Endocrine and Antitumoral Effects of R76713 in Rats

Coster, R. De; Ginckel, R. Van; Wouters, Walter; Goeminne, Nick; Vanherck, W.; Byloos, M.

doi:10.3109/14756369009040738

Cited by 10 publications

(1 citation statement)

References 10 publications

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“…Using the P450arom model, we have overlaid both enantiomers of the inhibitor vorozole (DeCoster et al, 1990;VandenBossche et al, 1990) over androstenedione. One of the enantiomers (the R form) overlays the androstenedione well and does not appear to act in a fashion consistent with an irreversible inhibitor.…”

Section: Modeling Of Vorozole In the Active Site Of P450arommentioning

confidence: 99%

A three‐dimensional model of aromatase cytochrome P450

et al. 1995

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P450 hemeproteins comprise a large gene superfamily that catalyzes monooxygenase reactions in the presence of a redox partner. Because the mammalian members are, without exception, membrane-bound proteins, they have resisted structure-function analysis by means of X-ray crystallographic methods. Among P450-catalyzed reactions, the aromatase reaction that catalyzes the conversion of C19 steroids to estrogens is one of the most complex and least understood. Thus, to better understand the reaction mechanism, we have constructed a three-dimensional model of P450arom not only to examine the active site and those residues potentially involved in catalysis, but to study other important structural features such as substrate recognition and redox-partner binding, which require examination of the entire molecule (excepting the putative membrane-spanning region). This model of P450arom was built based on a "core structure" identified from the structures of the soluble, bacterial P450s (P450cam, P450terp, and P450BM-P) rather than by molecular replacement, after which the less conserved elements and loops were added in a rational fashion. Minimization and dynamic simulations were used to optimize the model and the reasonableness of the structure was evaluated. From this model we have postulated a membrane-associated hydrophobic region of aliphatic and aromatic residues involved in substrate recognition, a redoxpartner binding region that may be unique compared to other P450s, as well as residues involved in active site orientation of substrates and an inhibitor of P450arom, namely vorozole. We also have proposed a scheme for the reaction mechanism in which a "threonine switch" determines whether oxygen insertion into the substrate molecule involves an oxygen radical or a peroxide intermediate.

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Section: Modeling Of Vorozole In the Active Site Of P450arommentioning

confidence: 99%

A three‐dimensional model of aromatase cytochrome P450

et al. 1995

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Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models: Methods and results from the NCI chemoprevention drug development program

et al. 1994

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In the NCI, Chemoprevention Branch drug development program, potential chemopreventive agents are evaluated for efficacy against chemical carcinogen-induced tumors in animal models. This paper summarizes the results of 144 agents in 352 tests using various animal efficacy models. Of these results, 146 were positive, representing 85 different agents.The target organs selected for the animals model are representative of high-incidence human cancers. The assays include inhibition of tumors induced by MNU in hamster trachea, DEN in hamster lung, AOM in rat colon (including inhibition of AOM-induced aberrant crypts), MAM in mouse colon, DMBA and MNU in rat mammary glands, DMBA promoted by TPA in mouse skin, and OH-BBN in mouse bladder.The agents tested may be classified into various pharmacological and chemical structural categories that are relevant to their chemopreventive potential. These categories include antiestrogens, antiinflammatories (e.g., NSAIDs), antioxidants, arachidonic acid metabolism inhibitors, GST and GSH enhancers, ODC inhibitors, protein kinase C inhibitors, retinoids and carotenoids, organosulfur compounds, calcium compounds, vitamin D3 and analogs, and phenolic compounds (e.g., flavonoids). The various categories of compounds have different spectra of efficacy in animal models. In hamster lung, GSH-enhancing agents and antioxidants appear to have high potential for inhibiting carcinogenesis. In the colon, NSAIDs and other antiinflammatory agents appear particularly promising. Likewise, NSAIDs are very active in mouse bladder. In rat mammary glands, retinoids and antiestrogens (as would be expected) are efficacious. Several of the chemicals evaluated also appear to be promising chemopreventive agents based on their activity in several of the animal models. Particularly, the ODC inhibitor DFh4O was active in the colon, mammary glands, and bladder models, while the dithiolthione, oltipraz, was efficacious in all the models listed above (ie., lung, colon, mammary glands, skin, and bladder).

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Clinical development plan: (+)-Vorozole

1996

J. Cell. Biochem.

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Endocrine and Antitumoral Effects of R76713 in Rats

Cited by 10 publications

References 10 publications

A three‐dimensional model of aromatase cytochrome P450

A three‐dimensional model of aromatase cytochrome P450

Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models: Methods and results from the NCI chemoprevention drug development program

Clinical development plan: (+)-Vorozole

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