retinol-palmitate and Skin-Neoplasms

The 1925 classical observation that vitamin A deficiency leads to squamous metaplasia and epithelial keratinization, coupled with the later finding that excess vitamin A inhibits keratinization of chick embryo skin, set the foundation for the potential therapeutic use of retinoids in cutaneous conditions of keratinization. Significant progress has since been made understanding the molecular biology, biochemistry, pharmacology, and toxicology of vitamin A and its derivatives, collectively named retinoids. Natural and synthetic retinoids are now routinely used to treat acne, psoriasis, skin keratinization disorders, and photodamage. Retinoids also inhibit tumor formation and skin cancer development in experimental systems and in humans. Retinol and retinyl palmitate (RP) are found in cosmetic products and in foods and dietary supplements, which are all considered safe, by inclusion in the Generally Recognized as Safe Substances Database. However, the safety of topical retinoids was questioned in one publication and in a recent National Toxicology Program report of RP-containing topical preparations, suggesting the possible earlier onset of ultraviolet-induced squamous cell carcinomas in the hairless mouse photocarcinogenesis model. This suggestion contradicts a large body of data indicating that topical retinoids are chemoprotective in humans, and it was immediately challenged by new reviews on the safety of RP in general and within sunscreens. This paper will review the preclinical and clinical data supporting the safety and chemopreventive activity of retinoids, with an emphasis on RP, and will examine the experimental systems used to evaluate the safety of topical vitamin A preparations in order to provide perspective relative to human skin.

Topics: Administration, Cutaneous; Animals; Anticarcinogenic Agents; Disease Models, Animal; Diterpenes; Humans; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Retinoids; Retinyl Esters; Skin Neoplasms; Species Specificity; Ultraviolet Rays; Vitamin A

Two chemoprevention randomized clinical trials were begun in 1984 to evaluate retinoids in the prevention of skin cancers. Moderate risk subjects with a history of at least 10 actinic keratoses and at most two prior skin cancers were enrolled in the SKICAP-AK trial and randomized to 25,000 IU retinol or placebo daily for 5 years. High risk subjects with a history of at least four prior skin cancers were enrolled in the SKICAP-S/B trial and randomized to receive 25,000 IU retinol, 5-10 mg isotretinoin or placebo daily for 3 years. Data from the SKICAP-AK trial indicate that retinol reduces incidence of first new squamous cell skin cancers but had no effect on the incidence of first new basal cell skin cancer. The effect of retinoids had no significant benefit on squamous or basal cell skin cancers in the high risk subjects on the SKICAP-S/B trial, although intervention duration was less than planned. Daily retinol was effective in preventing squamous cell cancers in moderate risk subjects.

Topics: Aged; Anticarcinogenic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Female; Humans; Male; Middle Aged; Nevus; Retinoids; Retinyl Esters; Skin Neoplasms; Vitamin A

Cosmetic products that contain retinyl palmitate are popular as antiaging skin treatments; however, recent studies suggest a risk for enhanced skin tumor development with topical retinyl palmitate applications and exposure to solar ultraviolet radiation (UVR). In this study, we investigated the potential of retinyl palmitate to enhance UVR-induced photo-co-carcinogenesis. Groups of 36 male and 36 female SKH-1 hairless mice were exposed to simulated solar light (SSL) and treated with the control cream or creams containing retinyl palmitate, 5 days per week for 40 weeks. Other groups of mice were exposed to SSL and received no cream treatment or received cream treatments and were exposed to ultraviolet-A or ultraviolet-B. Mice were monitored for the development of skin tumors, and the incidences and multiplicities of squamous cell neoplasia were determined by histopathology. In both the absence and presence of SSL, mice administered the control cream developed skin tumors earlier and had higher incidences and multiplicities of skin squamous cell neoplasms than mice that received no cream treatment. Compared to the control cream groups, mice exposed to SSL and administered the retinyl palmitate creams demonstrated earlier onsets of skin tumors and had increased incidences and multiplicities of squamous cell skin neoplasms.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Cocarcinogenesis; Diterpenes; Female; Male; Mice, Hairless; Neoplasms, Radiation-Induced; Retinyl Esters; Skin Neoplasms; Sunlight; Ultraviolet Rays; Vitamin A

