Pharmacological basis for cladribine resistance.
The inherent or acquired resistance of leukemic cells to cytostatic agents is a major clinical challenge. The purpose of this review was to elucidate and analyse the available data concerning mechanisms of resistance of cladribine with emphasis on recent advances in the characterization of activating and inactivating enzymes in the induction of resistance to cladribine. All available in vitro and clinical data on cladribine was undertaken. Cladribine, unlike many other drugs, is toxic to both dividing and indolent lymphoid malignancies. Cladribine is a prodrug and must be phosphorylated intracellularly to cladribine-monophosphate (MP) by the nuclear/cystosol enzyme deoxycytidine kinase (dCK) and the mitochondrial enzyme deoxyguanosine kinase. The cytotoxicity mainly depends on the accumulation of cladribine-triphosphates (TP) after phosphorylation of cladribine-MP by nucleoside monophosphate kinase and nucleoside diphosphate kinase. 5'-Nucleotidase (5'-NT) dephosphorylates cladribine-MP and the accumulation of cladribine-TP depends on the ratio of dCK and 5'-NT in the cells. The mechanisms underlying cladribine resistance are multifactorial, e.g. decreased nucleoside transport, decreased activity or deficiency of dCK, altered intracellular pools of competing nucleotides, altered regulation of ribonucleotide reductase and increased drug inactivation by 5'-NT. Finally, cladribine resistance may be a consequence of a defective induction of apoptosis. In spite of the fact that more than one mechanism can contribute to a cladribine resistance phenotype, a reduction in dCK activity is probably the major determinant of cladribine resistance. Insight into the mechanism of action and resistance to cladribine is crucial for its optimal use as well as for the development of newer analogues.
Lotfi
Kourosh
K
Department of Medicine and Care, Clinical Pharmacology, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85 Sweden.
Juliusson
Gunnar
G
Albertioni
Freidoun
F
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D017338:Cladribine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D012264:Ribonucleotide Reductases / Q000378:metabolism*
D000970:Antineoplastic Agents; C097601:cladribine triphosphate; D017338:Cladribine; D000255:Adenosine Triphosphate; D012264:Ribonucleotide Reductases; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase