Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An inhibitor of alkaline phosphodiesterase was isolated from a soil Streptomyces. The agent was identified with 2-crotonyloxymethyl-4,5,6-trihydroxycylohex-2-enone (COTC) by UV, IR, 1H HMR and 13C NMR spectrometry. The mechanism of tumor-inhibitory action of COTC was studied with murine lymphoblastma L5178Y cells. COTC blocked alkaline phosphodiesterase; IC 50 was 60 micrograms/ml by the method employed. The growth of L5178Y cells was inhibited by COTC; IC50 was 4.4 micrograms/ml. DNA biosynthesis was preferentially prevented by COTC over RNA and protein syntheses; IC50 of DNA synthesis was 7 or approximately 25 micrograms/ml. COTC significantly inhibited DNA polymerase alpha even in the presence of dithiothreitol. The mitosis was markedly blocked by COTC; complete inhibition was observed at a drug concentration of 20 microgram/ml. Adriamycin-, aclarubicin- and bleomycin-resisant cell subline showed collateral sensitivity to COTC. COTC and aclarubicin exhibited synergistic activity on aclarubicin-resistant cells, but not on the parental cells. COTC increased uptake of [3H]adriamycin or blocked the drug efflux in the resistance cells, but not in the parental cells. The effects of COTC on macromolecular syntheses, mitosis and membrane functions may be attributed to the interaction with the sulfhydryl group of various enzymes. Although COTC is multifunctional drug, the inhibition of DNA polymerase alpha and a certain mitotic process seems to be related to the lethal action.
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PMID:Mechanism of action of 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone, a SH inhibitory antitumor antibiotic, and its effect on drug-resistant neoplastic cells. 714 23

Adriamycin (ADR) induces nonimmunological and noncytotoxic histamine release from peritoneal and pleural rat mast cells. This secretion is unaffected by the pretreatment with pertussis toxin, cholera toxin and benzalkonium chloride. Histamine release induced by compound 48/80, was markedly inhibited by pertussis toxin, cholera toxin, benzalkonium chloride and neuraminidase. The ADR dose-response curve is significantly shifted to the right when cells were preincubated with the unspecific phosphodiesterase inhibitor IBMX. The activation of protein kinase C (PKC) with the phorbol esther TPA increases the response to ADR, while PKC inhibition with trifluoperazine decreases histamine release. The pretreatment of mast cells with okadaic acid did not modify the response to ADR. These results suggest that ADR elicits histamine release with a mechanism notably different from compound 48/80.
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PMID:Study of the activation mechanism of adriamycin on rat mast cells. 753 76