Topical retinoids, compounds that are metabolites, analogues, or derivatives of retinol and possess biological vitamin A activity, are among the most used adjunctive agents for the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of photodamaged and chronically aged skin. Retinoic acid (RA) is the most active biological form of vitamin A and remains the medical treatment of choice for photoaged skin. Retinyl palmitate (RP) is the major storage form of vitamin A in the skin and, because RP is also the most stable of available vitamin A esters, it is readily incorporated into the oil phase of cosmetic creams or lotions. Therefore, the topical application of RP is a practical strategy for increasing the levels of vitamin A in the skin. Usual cosmetic product concentrations of RA range from 0.025% to 0.1% and those of RP range from 0.1% to 5%. With a maximum absorbance around 325 nm, RA and RP absorb both ultraviolet A and B radiation (UVA and UVB) in incident sunlight. A 1-year study was conducted in mice to determine whether RA and RP would alter the photocarcinogenicity of broad-UV spectrum light generated by xenon arc lamps, termed simulated solar light (SSL), or narrow spectrum UV light generated by UVA and UVB lamps.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Carcinogenicity Tests; Carcinoma, Squamous Cell; Diterpenes; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred Strains; Mice, Nude; Retinyl Esters; Skin; Skin Neoplasms; Sunlight; Tretinoin; Vitamin A

Topics: Animals; Antioxidants; Disease Models, Animal; Diterpenes; Drug Approval; Humans; Mice; Retinyl Esters; Skin Neoplasms; Sunscreening Agents; United States; Vitamin A

Retinoids have been studied extensively for their chemopreventive properties. The biological activity of retinoids is acquired through their conversion to retinoic acid (RA). Characterization of endogenous circulating RA concentrations after supplementation with vitamin A over longer time periods has not been done previously. Our investigation was conducted to determine whether vitamin A (retinyl palmitate) supplementation significantly increases circulating RA concentrations of all-trans-, 9-cis-, and 13-cis-RA. Using plasma samples from 41 participants enrolled in a randomized clinical trial of placebo, 25,000, 50,000, or 75,000 IU supplemental retinyl palmitate daily, high-performance liquid chromatography analyses were conducted for concentrations of three RA isomers. Seven plasma samples were analyzed for each participant over a 16-month period. Based on an intention-to-treat analysis, results obtained using linear mixed models showed that supplementation with retinyl palmitate statistically significantly increased concentrations of all three RA isomers from baseline levels. This study suggests that supplementation with retinyl palmitate is an effective means to increase circulating all-trans, 9-cis-, and 13-cis-RA concentrations among humans.

Topics: Aged; Anticarcinogenic Agents; Chromatography, High Pressure Liquid; Diterpenes; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Retinyl Esters; Skin Neoplasms; Stereoisomerism; Tretinoin; Vitamin A

The construction of transgenic FVB/N mice targeting the PMLRARA fusion gene under the control of a human MRP8 promoter recapitulated the phenotype of acute promyelocytic leukemia but had the unexpected result of multiple squamous papillomas of the skin (Brown et al., PROC: Natl. Acad. Sci. USA, 94:2551-2556, 1997). In addition, transgenic MRP8-PMLRARA mice exhibited a skin phenotype characteristic of vitamin A deficiency. The severity of the skin phenotype and spontaneous papilloma development correlated with the level of transgene expression. Papilloma formation was preceded by follicular hyperplasia and the expression of epidermal differentiation markers in the follicular epithelium. Mutations in the Ha or Ki alleles of ras were not detected in papillomas that developed on transgenic skin, and papilloma formation was accentuated on the C57/Bl6 background, unlike the usual resistance of this strain to skin tumor induction. Analysis of liver extracts from transgenic mice indicated a deficiency in the production of retinoic acid. Furthermore, affected transgenic epidermis had reduced levels of retinoic acid receptoralpha (RARalpha) and retinoic X receptor (RXRalpha), and supplementation with exogenous retinoic acid prevented the skin phenotype. When transgenic keratinocytes were grafted to nude mice, the resulting integument was normal, and conversely, when transgenic bone marrow was grafted to normal mice, a skin phenotype did not develop. Together these results suggest that local interruption of PML and RARalpha signaling in the skin, together with a systemic retinoid deficiency, initiates a tumor induction pathway that is independent of ras activation.

Topics: Animals; Calgranulin A; Cell Differentiation; Diterpenes; Genes, ras; Genetic Predisposition to Disease; Hair Follicle; Humans; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neoplasm Proteins; Oncogene Proteins, Fusion; Papilloma; Promoter Regions, Genetic; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; Retinoids; Retinyl Esters; Skin Neoplasms; Transcription Factors; Transgenes; Tretinoin; Vitamin A

