Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) is an enzyme family with serine/threonine kinase function which is involved in the transduction of signals for cell proliferation and differentiation. The important role played in processes relevant to neoplastic transformation, carcinogenesis and tumor cell invasion renders PKC a potentially suitable target for anticancer therapy. Bryostatin 1, a macrocyclic lactone isolated from Bugula nerutina, is a partial PKC agonist, and has shown potent antineoplastic properties in vitro and in vivo. Staurosporine, an alkaloid isolated from microbial sources, is ine of the most potent PKC inhibitors and has shown high antiproliferative activity in vitro, but poor selectivity. Staurosporine analogs have thus been synthesize with the aim of obtaining more selective PKC inhibition; among these, CGP 41251 has shown reduced PKC inhibitory activity, but a higher degree of selectivity when assayed for inhibition of different kinases. Several studies indicate a role for PKC in the regulation of the multidrug resistance (MDR) phenotype, since several PKC inhibitors are able to partially reverse MDR and inhibit P-glycoprotein (Pgp) phosphorylation. The MDR phenotype is also associated with variation in PKC isoenzyme content, in particular with PKC-alpha overexpression. While adequate PKC modulation might offer an attractive concept to modulate MDR, other potential mechanisms of PKC interaction with anticancer drugs exist and have been documented, such as the enhancement of chemotherapy-induced apoptosis by safingol, a specific PKC inhibitor. Three phase I clinical trials with bryostatin have been completed so far and have shown that myalgia is the dose-limiting toxicity, while some antitumor activity is evident. Safingol is presently undergoing a phase I clinical trial in combination with doxorubicin. While no definitive data are presently available, it appears that safingol plasma levels approach those associated with chemopotentiation in animals and no pharmacokinetic interaction between the two drugs exists. Drugs targeting PKC are well work considering for clinical trials, particularly for their potential as modulators of currently available cytotoxic agents.
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PMID:Protein kinase C: a worthwhile target for anticancer drugs? 914 7

Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.
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PMID:Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients. 1738 88