As a purine analogue,<unk>  (2-chloro-2'-deoxyadenosine<unk>  is taken up into rapidly proliferating cells, including B and T lymphocytes, to be incorporated into DNA synthesis. Chemically, it mimics nucleoside adenosine; however, unlike adenosine,<unk>  has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase. This causes it to accumulate in cells and interfere with the targeted cell's ability to process DNA.<unk>  is taken up by specific nucleoside transporter proteins. Once inside a cell,<unk>  undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate <unk> MP), which is subsequently phosphorylated to the triphosphorylated active compound, 2-chlorodeoxyadenosine 5’triphosphate <unk> TP). Activated<unk>  is incorporated into the DNA synthesis pathway, where it disrupts DNA repair and synthesis, resulting in an accumulation of DNA strand breaks This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis). This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment. Another family of enzymes, the 5'-nucleotidase (5'-NT) family, is also capable of dephosphorylating<unk> , making it inactive. The most important subtypes of this group appear to be cytosolic 5'-NT, c-5NCT1A and c-NT1B, which are cytosolically active and specific for purine analogues. Accumulation of<unk>  into cells is dependent on the ratio of<unk> TP and 5'-NT. This ratio differs between cell types, with high levels in T and B lymphocytes, making them particularly susceptible to cell death. The cells with the highest ratios are B cells, especially germinal centre and naïve B cells. This helps to explain which B cells are more vulnerable to<unk> -mediated apoptosis. DCK is the rate-limiting enzyme for conversion of the<unk>  prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes. In contrast, the<unk> TP:5'-NT ratio is relatively low in other cell types, thus sparing numerous non-hematologic cells. In multiple sclerosis,<unk> 's effectiveness may be due to depletion of B cells, in particular memory B cells. In the pivotal phase 3 clinical trial of oral<unk>  in multiple sclerosis, CLARITY,<unk>  selectively depleted 80% of peripheral B cells, compared to only 40–45% of CD4+ T cells and 15‒30% CD8+ T cells. More recently,<unk>  has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells. Although<unk>  is selective for B cells, the long-term suppression of memory B cells, which may contribute to its effect in multiple sclerosis, is not explained by gene or protein expression. Instead,<unk>  appears to deplete the entire B cell department, but while naïve B cells rapidly move from lymphoid organs, the memory B cell pool repopulates slowly from the bone marrow. Both hairy cell leukemia and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers.
Cladribine
Ifosfamide
Fludarabine
Cytarabine
Clofarabine
Vincristine
Nelarabine
Cyclophosphamide