Our previous work has shown that dietary retinoic acid (RA) is necessary for skin tumor formation induced by the two-stage protocol with the initiator 7,12-dimethylbenz[a]anthracene (DMBA) and the promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA) (De Luca et al., Cancer Res., 36 (1976) 2334-2339). Here we report that retinoids are required for tumorigenesis by the two-stage as well as by the complete tumorigenesis protocol. Mice were treated with a single dose of DMBA (20 micrograms), followed by 20 applications of TPA (2 micrograms), or by 20 applications of DMBA (25 micrograms for 2 weeks and 51 micrograms thereafter). Regardless of the tumor induction protocol, tumor formation was inhibited by vitamin A-deficiency, while RA (3 micrograms/g of diet) or retinyl palmitate (RP, 6 micrograms/g) supplementation permitted the appearance of tumors. In addition, in comparison to the purified diets and regardless of their RA levels, the non-purified Purina chow diet enhanced tumor yield especially in the two-stage tumorigenesis protocol. This effect was less striking in mice with tumors induced by the complete tumorigenesis protocol. In summary, dietary retinoids are essential for skin tumor formation induced either by the two-stage or the complete tumorigenesis protocol.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Diet; Diterpenes; Female; Mice; Mice, Inbred Strains; Papilloma; Retinyl Esters; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Vitamin A; Vitamin A Deficiency

The effects of dietary supplementation with retinyl palmitate, canthaxanthin, or the combination of both, on photocarcinogenesis was determined in pigmented C3H/HeN mice. The basal diet was the American Institute of Nutrition Diet 76A, to which was added 120 IU of retinyl palmitate per g diet, 1% canthaxanthin, or the combination of both. Administration of the diets began 18 weeks before the first UVB radiation (280-320 nm) treatment and continued throughout the study. The UV source was a bank of 6 Westinghouse FS40 lamps which delivered to the mice a total dose of 9.9 x 10(5) J/m2, delivered over 24 weeks. These diets significantly reduced the tumor burden per mouse induced by UV irradiation, however they did not influence tumor incidence. The combination of retinyl palmitate plus canthaxanthin was more effective than either agent alone at reducing autochthonous tumor growth, a result which has not been previously reported.

Topics: Animals; Body Weight; Canthaxanthin; Carotenoids; Diterpenes; Drug Synergism; Drug Therapy, Combination; Female; Mice; Retinyl Esters; Skin; Skin Neoplasms; Ultraviolet Rays; Vitamin A

In view of the clinical trials of retinoids as therapeutic agents for premalignant skin lesions, a radiographic study was undertaken to measure skeletal toxicities after chronic dietary administration of retinoids in mice exposed to tumor initiation and promotion. CD-1 mice were initiated with 0.15 moles of 7,12-dimethylbenz[a]anthracene and promoted twice daily with 8 nmoles of 12-0-tetradecanoylphorbol-13-acetate for 23 weeks. Diets were supplemented with 60 IU, 200 IU, or 700 IU of retinyl palmitate (RP) per g diet. After 5 weeks, the 700 IU of RP /g diet was lowered to 350 IU/g diet. Administration of these diets to mice during the 23 weeks of tumor promotion resulted in a 0-fold, 2-fold, or 10-fold increase in bone fractures, respectively. Osteoporotic bone lesions identified on radiographs rose 0-fold, 0-fold, and 10-fold at the respective doses, whereas metaphyseal flares increased 0-fold, 1.4-fold, and 3.6-fold. Bone deformities were augmented 0-fold, 1.8-fold and 2.9-fold at the respective doses. Addition of selenium (2 ppm in the drinking water) did not alter the bone toxicity of RP. 13-cis-retinoic acid (CRA) was less toxic at 700 IU/g diet than was RP at that dose, as evidenced by the death of 12 of 70 mice by the 6th week of dietary RP and no deaths in the 35 mice fed 700 IU CRA/g diet for 23 weeks. CRA at 700 IU/g diet resulted in 3/4 as many osteoporotic bones, 1/3 as many bone fractures, 4/5 as many metaphyseal flares, and a similar number of bone deformities as mice fed 700/350 IU/g diet. At the dose of 200 IU/g food, osteotoxicities were similar in the mice fed diets supplemented with RP and CRA. Thus, the light dose of CRA (700 IU/g diet) was less toxic than the high dose of, RP but at a lower dose (200 IU/g), CRA was as osteotoxic as was RP. Bone fractures in mice exposed to prolonged dietary administration of retinoids was a more sensitive index of retinoid toxicity than was body weight. We have detected osteotoxicity in mice at a total dose of CRA which was about twice the total dose used clinically.

