Manjusha M.P., Aswathy S.V. and Merlin N. J.*,
Ezhuthachan College of Pharmaceutical Sciences, Marayamuttom, Neyyattinkara, Thiruvananthapuram, Kerala
*Corresponding Author E-mail: email@example.com
Gastro intestinal stromal tumor (GIST) is the most common mesenchymal tumors of the gastro intestinal tract. They are typically defined as tumors whose behavior are given by mutations in the KIT gene or PDGFRA gene and may or may not stain positively for KIT. Standard treatment for primary GIST is complete surgical resection, with the aim to obtain negative microscope margins over the organ of origin. Imatinib mesylate is a very active agent for tumor control in advanced and metastatic relapse.
Imatinib, an orally administered inhibitor of the KIT receptor tyrosine kinase, is prompting revision of the management algorithms that have traditionally guided the treatment of GIST. Historically, patients with GIST’s have had substantial rates of relapse as well as limited long term survival even after complete surgical resection of a primary tumor. Imatinib has been shown to induce durable tumor response in more than half of the patients with malignant metastatic or unresectable GISTs and to halt disease progression in an additional third. These encouraging results have led to the initiation of clinical trials of imatinib as an adjuvant or neoadjuvant therapy with surgery. Until relevant data are reported to provide definite direction for the management of operable or potentially operable GISTs, treatment decisions must be made on the basis of the available evidence and clinical experience with imatinib1. This review takes into account the epidemiology, pathophysiology and diagnosis of GIST and the management of the same by making use of imatinib therapy, which also includes pharmacological mechanism of action of the drug as well as its pharmacokinetics, ADR, dosing, formulation, interactions, uses, precautions and some selected case study reports and future of the drug..
Cellular origin of GIST:
Intestitial cells of Cajal [ICCs], which are intercalated between the autonomic nerves and muscle walls of the gut, are believed to function as ‘pacemaker’ cells for GI motility. ICCs have been shown to express the KIT proto-oncogene receptor (KIT, CD117) on their surface. This receptor, a transmembrane tyrosine kinase, binds the stem cell factor (scf) and is believed to be essential for development of normal haematopoiesis, Proliferation and migration of primordial germ cells during embryogenesis, as well as for pacemaker functions in ICCs. Similarly, GISTs express the KIT protein tyrosine kinase receptor in most cases, unlike gastrointestinal leiomyomas and leiomyosarcomas, which do not express KIT receptors. The ultrastructure of ICCs is also consistent with GIST cells, both of which have abundant mitochondria, intermediate filaments, microtubules and cytoplasmic interdigitating projections. The shared histologic morphology and immunohistochemical reactivity of ICCs and GISTs suggest that GIST is derived from ICCs or their stem cell precursors. In the majority of GISTs, the ICCs which mediate peristalsis in the upper intestine undergo uncontrolled growth. Growing tumors stimulate angiogenesis of formulation of new blood vessels via. Production of cytokines, such as vascular endothelial growth factor (VEGF). Cells located within growing blood vessels then secrete other cytokines, including platelet – derived growth factors (PDGFs). These bind to associated PDGF receptors on pericytes, resulting in increased vascular and endothelial cell stability2.
The molecular formula for imatinib is C29H31N7O. It is chemically 4-[(4-methyl piperazine-1-yl)methyl]-N-[4methyl-3-[(4-pyridin-3yl [pyrimidin 2-yl)amino] phenyl] benzamide3 . It is structurally as
Figure 1: Chemical structure of Imatinib
It has a molecular mass of 493.603g/mol at free state and 589.7 g/mol at mesylate form.
Mechanism of Action:
Imatinib is a 2-phenylaminopyrimidine 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 insulin receptor. Imatinib is specific for the TK domain in ABL (the Abelson proto oncogene), c-KIT and PDDGFR (Platelet derived growth factor receptor).
Figure 2: Mechanism of action of Imatinib4
In chronic myelogenous leukemia the philadalphia chromosome leads to a fusion protein of abl with bcr (break point cluster region), termend bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity. The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of c-KIT, locking it in a closed or self inhibited conformation and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many c-KIT mutations can cause resistance to imatinib by shifting its equilibrium towards the open or active confirmation. Imatinib is quite selective for bcr-abl as well as c-KIT and PDGfR, but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl-tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.
