Imatinib

Imatinib is a drug used to treat certain types of cancer. It is currently marketed by INN). It was originally coded during development as CGP57148B or STI-571 (these terms are used in early preclinical publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.

It is the first member of a new class of agents that act by inhibiting particular enzymes, instead of non-specifically inhibiting rapidly dividing cells.

Molecular biology

Imatinib is a 2-phenylpyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

There are a large number of TK enzymes in the body, including the platelet-derived growth factor receptor).

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

The active sites of tyrosine kinases each have a binding site for competitively.

Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known apoptopic functions.^[2]

Uses

  Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit.^[3] Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Early clinical trials also show its potential for treatment of hypereosinophilic syndrome and dermatofibrosarcoma protuberans.

In laboratory settings, imatinib is being used as an experimental agent to suppress diabetes.^[4]

Recent mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.^[5]

Gleevec is also being used in the treatment of certain brain tumors to include high grade glioblastoma.

Tolerability and side effects

  In the United States, the side effects of imatinib have not yet been ascertained, research suggests that it is generally very well tolerated (eg. liver toxicity was much less than predicted). Broadly, side effects such as edema, nausea, rash and musculoskeletal pain are common but mild.

Severe congestive cardiac failure is an uncommon but recognised side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.^[6]

Metabolism

Metabolism of imatinib occurs in the liver and the main metabolite, N-demethylated half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively.

History

Imatinib was identified in the late 1990s by Novartis chemists. Dr Brian J. Druker led many of the key clinical trials confirming the efficacy of imatinib in CML. Its development is the template for rational drug design. Soon after identification of the bcr-abl target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.^[7]

Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the "magic bullet" to cure cancer.

Gleevec, which costs $32,000 per year for a 400 mg/day dose, is often cited as an example of pharmaceutical industry innovation that justifies the high cost of drugs. Marcia Angell and Arnold S. Relman argue that Gleevec is actually an example of the contribution of taxpayer-supported research and of industry inaction. Novartis patented several tyrosine kinase inhibitors, and lost interest, they write. Drucker tested several, and imatinib was the most potent, and unusually, had almost no effect on normal cells. Novartis had "little corporate enthusiasm," they write, but Drucker persisted^[8].

In 2007, imatinib became a test case through which Novartis challenged India's patent laws. This would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Organisations such as Médecins Sans Frontières argue that a change in law would make it impossible for Indian companies to produce cheap antiretrovirals (anti-AIDS medication), endangering access to these drugs in Third World countries.^[9] On 6 August 2007 The High Court in Chennai, India, dismissed the writ petition filed by Novartis, challenging the constitutionality of Section 3(d)of Indian Patent Act and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question.

References

See also

• History of cancer chemotherapy