug used in the treatment of certain types of cancer. Acting in a similar manner to imatinib, gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa®.

Contents

1 Mechanism of action 2 Clinical uses 3 Adverse effects 3.1 Common 3.2 Infreqent 4 References

Mechanism of action

Gefitinib is the first selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. The target protein (tyrosine kinase) is also sometimes referred to as Her1 or ErbB-1 depending on the literature source.

EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. This leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation. Research on Gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways. (Pao et al. 2004, Sordella et al. 2004)

Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited.

Clinical uses

Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy.

Whilst gefitinib has yet to be proven to be effective in other cancers, there is certainly potential for its use in the treatment of other cancers where EGFR overexpression is involved.

In 2004, AstraZeneca informed the United States Food and Drug Administration (FDA) that a large randomized study [1] failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC). Whether progression-free survival is prolonged is not clear from this statement. AstraZeneca also withdrew their application to market gefitinib in Europe shortly after this announcement.

Adverse effects

As gefitinib is a selective chemotherapeutic agent, its tolerability profile is far superior to previous cytotoxic agents. Adverse drug reactions (ADRs) do still occur, however, but are preferable to the fatal consequences of not taking with the therapy.

Common

These include: diarrhoea, nausea, vomiting, anorexia, stomatitis , deydration, skin reactions, paronychia , asymptomatic elevations of liver enzymes, asthenia, conjunctivitis, blepharitis. (Rossi, 2004)

Infreqent

These include: interstitial lung disease, corneal erosion, aberrant eyelash and hair growth. (Rossi, 2004)

References

• Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
• Pao W, Miller V, Zakowski M, et al. (2004). EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Nat Acad Sci USA 101 (36), 13306-11.
• Sordella R, Bell DW, Haber DA, Settleman J (2004). Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways. Science 305 (5687), 1163-7.