Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice

Parnaud, Géraldine; Taché, Sylviane; Peiffer, Ginette; Corpet, Denis E.

doi:10.1054/bjoc.2000.1540

Cited by 18 publications

(10 citation statements)

References 12 publications

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“…PEG has been shown to reduce both ACF and colon carcinogenesis. 10,14,17,18 Accordingly, we found that ACF were dramatically reduced in rats treated with PEG. In addition, we demonstrated that PEG almost inhibited MDF, since there was only 1 MDF in the rats treated with PEG, a finding that supports the correlation between MDF and carcinogenesis.…”

Section: Discussionmentioning

confidence: 67%

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Femia

Caderni

Bottini

et al. 2007

Intl Journal of Cancer

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The correlation between mucin-depleted foci (MDF) and colon carcinogenesis was studied in F344 rats initiated with 1,2-dimethylhydrazine and treated with a chemopreventive regimen (polyethylene glycol, PEG) or with a promoting diet (high-corn oil). High corn oil diet increased MDF, while PEG reduced them. The expression of p27 and p16, inhibitors of cyclin-dependent kinases, which inhibit the progression of the cell cycle, was studied by immunohistochemistry in MDF and in aberrant crypt foci (ACF) of control rats. In both MDF and ACF, the nuclear expression of p27 was markedly reduced, while p16 was reduced to a lower extent. Mitotic activity was higher in MDF and ACF than in normal mucosa of control rats. MDF were also identified in azoxymethane-initiated SWR/J mice. These results further confirm that MDF are preneoplastic lesions and could be useful biomarkers of colon carcinogenesis. ' 2007 Wiley-Liss, Inc.Key words: colon carcinogenesis; preneoplastic lesions; mucindepleted foci; colon proliferative activity Mucin-depleted foci (MDF) were recently described by our group as dysplastic lesions that occur in the colon of carcinogentreated rats and are easily recognizable in unsectioned colon as foci of crypts with defective mucous production.1 The number of MDF/colon increases in rats treated with promoters of colon carcinogenesis, such as cholic acid, while it is decreased by chemopreventive agents.1,2 MDF are induced dose-dependently by the specific colon carcinogen 1,2-dimethylhydrazine (DMH) and progressively increase in size after carcinogen administration.3 Recently, we showed that MDF carry alterations in the Wnt signaling pathway and mutations in the b-catenin gene, 3 2 characteristic phenomena in colon tumorigenesis.4 Therefore, MDF are suspected preneoplastic lesions.To obtain further data on the preneoplastic nature of MDF, we studied MDF in 2 different experimental settings in which DMHinitiated rats were treated with an inhibitor of colon carcinogenesis (polyethylene glycol, PEG), 5 or with a promoter (a high-fat diet). 6In the same rats, we also determined aberrant crypt foci (ACF), routinely used as an endpoint in short-term carcinogenesis studies. 5Since deregulation of the cell cycle is an important mechanism for uncontrolled growth in most preneoplastic lesions and cancers, we also studied the mitotic index (MI) in MDF and ACF and the expression of p27 and p16, 2 inhibitors of cyclin-dependent kinases (CKI).7 Progression through the cell cycle is regulated by cyclin-dependent kinases and their inhibitors, either the cip/kip family (p27) or the INK4 family (p16), which inhibit cyclin/cyclin kinase complexes and block the cell cycle.7 The CKI and MI studies were also carried out in ACF identified in the same rats. Moreover, since MDF have been so far described only in rats, we investigated whether similar lesions would be present in the colon of SWR/J mice treated with the specific colon carcinogen azoxymethane (AOM). Materials and methods1,2-Dimethylhydrazine (DMH) and azoxymethane (AOM) were o...

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Section: Discussionmentioning

confidence: 67%

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Femia

Caderni

Bottini

et al. 2007

Intl Journal of Cancer

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“…Poloxamer 407 halved the number of ACF but Pluronic L64 and NP30 had little effect. Poloxamer 181 also had little effect on the ACF number in the rats, as compared to controls (Parnaud et al 2001).…”

Section: Anticarcinogenicitymentioning

confidence: 84%

“…Also, 80% of the rats of the test group survived the 8-week trial period compared to 23% of the control group (Silk and Sigman 1972). Parnaud et al (2001) conducted in vivo studies on the effect of Poloxamer 188 on colon cancer in rats and mice. A total of 158 4-week-old F344 rats and OF1 mice were included in the studies.…”

Section: Anticarcinogenicitymentioning

confidence: 99%

Safety Assessment of Poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, Poloxamer 105 Benzoate, and Poloxamer 182 Dibenzoate as Used in Cosmetics

2008

Int J Toxicol

144

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Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multid...

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“…5 It has also been used as antiplatelet therapy in coronary angioplasty, 2,44 an antisludging agent in extracorporeal membrane oxygenators, 2,28,49 a soluble bone wax for hemostasis, 47 and as a suppressor of carcinogenesis in a rodent model of colon cancer. 33 The effects of poloxamer on excitable tissues have been mostly protective. Poloxamer 188 has been found to reduce neurological injury in a dog model of hypothermic circulatory arrest, 27 and to reduce tissue injury in a rabbit model of frostbite.…”

Section: Discussionmentioning

confidence: 99%

Surfactant poloxamer 188—related decreases in inflammation and tissue damage after experimental brain injury in rats

Curry¹,

Wright²,

Lee³

et al. 2004

Journal of Neurosurgery: Pediatrics

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Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice

Cited by 18 publications

References 12 publications

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Safety Assessment of Poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, Poloxamer 105 Benzoate, and Poloxamer 182 Dibenzoate as Used in Cosmetics

Surfactant poloxamer 188—related decreases in inflammation and tissue damage after experimental brain injury in rats

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