Cladribine: mode of action and implications for treatment of multiple sclerosis.
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The inflammation is driven significantly by autoreactive lymphocytes, which recruit cells of the innate immune system such as macrophages that contribute to subsequent tissue damage, ultimately resulting in demyelination and axonal damage that are characteristic in MS lesions. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic chlorinated deoxyadenosine analog that is biologically active in selected cell types and provides targeted and sustained reduction of circulating T and B lymphocytes implicated in the pathogenesis of MS. The biologic activity of cladribine depends on the preferential accumulation of cladribine phosphates in cell types with a high intracellular ratio of deoxycytidine kinase to 5'-nucleotidases. Cladribine-phosphates interfere with DNA synthesis and repair through incorporation into DNA and through inhibition of enzymes involved in DNA metabolism, including DNA polymerase and ribonucleotide reductase. This in turn leads to DNA strand breaks and ultimately cell death. This review explores the mechanism of action of cladribine further, in the context of recent clinical data, after completion of the phase III, 96-week, placebo-controlled CLARITY study. In this study, cladribine tablets demonstrated significant efficacy on clinical and neuroimaging outcomes in relapsing-remitting MS.
Thomas Jefferson University, Philadelphia, PA, USA.
Thomas P
TP
Leist
Robert
R
Weissert
D000284:Administration, Oral; D017338:Cladribine / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D017338:Cladribine