Imatinib mesylate- an anticancer drug for CML patients

Imatinib mesylate is often prescribed under the brand name Gleevec or Glivec and is used to treat certain cancers, especially leukemia.

FDA approved the drug on February 1, 2001. 

Mode of administration- oral, given as a yellow coloured 100 mg capsule. 

Indications- who will benefit from this drug?

1. Patients diagnosed with Philadelphia chromosome (bcr-abl) 
2. Patients diagnosed with chronic myeloid leukemia (CML) and CML patients who failed to respond to interferon-alpha treatment
3. Lymphoblastic leukemia– given along with chemotherapy
4. Cancer patients with a relapse
5. Patients with myelodysplastic and myeloproliferative diseases (MDS/MPD)
6. Patients with advanced hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL)
7. Patients with Gastro-Intestinal Stromal Tumour (GIST) 

Who requires constant monitoring?

Patients with the following conditions need special monitoring:

1. Hypothyroidism- closely monitor the TSH levels
2. Hepatotoxicity- carefully monitor the levels of blood counts and liver enzymes as the metabolism of this drug is primarily hepatic
3. Fluid retention- check the weight of the patient regularly. An abnormally rapid weight gain requires special attention
4. Cardiac diseases- any signs and symptoms of cardiac or renal failure requires immediate treatment

Mechanism of action

As a protein kinase inhibitor, it inhibits the activity of Bcr-Abl tyrosine kinase (TK) and other TKs including Kit, DDR1 & DDR2, CSF, and, PDGFR. It also inhibits cellular events mediated by activation of receptor kinases

The above information was taken from the spmc of the drug

Current research on Imatinib

C-myc and resistance to CML

Imatinib is the first line of treatment against Chronic Myeloid Leukemia (CML). In some patients, complete eradication of leukemic cells leading to resistance to the drug. A recent study has proved it was because of an over-expression of c-myc which could potentially be a therapeutic target. Upon performing trypan blue and MTT assay along with FACS and qPCR, they could assess the cell cycle progression and apoptosis. They finally concluded that c-myc suppression has led to an increased effectiveness of Imatinib

PDGFRA as a therapeutic target for imatinib

This research work identifies an isoform of Kit or kinase platelet-derived growth factor receptor alpha (PDGFRA) as a therapeutic target of Imatinib Mesylate (IM). The above finding has implications in the treatment of Gastro-Intestinal Stromal Tumour (GIST)

Imatinib and solution for GIST relapse

GIST patients benefit from Imatinib. However, nearly 40% of these patients exhibit a relapse within three years. One cannot predict the poor outcome after treating with imatinib. Upon studying the genomic and transcriptomic profiles of patients with a relapse, they identified somatic mutations and deregulated miRNA & mRNA. This resulted in Chromosome Instability (CIN), indicating this could be a novel prognostic biomarker for high-risk GIST

Resistance to Imatinib by GIST

Scientists identify a more severe problem in addition to relapse. Most GIST patients develop resistance to Imatinib and exhibit IM resistance. With the 2nd and 3rd lines of treatments showing modest clinical outcomes, we must find novel therapeutic approaches to treat GIST. Through their work, they identified BCL6, an oncogenic driver and repressor of transcriptional repressor. BCL6 helped induce GIST cells after treatment with IM. How BCL6 acts is by recruiting SIR1 to suppress the expression of TP53. A reduced TP53 reduces apoptosis and increases the tolerance of GIST cells to IM

Imatinib and implications in long COVID

They identify that IM can restore the endothelial barrier in long COVID patients. This prevents the leaking of cytokine from the alveolar compartment in the lungs. Imatinib does this by modulating the NF-kB signaling pathway.