The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function.
The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Dose reductions are necessary for patients with moderate and severe renal impairment.
Duchenne-Meryon muscular dystrophy (DMD) is the most common and lethal genetic muscle disease. Ameliorating muscle necrosis, inflammation, and fibrosis represents an important therapeutic approach for DMD. Imatinib, an antineoplastic agent, demonstrated antiinflammatory and antifibrotic effects in liver, kidney, lung, and skin of various animal models. This study tested antiinflammatory and antifibrotic effects of imatinib in mdx mice, a DMD mouse model. We treated mdx mice with intraperitoneal injections of imatinib at the peak of limb muscle inflammation and the onset of diaphragm fibrosis. Controls received PBS vehicle or were left untreated. Muscle necrosis, inflammation, fibrosis, and function were evaluated by measuring serum CK activity, endomysial CD45 immunoreactive inflammation area, endomysial collagen III deposition, and hind limb grip strength. Phosphorylation of the tyrosine kinase targets of imatinib was assessed by Western blot in diaphragm tissue and in primary cultures of peritoneal macrophages and skeletal muscle fibroblasts. Imatinib markedly reduced muscle necrosis, inflammation, and fibrosis, and significantly improved hind limb grip strength in mdx mice. Reduced clinical disease was accompanied by inhibition of c-abl and PDGFR phosphorylation and suppression of TNF-α and IL-1β expression. Imatinib therapy for DMD may hold promise for ameliorating muscle necrosis, inflammation, and fibrosis by inhibiting c-abl and PDGFR signaling pathways and downstream inflammatory cytokine and fibrotic gene expression.
Future of the drug:
Drugs of increased resistance and intolerance to imatinib, efforts were made to develop new drugs that could inhibit the Bcr- Abl tyrosine kinase. This leads to the discovery of second generation drugs. Thus by making changes in the chemistry of imatinib, newer second generation drugs are introduced.
More potent and selective Bcr-Abl TK inhibitor.10-30 fold more portent activity in inhibiting TK. Also more proliferative for Bcr-Abl expressing cells. Effective against most mutations than imatinib. But T3151mutant remains resistant, due to loss of hydrogen bond interactyion.
Multitargeted inhibitor of Bcr-Abl and src family kinases. Also shows inhibitory actions against additional downstream kinases. 325 fold more potent than imatinib. Potency against cell expressing wild type of Bcr-Abl than imatinib.
An orally multitargetted tyrosine kinase receptor inhibitor. Only side effect is fatigue.
A monoclonal antibody targeted against VEGF receptor in advanced GIST
A small molecular inhibitor of Raf kinase, PDGfR and VEGfR receptor kinase. It is important future drug for GIST. Clinical trial studies are ongoing for the future recommendations of the drug imatinib as well as for advanced GISTs.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI system. In most cases, GISTs are characterized by gain- of function mutations in the KIT proto-oncogene, most commonly involving exon 11, less frequently involving exon 9 and rarely involving exons 13 and 17. In GISTs without KIT mutations, gain of function mutations may occur in the platelet derived growth factor receptor a [PDGfRa] gene, thereby providing an alternative oncogenic mechanism. GIST’s incidence, although rare, is on the riser, because of the improved diagnostic modalities, which offer accuracy.
There has been a rapid progress in the management of GIST in the 15 years. Since they were recognized as a distinct tumor entity. This has lead to changes in the surgical and oncological approach to GIST patients. Their management by specialist teams has facilitated multicentre international research, leading to the participation of astonishingly high proportions of patients in high quality clinical trials. The introduction of imatinib mesylate has revolutionized the treatment of patients will locally advanced and metastatic GISTs leading to important gains in quality of life and survival. The process of discovery, development and evaluation of this drug acts as a new paradigm for the introduction of other biologically targeted agents in cancer.
REFERENCES:) (2008) 184-189.
5. Ping Huang, Xinyu S. Zhao, Matthew Fields, Richard M. Ransohoff, and Lan Zhou “Imatinib attenuates skeletal muscle dystrophy in mdx mice”Department of Neurology, Neurological Institute, and Neuroinflammation Research Center,