Strategy and planning for chemopreventive drug development: Clinical development plans

Gj, Kelloff; Ja, Crowell; Cw, Boone; Ve, Steele; Ra, Lubet; Greenwald, Peter; Ds, Alberts; Jm, Covey; La, Doody; Gg, Knapp

doi:10.1002/jcb.240560906

Cited by 56 publications

(43 citation statements)

References 17 publications

(3 reference statements)

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“…[15,33] and possible suppression of BACE1 induction, it is likely that no one mechanism is involved. Curcumin also inhibits known amyloid response pathways including JNK kinase and iNOS expression in vitro [5,12,23] and in vivo [10,13] and in CNS (our data). Thus, curcumin should be able to suppress not only A␤ but key aspects of the response to A␤ that are JNK-and iNOS-dependent including LTP inhibition [30], reported to depend on JNK, iNOS, and microglial radicals [31].…”

Section: Curcumin Is a Combined Polyphenolic Anti-oxidant/nsaid That supporting

confidence: 66%

“…In particular, recent data with anti-oxidants like Vitamin E and NSAIDs, including the COX-2 inhibitors and naproxen, have raised concerns about both their chronic safety and efficacy. Because of its potent anti-carcinogenic activity, curcumin has already been through extensive preclinical toxicology and clinical testing and has a very favorable safety profile [1,13]. Because of its availability and low cost, coupled with preclinical data showing its potential for intervention at multiple sites in AD pathogenesis, curcumin is now in clinical trials in mild to moderate AD patients under an FDA approved IND by the UCLA Alzheimer Center.…”

Section: Discussionmentioning

confidence: 99%

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Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Cole

Lim

Yang

et al. 2005

Neurobiology of Aging

200

123

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Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.)

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Section: Curcumin Is a Combined Polyphenolic Anti-oxidant/nsaid That supporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Cole

Lim

Yang

et al. 2005

Neurobiology of Aging

200

123

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“…Pulmonary adenoma formation induced by uracil mustard or diethylnitrosamine was also significantly reduced by oltipraz pretreatment, but to a lesser degree. As reviewed elsewhere [27,28], oltipraz has now shown chemoprotective activity against different classes of carcinogens targeting the trachea, lung, stomach, small intestine, colon, pancreas, liver. Urinary bladder, mammary gland, hematopoietic cells, and skin.…”

Section: Protection Against Experimental Carcinogenesis By Dithiolethmentioning

confidence: 97%

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

Kwak

Egner

Dolan

et al. 2001

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

227

127

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One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, terpenoids and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B 1 (AFB 1 )-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB 1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the "antioxidant response element" (ARE), leading to transcriptional activation of a score of genes involved in carcinogen detoxication and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to dithiolethiones; moreover, basal expression of these genes is typically repressed. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, PR China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB 1 , AFM 1 , when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population.

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“…It is critically important to understand the toxicity of retinoids and their clearance from the eye and liver (44). Analogs of 11-cis-retinal may be metabolized with different rates, and they themselves, and their degradation intermediates, could display different toxicity profiles.…”

Section: ϫ3mentioning

confidence: 99%

Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

Hooser

Alemán

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

232

234

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Mutations in the retinal pigment epithelium gene encoding RPE65 are a cause of the incurable early-onset recessive human retinal degenerations known as Leber congenital amaurosis. Rpe65-deficient mice, a model of Leber congenital amaurosis, have no rod photopigment and severely impaired rod physiology. We analyzed retinoid flow in this model and then intervened by using oral 9-cis-retinal, attempting to bypass the biochemical block caused by the genetic abnormality. Within 48 h, there was formation of rod photopigment and dramatic improvement in rod physiology, thus demonstrating that mechanismbased pharmacological intervention has the potential to restore vision in otherwise incurable genetic retinal degenerations.

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Strategy and planning for chemopreventive drug development: Clinical development plans

Cited by 56 publications

References 17 publications

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

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