Antitumour drug Lenalidomide: Indications and Side Effects

What is Lenalidomide?

Lenalidomide is a targeted immunomodulatory drug with multiple mechanisms of action. It has anti-tumour, anti-angiogenic and anti-inflammatory properties. In the United States and the European Union, oral lenalidomide is used in combination with rituximab or rituximab products for the treatment of patients with previously treated follicular lymphoma.

Lenalidomide is also a thalidomide derivative that exists as a racemic mixture with active S(-) and R(+) forms. However, lenalidomide is safer and more effective than thalidomide, with fewer adverse reactions and toxicities. Lenalidomide promotes malignant cell death and enhances host immunity, is available as an oral capsule, and has been approved by the FDA and the European Union for the treatment of multiple myeloma, myelodysplastic syndromes, set-cell lymphomas, follicular lymphomas, and marginal zone lymphomas in selected patients. Due to severe teratogenicity, pregnancy must be ruled out prior to initiation of therapy and patients must participate in a lenalidomide Risk Evaluation and Mitigation Strategies (REMS) programme, in order to ensure contraceptive adherence.

Mechanism of action

Lenalidomide has multiple mechanisms of action. It exerts its immunomodulatory effects by altering cytokine production, modulating T-cell co-stimulation and enhancing NK-cell-mediated cytotoxicity.

Lenalidomide directly inhibits the cullin ring E3 ubiquitin ligase complex: binding to cereblon, the substrate aptamer of the complex, modulates the substrate specificity of the complex, thereby recruiting ligase substrate proteins, including Ikaros (IKZF1), Aiolos (IKZF3), and CK1α9. IKZF1 and IKZF3 are B cell transcription factors that are essential for B cell differentiation and malignant cell survival.IKZF3 also regulates the expression of interferon regulatory factor 4 (IRF4), a transcription factor that regulates aberrant expression of myeloma-specific genes. The immunomodulatory effects of lenalidomide can be partially attributed to the degradation of IKZF3, which is an inhibitor of the interleukin 2 gene (IL2): when lenalidomide reduces IKZF3 levels, IL-2 production is increased, which in turn increases the proliferation of natural killer (NK) cells, NKT cells, and CD4+ T cells. Lenalidomide inhibits the production of the pro-inflammatory cytokines TNF-alpha, IL-1, IL-6, and IL-12, while increasing the production of the anti-inflammatory cytokine IL-10. Lenalidomide is a T-cell costimulatory molecule that promotes the proliferation of CD3 T cells and increases the production of IL-2 and IFN-γ in T lymphocytes, which enhances NK cell cytotoxicity and ADCC.It inhibits the expression and function of T regulatory cells, which tend to be excessive in some haematological malignancies.

Lenalidomide exerts direct anti-tumour effects by inhibiting the proliferation of tumour cells and inducing their apoptosis. It activates pro-apoptotic Caspase-8, increases the sensitivity of tumour cells to FAS-induced apoptosis, and down-regulates the anti-apoptotic protein NF-κB.Lenalidomide exerts its anti-angiogenic effects by inhibiting angiogenic growth factors released from tumour cells, such as VEGF, BFGF and hepatocyte growth factor, rather than its immunomodulatory effects. than its immunomodulatory effects. In vitro, lenalidomide inhibits cell adhesion molecules such as ICAM-1, LFA-1, β2 and β3 integrins, and gap junction function, thereby preventing malignant cell metastasis.

Side Effects of Lenalidomide

Common side effects of lenalidomide include: headache and dizziness, increased risk of infection, breathlessness, pallor (anaemia), bruising, bleeding gums or nosebleeds, fatigue, diarrhoea or constipation, rash, vision problems, tremor, numbness or tingling in the fingers or toes, changes in the level of minerals in the blood, swelling, loss of appetite and weight loss, low blood pressure, coughing, blood glucose levels, changes in the kidneys or liver. The above adverse reactions do not occur in everyone and vary from person to person.

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