Search results for "pyrimidines"

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK …

2013

Background: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. Methods: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m−2 twice daily on days 1–14; oxaliplatin 100/130 mg m−2 on day 1; bevacizumab 7.5 mg kg−1 on day 1; imatinib 300 mg day−1 on days 1–21 every 21 days. The primary study endpo…

Postsynaptic NO/cGMP Increases NMDA Receptor Currents via Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Hippocampus

2013

The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiologi…

Dermatofibrosarcoma protuberans: a comprehensive review and update on diagnosis and management

2013

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial tumor characterized by high rates of local recurrence and low risk of metastasis. DFSP occurs most commonly on the trunk and proximal extremities, affects all races, and often develops between the second and fifth decade of life. The tumor grows slowly, typically over years. Histologically, several variants of DFSP have been described and should be well characterized to avoid misdiagnosis with other tumors. These include pigmented (Bednar tumor), myxoid, myoid, granular cell, sclerotic, atrophic DFSP, giant cell fibroblastoma, and DFSP with fibrosarcomatous areas. Of all these variants, only the DFSP with fibrosarcomatous areas is…

Leflunomide, a reversible inhibitor of pyrimidine biosynthesis?

1995

Influence of peroxisome proliferators on phosphoprotein levels in human and rat hepatic-derived cell lines.

1995

To elucidate the effect of peroxisome proliferators on the signal-transduction pathway, we have compared the effect of ciprofibrate, an hypolipaemic agent, on the overall phosphoprotein level between rat and human well differentiated hepatic derived cell lines. The phosphorylation status of several phosphoproteins in the rat Fao cell line was increased by the drug while no changes were observed in the human HepG2 cell line. In rat Fao cells, this increase, which is concentration and time dependent, can be as much as eightfold for 20-kDa and 22-kDa proteins. Wy-14,643, a non-fibrate molecule and a more potent peroxisome proliferator than ciprofibrate, increased the phosphorylation status of …

Effects of carboxyamidotriazole on in vitro models of imatinib-resistant chronic myeloid leukemia.

2008

Although imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid leukemia (CML), some patients develop resistance with progression of leukemia. Alternative or additional targeting of signaling pathways deregulated in bcr-abl-driven CML cells may provide a feasible option for improving clinical response and overcoming resistance. In this study, we show that carboxyamidotriazole (CAI), an orally bioavailable calcium influx and signal transduction inhibitor, is equally effective in inhibiting the proliferation and bcr-abl dependent- and independent-signaling pathways in imatinib-resistant CML cells. CAI inhibits phosphorylation of cellular proteins including STAT5 and CrkL a…

An unexpected Dimroth rearrangement leading to annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines with potent antitumor activity.

2013

An unusual Dimroth rearrangement occurring in the reaction leading to annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core allowed the isolation of the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. By decorating the linear isomer with the same chains that improved the biological activity of the angular isomers, new annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines were designed and synthesized. They were selected by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited strong antiproliferative …

New annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines, with potent anticancer activity, designed through VLAK protocol

2012

Drug design was performed through the Virtual Lock-and-Key (VLAK) protocol. This in silico approach allowed to select new annelated thienotriazolopyrimidine derivatives, potentially antitumor drugs. Starting from benzothieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine and Pyrido[3',2':4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core structures, new derivatives of these nuclei were designed and synthesized. Three of them were selected by the Development Therapeutical Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited an excellent antiproliferative act…

Conformational and Tautomeric Control by Supramolecular Approach in Ureido-N-iso-propyl,N’-4-(3-pyridin-2-one)pyrimidine

2019

Ureido-N-iso-propyl,N&rsquo

A new pyrazolo pyrimidine derivative inhibitor of cyclooxygenase-2 with anti-angiogenic activity

2003

In a previous study, we reported a new pyrazolo pyrimidine derivative, N(4)-benzyl-N(6),N(6)-dimethyl-1-1(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-6,4-diamine (DPP), which inhibited potently cyclooxygenase-2 activity in intact cell assays with minor activity against cyclooxygenase-1 (IC(50)=0.9 nM for cyclooxygenase-2 versus IC(50)=59.6 nM for cyclooxygenase-1). In the present work, this behaviour was confirmed in vivo by using the 24-h zymosan-injected mouse air pouch model (ID(50)=1.36 nM/pouch for prostaglandin E(2) level). We also studied the possible beneficial effect of DPP in the angiogenesis-dependent murine air pouch granuloma and rat paw carrageenan-induced hyperalgesia models. DP…