retinol-acetate and Precancerous-Conditions

A Phase I-II clinical trial has been conducted with a retinyl acetate (RA) gel applied cervicovaginally in women having a histopathologic lesion diagnosed as mild or moderate dysplasia. With informed consent, volunteer subjects were observed and followed with Pap smears and colposcopy in a standardized protocol involving a self-administered 7-day treatment course for three successive menstrual cycles. Varying dosages of RA including placebo, 3, 6, 9, and 18 mg per 6 g of an inert vehicle were employed. A total of 50 subjects were monitored for local and systemic side effects. No intolerable side effects or disturbing toxicity was reported or detected at any of these doses. With the 18-mg dosage, significant discomfort was reported by all women. Despite associated side effects and a considerable patient effort involved in carrying out the self-administration of the gel, a high level of compliance was achieved in this trial. It has been established that women will voluntarily participate in an intervention clinical trial to determine whether retinyl acetate is an alternative method of therapy of presumed precancerous lesions of the cervix. The analysis of the side effects of the gel at the various dosage concentrations favors the selection of the 9-mg dosage for a multicenter Phase III clinical trial to determine efficacy.

Topics: Colposcopy; Diterpenes; Drug Administration Schedule; Drug Evaluation; Female; Gels; Humans; Pain; Papanicolaou Test; Patient Compliance; Placebos; Precancerous Conditions; Pruritus; Retinyl Esters; Uterine Cervical Neoplasms; Vaginal Smears; Vaginitis; Vitamin A; Vulvitis

Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-Apc(Min)/J (Apc(Min)) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.

Topics: Adenomatous Polyposis Coli Protein; Animals; Apoptosis; beta Catenin; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Proliferation; Colorectal Neoplasms; Diterpenes; Gene Expression Regulation; Genes, APC; Humans; Intestinal Polyps; Mice; Mice, Inbred C57BL; Precancerous Conditions; Proto-Oncogene Proteins c-myc; Receptors, TNF-Related Apoptosis-Inducing Ligand; Retinyl Esters; Signal Transduction; Survival Rate; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Vitamin A

To determine the chemotherapeutic effect of retinoids on albino mouse skin.. Eighty albino mice were selected for this study and were divided into four groups (A-D, 20 mice in each group). 7,12-Dimethylbenz(a)anthracene (DMBA) and tetradecanoylphorbal-13-acetate (TPA) were given for 15 weeks to produce tumors. Retinoids were given topically and orally after the development of tumors for the following 15 weeks.. Of the 80 mice, 69 (86.25%) developed different types of lesion and 11 (13.75%) remained lesion free. Of the 69 mice that developed lesions, 50 (62.50%) developed benign lesions and 19 (23.75%) developed malignant lesions. In all groups of mice, treatment with retinoids was effective against all benign lesions and the early stages of carcinogenesis of the skin. The chemotherapeutic effect against malignant tumors was not satisfactory.. This study demonstrates that retinoids are effective as chemopreventive agents in premalignant lesions of the skin, but have a very weak chemotherapeutic role in malignant neoplasms. If retinoids are given at an early stage, they can cause regression of premalignant lesions of the skin. They are best administered both orally and parenterally. These agents should be recommended as they reduce the potential effects of carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Diterpenes; Isotretinoin; Mice; Precancerous Conditions; Retinyl Esters; Skin Neoplasms; Tetradecanoylphorbol Acetate; Vitamin A

1. Retinyl acetate protected female rats from the hepatocarcinogenic effect of 0.06% 3'-Me-DAB up to 18 weeks. 2. The net effect of retinyl acetate was to retard, not prevent, the action of the hepatocarcinogen since the protection broke down prior to the 30 week time point. 3. The observed elevation of serum LSA by retinyl acetate was unexpected and suggested that some of the difficulties found in its use as a tumor marker may be due to dietary factors. 4. The time necessary for development of preneoplastic lesions in the rats fed 0.01% 3'-Me-DAB was 71 vs 8 weeks for those fed 0.06% 3'-Me-DAB. 5. The effect of retinyl acetate on the lower level of 3'-Me-DAB was to prevent formation of nodules through 71 weeks by which time the unprotected rats fed 0.01% 3'-Me-DAB alone had extensive hepatic nodular development.

Topics: Adenylosuccinate Lyase; Animals; Diterpenes; Female; gamma-Glutamyltransferase; Liver; Liver Neoplasms, Experimental; Methyldimethylaminoazobenzene; N-Acetylneuraminic Acid; p-Dimethylaminoazobenzene; Precancerous Conditions; Rats; Rats, Inbred Strains; Retinyl Esters; Sialic Acids; Time Factors; Vitamin A

The administration of a 250-ppm retinyl acetate dietary supplement for various periods relative to intragastric administration of 50 mg benzo[a]pyrene (BP) significantly inhibited the induction of mammary cancers in virgin female inbred LEW/Mai rats. with day of BP administration taken as time 0, groups receiving the retinoid from weeks -2 to +1, +1 to +90, +20 to +90, and -2 to +90 showed a significant reduction in tumor response as compared to controls. The inhibition of carcinogenesis achieved by a +1 to +20 administration schedule was temporary; the tumor yield was suppressed initially but returned to control levels by week 60. Autoradiographic analysis of mammary glands from 50-day-old rats indicated that a 2-week exposure to supplemental retinyl acetate significantly reduced the mammary gland parenchymal cell labeling index in ductal, alveolar, and terminal end bud structures. Beginning the retinyl acetate supplement 1 week after the administration of BP significantly reduced the number of terminal ductal hyperplasias. The inhibition of carcinogenesis achieved by a short period of retinyl acetate administration before and during the period of carcinogen availability as well as the inhibition achieved by long-term postcarcinogen retinoid exposure may involve an antiproliferative effect on the rat mammary gland.

Topics: Animals; Benzopyrenes; Body Weight; Cell Division; Diet; Diterpenes; Female; Hyperplasia; Intubation, Gastrointestinal; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Lew; Retinyl Esters; Vitamin A

The effect of retinoids on DNA synthesis was studied in the female Sprague-Dawley rat. Animals were treated with either solvent, 7,12-dimethylbenz(a)anthracene, or 1-methyl-1-nitro-sourea at 50 days of age and were placed on either placebo or retinyl acetate diet at 57 days of age. [3H]Thymidine incorporation into purified DNA isolated from mammary parenchymal cells was determined. Retinyl acetate effectively inhibited mammary cell DNA synthesis in both 1-methyl-1-nitrosourea- and 7,12-dimethylbenz(a)anthracene-treated animals; however, DNA synthesis in solvent-treated animals was unaffected.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Diterpenes; DNA, Neoplasm; Female; Mammary Neoplasms, Experimental; Methylnitrosourea; Precancerous Conditions; Rats; Retinyl Esters; Vitamin A

The cell-differentiating agents (inducers) dimethylacetamide, dimethylurea and tetramethylurea significantly lowered the yields and/or incidences of total tumors, benign plaques, benign hyperkeratotic lesions and advanced tumors promoted by retinyl acetate or croton oil after initiation by 7,12-dimethylbenz(a)anthracene. The percentage of plaques was increased by the inducers suggesting that they inhibited progression of plaques to more advanced tumors. These results suggest that topical application of inducers might have therapeutic potential in epidermal carcinoma.

Topics: Acetamides; Animals; Cell Differentiation; Cricetinae; Croton Oil; Diterpenes; Female; Mesocricetus; Methylurea Compounds; Neoplasms, Experimental; Precancerous Conditions; Retinyl Esters; Skin Neoplasms; Vitamin A