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  • 1
    Electronic Resource
    Electronic Resource
    Chemopreventive effect of perillyl alcohol on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced tumorigenesis in (C3H/HeJ X A/J)F1 mouse lung (1997)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 67 (1997), S. 20-25 
    Details
    ISSN: 0730-2312
    Keywords: CAAX motif ; farnesyltransferase inhibitor ; K-ras ; lung cancer ; monoterpene ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: This study was designed to test the chemopreventive potential of perillyl alcohol, an inhibitor of farnesyltransferase, in a mouse lung tumor bioassay. Perillyl alcohol is a naturally occurring monoterpene found in lavender, cherries, and mint. We have shown previously that the majority of lung tumors in this bioassay have an activating mutation in the K-ras gene, which occurs early in the development of mouse lung carcinogenesis. The Ras protein undergoes a series of post-translational modifications, the first of which is farnesylation at the cysteine of the C-terminal CAAX motif. These modifications lead to the anchoring of Ras p21 to the plasma membrane in its biologically active state. Activated Ras p21 couples growth regulatory signals from receptor tyrosine kinases to cytoplasmic second messengers. In a preliminary study, we determined the maximum tolerated dose of perillyl alcohol to be 75 mg/kg body weight. For the bioassay, 5-week-old male (C3H/HeJ X A/J) F1 hybrid mice were randomized into trial groups, and treated with perillyl alcohol three times per week i.p., starting 1 week prior to initiation with the carcinogen NNK, and continuing for 22 weeks after initiation. Our results show a 22% reduction in tumor incidence, and a 58% reduction in tumor multiplicity. Our study demonstrates that perillyl alcohol is an effective chemopreventive compound in the mouse lung tumor bioassay. J. Cell. Biochem. Suppl. 27:20-25. © 1998 Wiley-Liss, Inc.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Mechanistic considerations in chemopreventive drug development (1994)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 56 (1994), S. 1-24 
    Details
    ISSN: 0730-2312
    Keywords: Chemoprevention ; drug development ; mechanism of action ; cancer ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: This overview of the potential mechanisms of chemopreventive activity will provide the conceptual groundwork for chemopreventive drug discovery, leading to structure-activity and mechanistic studies that identify and evaluate new agents. Possible mechanisms of chemopreventive activity with examples of promising agents include carcinogen blocking activities such as inhibition of carcinogen uptake (calcium), inhibition of formation or activation of carcinogen (arylalkyl isothiocyanates, DHEA, NSAIDs, polyphenols), deactivation or detoxification of carcinogen (oltipraz, other GSH-enhancing agents), preventing carcinogen binding to DNA (oltipraz, polyphenols), and enhancing the level or fidelity of DNA repair (NAC, protease inhibitors). Chemopreventive antioxidant activities include scavenging reactive electrophiles (GSH-enhancing agents), scavenging oxygen radicals (polyphenols, vitamin E), and inhibiting arachidonic acid metabolism (glycyrrhetinic acid, NAC, NSAIDs, polyphenols, tamoxifen). Antiproliferation/antiprogression activities include modulation of signal transduction (glycyrrhetinic acid, NSAIDs, polyphenols, retinoids, tamoxifen), modulation of hormonal and growth factor activity (NSAIDs, retinoids, tamoxifen), inhibition of aberrant oncogene activity (genistein, NSAIDs, monoterpenes), inhibition of polyamine metabolism (DFMO, retinoids, tamoxifen), induction of terminal differentiation (calcium, retinoids, vitamin D3), restoration of immune response (NSAIDs, selenium, vitamin E), enhancing intercellular communication (carotenoids, retinoids), restoration of tumor suppressor function, induction of programmed cell death (apoptosis) (butyric acid, genistein, retinoids, tamoxifen), correction of DNA methylation imbalances (folic acid), inhibition of angiogenesis (genistein, retionoids, tamoxifen), inhibition of basement membrane degradation (protease inhibitors), and activation of antimetastasis genes.A systematic drug development program for chemopreventive agents is only possible with continuing research into mechanisms of action and thoughtful application of the mechanisms to new drug design and discovery. One approach is to construct pharmacological activity profiles for promising agents. These profiles are compared among the promising agents and with untested compounds to identify similarities. Classical structure-activity studies are used to find optimal agents (high efficacy with low toxicity) based on good lead agents. Studies evaluating tissue-specific and pharmacokinetic parameters are very important. A final approach is design of mechanism-based assays and identification of mechanism-based intermediate biomarkers for evaluation of chemopreventive efficacy. 1994 Wiley-Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
    Additional Material: 1 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240560903
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  • 3
    Electronic Resource
    Electronic Resource
    Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models: Methods and results from the NCI chemoprevention drug development program (1994)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 56 (1994), S. 32-54 
    Details
    ISSN: 0730-2312
    Keywords: Animal models ; carcinogenesis ; chemoprevention ; drug development ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: 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 antioidants 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 DFMO was active in the colon, mammary glands, and bladder models, while the dithiolthione, oltipraz, was efficacious in all the models listed above (i. e., lung, colon, mammary glands, skin, and bladder). 1994 Wiley-Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
    Additional Material: 1 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240560905
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  • 4
    Electronic Resource
    Electronic Resource
    New agents for cancer chemoprevention (1996)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 63 (1996), S. 1-28 
    Details
    ISSN: 0730-2312
    Keywords: cancer chemopreventive agents ; drug development ; retinoids ; DFMO ; NSAIDs ; oltipraz ; Phase I clinical trials ; Phase II clinical trials ; Life Sciences ; Molecular Cell Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, βcarotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA).A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., α-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors. 1997 Wiley-Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240630703
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