Antiproliferative Drugs

Antiproliferative drugs Azathioprine  Purine analogue and antimetabolite.  Mechanism of action-  More marked immunosuppressant than anti tumor action.  Selctively uptaken by immune cells, particularily T cells.  Inhibit de novo purine synthesis and cause DNA damage.  Prevents clonal expansion of T lymphocytes.  Cell mediated immunity is primarily depressed. Mechanism of action Uses Prevention of renal and other graft rejection.  Less effective than cyclosporine, generally combined or used in patients developing cyclosporine toxicity .  Used in progressive RA and some other autoimmune diseases.  Toxicity : Causes bone marrow suppression, Hepatotoxicity, Alopecia, GI toxicity. Cyclophosphamide • Alkylating agent. • Mechanism of action- • Main effect is due to its metabolite Phosphoramide Mustard. • It cause interstrand and intrastrand cross linkage in DNA. • Cause interference with duplication of DNA leading to cell death. • More marked effect on B cells and humoral immunity. Use• BM transplantation in which short course with high dose is given. • Also used in other organ transplantations, RA, Pemphigus, SLE and Idiopathic thrombocytopenic purpura. Toxicity• Leucopenia, Hair loss, Bleeding from bladder, Infertility, Pulmonary fibrosis etc. Methotrexate  Folate antagonist.  Mechanism of action-  Inhibit DHFR- Inhibit purine and pyrimidine base synthesis.  Markedly depresses cytokine production and cellular immunity and has anti-inflammatory property .  Uses- Ist line drug in many autoimmune diseases like Rapidly progressing RA, Severe Psoriasis, Pemphigus, Myasthenia gravis, Uveitis, Chronic active hepatitis.  Low dose as maintenance therapy is relatively well tolerated. Mycophenolate mofetil (MMF)  Newer immunosuppressant.  Mechanism of action-  Prodrug of mycophenolic acid.  Selectively inhibit IMP dehydrogenase, an enzyme essential for denovo synthesis of guanosine nucleotides in the T & B cells.  Inhibits lymphocyte proliferation, Ab production and CMI.  Uses- ‘ Add on’ drug to Cyclosporine + glucocorticoid in renal transplantation.   Help to reduce the dose of cyclosporine and thus its toxicity. Toxicity : Vomiting, diarrhoea, leucopenia and predisposition to CMV infection. Fingolimod (FTY720)  Sphingosine 1 phosphate receptor agonist.  Mechanism of action-  Reduce recirculation of lymphocytes from lymphatic system to blood & peripheral tissues.  ‘Lymphocyte homing’ – migration to periphery into lymph node.  Protect graft from T cell mediated attack.  Use- Combination immunosuppression in graft rejection.  Toxicity – Lymphopenia, Bradycardia, Macular edema Immunosuppressant Antibodies  Monoclonal antibodies • Anti - CD3 monoclonal antibody (Muromonab-CD3) • Anti IL-2 receptor antibody (Daclizumab, Basiliximab) • Campath 1H (Alemtuzumab) • Anti –D immunoglobulin  Antithymocyte globulin  Anti TNF agents • Infliximab • Etanercept • Adalimunab