Topics: Administration, Oral; Animals; Bone and Bones; Bone Diseases; Carcinogens; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred Strains; Osteoporosis; Retinyl Esters; Selenium; Skin Neoplasms; Tretinoin; Vitamin A

The present study was designed to determine the effects of dietary 13-cis-retinoic acid and retinyl palmitate on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). Female CD-1 mice were initiated with 150 nmol of 7,12-dimethylbenz(a)anthracene and promoted twice weekly with 8 nmol of TPA. Diets supplemented with retinyl palmitate to yield 60,000 or 200,000 IU or 700,000 for 5 wk followed by 350,000 IU per kg of diet (700,000/350,000) fed to mice during tumor promotion resulted in 9%, 37%, and 65% inhibition of the papilloma yield, respectively, at 21 wk of promotion. Although topical applications of 13-cis-retinoic acid have been almost as effective as retinoic acid in preventing the appearance of mouse skin tumors, dietary 13-cis-retinoic acid at 200,000 or 700,000 IU per kg of diet resulted in no reduction in papilloma yield but did result in a dose-dependent decrease in the tumor burden (weight of tumors per mouse). Therefore, dietary retinyl palmitate yielded a dose-dependent inhibition of the number and weight of tumors promoted by TPA, whereas dietary 13-cis-retinoic acid resulted in a decrease in weight but not in number of tumors promoted by TPA.

Topics: Administration, Cutaneous; Animals; Cell Transformation, Neoplastic; Diet; Diterpenes; Dose-Response Relationship, Drug; Female; Isotretinoin; Mice; Papilloma; Retinyl Esters; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin; Vitamin A

Two retinoids (13-cis-retinoic acid and retinyl palmitate ) have been shown to exert a good preventive effect in chemically induced papillomas and carcinomas of the skin in female Swiss mice; this effect was investigated over a period of 23 weeks. The tumors were induced by repeated topical application of 3-methylcholanthrene (0.3% MCA, dissolved in acetone; 14 applications). Retinyl palmitate (RP; 6 mg in 0.1 ml acetone/mouse; 10 applications) and 13-cis-retinoic acid (RA; 3 mg in 0.1 ml acetone/mouse; 10 applications) were also administered topically for the 3rd to 9th week from the start of the experiment. This investigation gave evidence for the fact that both the retinoids did not only inhibit the development of skin papillomas but had also a marked effect on skin carcinomas.

Topics: Animals; Diterpenes; Isotretinoin; Methylcholanthrene; Mice; Papilloma; Retinyl Esters; Skin Neoplasms; Tretinoin; Vitamin A

Investigation of retinoids for anticancer activity in humans, either in the chemopreventive or treatment mode, has been little studied. We summarize here our ongoing investigations in four different areas: (1) secondary prevention of cervical dysplasia with topical application of all-trans-retinoic acid; (2) adjuvant treatment of resected high-risk stage I and II malignant melanoma with bacille Calmette Guérin (BCG) plus or minus oral vitamin A; (3) topical vitamin A acid therapy for cutaneous metastatic melanoma; an (4) oral isotretinoin as an anticancer agent.

Topics: Diterpenes; Female; Humans; Isomerism; Isotretinoin; Melanoma; Neoplasms; Palmitates; Retinyl Esters; Skin Neoplasms; Tretinoin; Uterine Cervical Dysplasia; Vitamin A

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; BCG Vaccine; Benz(a)Anthracenes; Diterpenes; Drug Evaluation, Preclinical; Drug Therapy, Combination; Male; Mice; Neoplasms, Experimental; Palmitates; Retinyl Esters; Skin Neoplasms; Vitamin A

The preneoplastic skin changes usually induced by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) to adult rat skin did not appear when animals were treated locally with depot im injections of high doses of retinyl palmitate (RP) prior to exposure to the carcinogen. The epidermal histology after RP-DMBA treatment was similar to that seen in areas exposed to RP alone. Keratinization was inhibited but there was no cellular atypia, evidence of cell injury, or mucous metaplasia. Other features were hyperplasia with acanthosis and thickened stratum granulosum, parakeratosis, intercellular edema, and loss of hair overlying the injection site. Ultrastructurally, the epidermal cells contained conspicuously fewer tonofibrils and increased dense chromatin, when compared to control cells. Skin changes observed following treatment of littermates with DMBA alone included the appearance of giant tumor cells, dyskeratotic cells, nuclear hyperchromatism, increased nucleocytoplasmic ratio, and pleomorphic nuclei and nucleoli. oss of desmosomes, increased tonofibrils, and defects in the basement membrane with epithelial projections into the dermis were also seen. These preneoplastic changes did not regress when application with DMBA was discontinued after 6 weeks; exposure to the carcinogen for longer than 6 weeks resulted in an exacerbation of the abnormal state. RP had profound effects on rat epidermis that interfered with the effects of a potent skin carcinogen. The mechanisms underlying the phenomenon have not been defined. The use of depot injections of the vitamin which avoids both systemic toxicity and the local irritation seen with topical exposure could serve as a model in which the anticarcinogenesis properties of retinoids could be explored.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Benz(a)Anthracenes; Diterpenes; Drug Administration Schedule; Injections, Intramuscular; Male; Neoplasms, Experimental; Palmitates; Precancerous Conditions; Rats; Retinyl Esters; Skin; Skin Neoplasms; Vitamin A