Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine if KRN5500, a spicamycin derivative with a unique acyl tail, would induce programmed cell death (PCD) of myeloid leukemia cell lines and cryopreserved leukemic blasts from newly diagnosed children with acute leukemia (AL). Cells were incubated with varying concentrations (0-5 ng/ml) of KRN5500 and the percent PCD determined using a modified in situ end labeling (ISEL) technique with Klenow fragment. The percent PCD was calculated using the formula: Percent PCD (% PCD)=[number of apoptotic cells/(viable cells+apoptotic cells)]x100. DMSO (0.30% w/v) was added to the cells in culture as the positive control for PCD; the negative control was media or albumin. KRN5500 increased the amount of PCD significantly in all five of the tested cell lines; U937 41+/-1.8%, KG1a 40+/-0.3%, HEL 14+/-2.2%, HL-60 41+/-0. 9%, K562 36+/-2% (mean PCD+/-SD). Patient blasts exposed to KRN5500 had an increase in PCD when exposed to 2 ng/ml of agent from 2 to 8 h; acute myeloid leukemia patients 7.5+/-0.5% at 2 h to 43.5+/-1.6% at 8 h, and acute lymphocytic leukemia patients rose from 12.4+/-3.8% at 2 h to 29.9+/-11.6% after 8 h (mean+/-SE). Overall the PCD for the patient samples was 3.7 versus 28+/-4% at 2 and 8 h, respectively. PCD was proportional to the dose of KRN5500 and incubation time. Further pre-clinical and clinical studies are required.
 ...
PMID:KRN5500 induces apoptosis (PCD) of myeloid leukemia cell lines and patient blasts. 1097 78

Approximately 4000 children and adolescents under the age of 20 years develop acute leukemia per year in the US. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Despite impressive improvements in outcome, relapsed ALL is the fourth most common pediatric malignancy. Therapy for relapsed ALL remains unsatisfactory, and the majority of relapse patients still succumb to leukemia. Between one-third and one-half of patients with acute myelogenous leukemia (AML) relapse, and no standard therapy is recognized for patients with relapsed and/or refractory AML. Novel therapeutic agents are needed to improve the cure rate for relapsed ALL and AML. Clofarabine is a next-generation nucleoside analog, designed to incorporate the best features and improve the therapeutic index of cladribine and fludarabine. Clofarabine inhibits both DNA polymerase and ribonucleotide reductase, leading to impaired DNA synthesis and repair, and directly induces apoptosis. Phase I and II single-agent trials in children have shown that clofarabine is safe and active in both myeloid and lymphoid relapsed/refractory acute leukemias. Clofarabine has been approved by the FDA for pediatric patients with relapsed/refractory ALL after at least 2 prior therapeutic attempts. Rational combinations of clofarabine with other active agents in refractory leukemias are currently under investigation.
 ...
PMID:Treating refractory leukemias in childhood, role of clofarabine. 1872 51

Clofarabine is a second-generation purine nucleoside analogue that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared with its precursors, clofarabine has an increased resistance to deamination and phosphorolysis, hence better stability, as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. In 1993, the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemia. Owing to its unique properties of biochemical modulation when used in combination with other established antileukemic drugs, mainly cytarabine, combination regimens containing clofarabine are being evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This article describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of acute leukemia, myelodysplastic syndrome and solid tumors.
 ...
PMID:Clofarabine in leukemia. 2108 31

Clofarabine is a second-generation purine nucleoside analog that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared to its precursors, clofarabine has an increased resistance to deamination and phosphorolysis, and hence better stability as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. Since the initiation of the first phase I study of clofarabine in 1993 in patients with hematologic and solid malignancies, clofarabine has demonstrated single-agent antitumor activity in adult acute leukemia, including acute myeloid leukemia (AML). Due to its unique properties of biochemical modulation when used in combination with other chemotherapy drugs, mainly cytarabine, combination regimens containing clofarabine have been evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This review describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of adult patients with AML and myelodysplastic syndrome.
 ...
PMID:The role of clofarabine in acute myeloid leukemia. 2295 15


<< Previous 1 2