The pattern of gene expression and gene dose profiles of 6-Mercaptopurine- and 6-Thioguanine-resistant human leukemia cells.

Exposure of MOLT4 human T-cell leukemia cells to 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) resulted in acquired resistance associated with attenuated expression of the genes encoding concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2). To identify other alterations at the RNA and DNA levels associated with 6-MP- and 6-TG resistance, we compared here the patterns of gene expression and DNA copy number profiles of resistant sublines to those of the parental wild-type cells. The mRNA levels for two nucleoside transporters were down-regulated in both of the thiopurine-resistant sublines.

Effect of clofarabine on apoptosis and DNA synthesis in human epithelial colon cancer cells.

Clofarabine, a new-generation purine nucleoside analogue, was thought to work via three mechanisms: incorporation into DNA; induction of apoptosis; and inhibition of ribonucleotide reductase, and showed significant efficacy in pediatric relapsed/refractory acute lymphoblastic leukemia (ALL) and hematologic malignancies in adults. By way of its unique metabolic properties, clofarabine is being explored in lymphoproliferative disorders and solid tumors. In this study, the effect of clofarabine on the DNA synthesis of human colon carcinoma cells (HCT116) was investigated by LigandTracer White which provides a simple and accurate method for investigating the uptake, phosphorylation, retention and DNA incorporation of nucleosides in cells.

Thiopurines: factors influencing toxicity and response.

Thiopurines are the backbone of current anti-leukemia regimens and have also been effective immunosuppressive agents for the past half a century. Extensive research on their mechanism of action has been undertaken, yet many issues remain to be addressed to resolve unexplained cases of thiopurine toxicity or treatment failure. The aim of this review is to summarize current knowledge of the mechanism of thiopurine action in experimental models and put into context with clinical observations.

Differences in cytosolic and mitochondrial 5'-nucleotidase and deoxynucleoside kinase activities in Sprague-Dawley rat and CD-1 mouse tissues: implication for the toxicity of nucleoside analogs in animal models.

Cytosolic and mitochondrial deoxynucleoside kinases (dNKs), as well as 5'deoxynucleotidases (5'-dNTs), control intracellular and intramitochondrial phosphorylation of natural nucleotides and nucleoside analogs used in antiviral and cancer chemotherapy. The balance in the activities of these two groups of enzymes to a large extent determines both the efficacy and side effects of these drugs. Because of the broad and overlapping substrate specificities of the nucleoside kinases and 5'-NTs, their tissue distribution and roles in the metabolism of both natural nucleosides and their analogs are still not fully elucidated.

Mechanisms of anti-cancer action and pharmacology of clofarabine.

Clofarabine, a next-generation deoxyadenosine analogue, was developed on the basis of experience with cladribine and fludarabine in order to achieve higher efficacy and avoid extramedullary toxicity. During the past decade this is the only drug granted approval for treatment of pediatric acute leukemia. Recent clinical studies have established the efficacy of clofarabine in treating malignancies with a poor prognosis, such as adult, elderly, and relapsed pediatric leukemia.