2-Chloro-2'-deoxyadenosine (2CdA) biochemical aspects of antileukemic efficacy.
The studies on the metabolism and toxic mechanism of 2-chloro-2'-deoxyadenosine (2CdA, Cladribine), a new antileukemic drug, were reviewed. 2CdA, being a 2-halogenated, adenosine deaminase-resistant analogue of deoxyadenosine, is phosphorylated to the mono-, di, and triphosphate chlorodeoxy adenosine and the first step of phosphorylation is taken in the presence of enzymes, mainly kinase deoxycytidine (although in mitochondria it is phosphorylated by kinase deoxyguanosine). Triphosphate derivative of 2CdA is commonly considered to be the agent inducing cell apoptosis resulting from inhibition of ribonucleotide reductase, DNA polymerases and DNA repair. Recent studies on toxicity of 2CdA showed that the nucleoside possesses inhibitory activity against enzymes which are responsible for metabolism of deoxyadenosine, which suggests that the mechanism of toxicity by 2CdA includes a block in dAdo metabolic pathways which is very important for normal function of immune system cells. The agent under discussion and two other adenosine analogues (i.e. fludarabine and 2'-deoxycoformycin) which exhibit cytotoxicity against dividing and resting lymphocytes revolutionized the treatment of indolent lymphoid malignancies (i.e. chronic lymphocytic leukemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma and hairy cell leukemia). Particularly, in the treatment of hairy cell leukemia, 2-chloro-2'-deoxyadenosine demonstrated excellent efficacy, achieved after a single 7-day course, with an acceptable tolerability profile, suggesting that cladribine is likely to be more effective than other agents recommended in this disease. Preliminary clinical data, extremely encouraging in the case of 2CdA indicate that biomolecular mechanisms of the drug cytotoxicity is worth wide presentation.
Fabianowska-Majewska
K
K
Department of General Chemistry, Medical University of Lódź, Poland.
Wyczechowska
D
D
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D017338:Cladribine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D019384:Nucleic Acid Synthesis Inhibitors; D015649:Pentostatin / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D015649:Pentostatin; D017338:Cladribine; D012264:Ribonucleotide Reductases; D014740:Vidarabine; C024352:fludarabine