Mechanisms of anti-cancer action and pharmacology of clofarabine

Human Biodistribution and Radiation Dosimetry of 18F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

“…the U.S. Food and Drug Administration for treatment of acute lymphoblastic leukemia, has shown promising results in acute myeloid leukemia and juvenile myelomonocytic leukemia, and is being tested for its efficacy in solid tumors (1).…”

“…Clofarabine is transported into cells primarily via human concentrated nucleoside transporters; however, human equilibrative nucleoside transporters play a role as well (1,2). On entry into the cell, clofarabine is phosphorylated by deoxycytidine kinase (dCK), monophosphate kinase, and diphosphate kinase into its active triphosphate form (1).…”

Clofarabine Has Apoptotic Effect on T47D Breast Cancer Cell Line via P53R2 Gene Expression

“…Clofarabin, one of the compounds that are used in chemotherapy, is a purine nucleoside analogue that has a strong inhibitory effect on wide-spread leukemia and some of solid tumors such as ovary, prostate, kidney and breast. [1][2][3] In the unphosphorylated form, clofarabine passes through the cell membrane using several transporting system including diffusion, facilitated diffusion and active transportation, and it is phosphorylates by intracellular kinases to its mono, di and three phosphates forms. 1 From these forms, only clolfarabine-3 phosphate is therapeutically active, and the remaining forms act as intracellular clofarabine reservoir.…”

“…1 From these forms, only clolfarabine-3 phosphate is therapeutically active, and the remaining forms act as intracellular clofarabine reservoir. [2][3][4] Clofarabine-3P plays its roles through different mechanisms including: a) it competes with dATP during DNA replication and repair. b) it binds to allostric site of regulatory subunits of Ribonucleotide Reductase (RR) enzyme and inhibts dCTP, dATP formation.…”

Towards novel paradigms for cancer therapy

“…Indeed, novel chemotherapeutic (genotoxic) compounds are continuously being developed, despite the induction of serious side effects arising from the damage caused to normal tissue. Although initially the development of anticancer therapies relied on empirical observations, the current challenge is to develop novel therapeutic paradigms exploiting the knowledge derived from molecular, cellular and systems biology studies of tumor formation and progression (Shipley and Butera, 2009;Zhenchuk et al, 2009). Despite the pleiotropic nature of tumors, several characteristics are shared by almost all malignancies namely: self-sufficiency in growth signals, evasion from apoptosis/immunosurveillance, insensitivity to growth inhibitory signals, limitless replicative potential, sustained angiogenesis and tissue invasion/ metastasis; as well as metabolic, mitotic, oxidative and DNA damage stress (Hanahan and Weinberg, 2000;Luo et al, 2009).…”