tretinoin and Carcinoma--Papillary

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates the active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular lactating mammary gland. Because of its crucial role in the ability of thyroid follicular cells to trap iodide, cloning of NIS opened an exciting and extensive new field of thyroid-related research. Cloning and molecular characterization of NIS allowed investigation of its expression and regulation in thyroidal and nonthyroidal tissues, and its potential pathophysiological and therapeutic implications in benign and malignant thyroid disease. In addition to its key function in thyroid physiology, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as effective therapeutic application of radioiodine in benign and malignant thyroid disease. Characterization and application of NIS as a novel therapeutic gene and the presence of high native NIS expression in the majority of breast cancers further suggest a promising role of NIS in diagnosis and therapy of cancer outside the thyroid gland.

Topics: Biological Transport, Active; Breast; Breast Neoplasms; Carcinoma, Papillary; Carcinoma, Papillary, Follicular; Female; Genetic Therapy; Humans; Iodine; Lactation; Male; Mutation; Prostatic Neoplasms; Symporters; Thyroid Diseases; Thyroid Gland; Thyroid Neoplasms; Thyroiditis, Autoimmune; Tretinoin

Topics: Animals; Antineoplastic Agents; beta Carotene; Butylhydroxybutylnitrosamine; Carcinoma in Situ; Carcinoma, Papillary; Carotenoids; Cell Differentiation; Dose-Response Relationship, Drug; Epithelium; Fenretinide; Humans; Isotretinoin; Neoplasms; Neoplasms, Experimental; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

The collaborative group chemotherapy studies of the National Bladder Cancer Project are summarized with regard to intravesical and systemic agents. The necessity for longitudinal observations and data collection in all cases of bladder cancer, and not just those receiving chemotherapy, is also stressed.

Topics: Adult; Aminoacridines; Amsacrine; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Papillary; Cisplatin; Clinical Trials as Topic; Drug Evaluation; Humans; Isotretinoin; Mitomycin; Mitomycins; Multi-Institutional Systems; Neoplasm Recurrence, Local; Thiotepa; Tretinoin; Urinary Bladder Neoplasms

Retinoids have shown potential for the inhibition of tumour growth and progression. The objective of this study was to investigate retinoic acid nuclear receptor subtypes RAR/RXR and iodothyronine 5'-deiodinase, type I expression pattern in papillary thyroid tumour tissue of 26 patients in order to compare with those of the non-neoplastic thyroid tissue of the corresponding patients. The expression of selected parameters mRNA was examined by semi-quantitative RT-PCR. Papillary thyroid carcinoma (PTC) expressed RXRγ, when compared to non-neoplastic thyroid tissues of the corresponding patients that were lacking expression of RXRγ or its expression was very low. Moreover, we found significantly increased expression of RARα and RARγ in the overall group of PTC. This increase was detected in cases with positive lymph node metastasis (LNM), but not in cases with negative LNM. RARβ was significantly reduced in the subgroup of classic variant (CV). We also detected absence or significantly lower expression of hDIO1 mRNA in tumour tissue when compared to non-neoplastic tissue in both overall PTC cases and in the CV subgroup. However, the significantly decreased levels of hDIO1 mRNA were detected in cases with negative LNM but not in cases with positive LNM when compared to corresponding non-tumour tissue in both overall PTC cases and in the CV subgroup. Differences in RAR and RXR subtype mRNA expression patterns in various PTCs may contribute to the immunochemistry data available, and may thus find exploitation in clinical oncology, particularly in the differential diagnosis of thyroid neoplasms.

Topics: Adult; Aged; Carcinoma; Carcinoma, Papillary; Diagnosis, Differential; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Male; Middle Aged; Neoplasm Metastasis; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptor gamma; Retinoid X Receptors; RNA, Messenger; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tretinoin

The aim of this study was to assess the clinical outcome of redifferentiation therapy using retinoic acid (RA) in combination with 131I therapy, and to identify biological parameters that predict therapeutic response in Korean patients with radioiodine-refractory papillary thyroid carcinoma (PTC).. A total of 47 patients (13 men, 34 women; age 54.2±13.6 years) with radioiodine-refractory PTC underwent therapy consisting of consecutive treatment with 131I and RA. Each 131I/RA treatment cycle involved the administration of oral isotretinoin for 6 weeks at 1-1.5 mg/kg daily followed by a single oral dose of 131I (range 5.5-16.7 GBq). Therapeutic responses were determined using serum thyroglobulin (Tg) levels and the change in tumour size 6 months after completing the 131I/RA therapy. Biological parameters and pathological parameters before and after combined therapy were compared.. After completing 131I/RA therapy, 1 patient showed a complete response, 9 partial response, 9 stable disease, and 28 progressive disease, representing an overall response rate of 21.3%. Univariate analysis revealed that an age of <45 years and a persistently high serum Tg level were related to a good response. No clinical response was achieved when metastases showing no iodine uptake were present. Multivariate regression analysis showed that an age of <45 years was significantly associated with a good response. Of the 24 patients with well-differentiated carcinoma, 5 (20.8%) responded to 131I/RA therapy, whereas all 6 patients with poorly differentiated carcinoma failed to respond.. 131I/RA therapy was found to elicit a response rate of 21.3% among patients with radioiodine-refractory PTC, and an age of <45 years was found to be significantly associated with a good response.

Topics: Carcinoma; Carcinoma, Papillary; Combined Modality Therapy; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Republic of Korea; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Failure; Tretinoin

The effectiveness rate of all-trans-retinoic acid (RA) is only about 30% in the clinical application of inducing thyroid carcinoma differentiation. In addition, there are severe toxic side effects, which limit its clinical application. Phase I-III clinical studies have been conducted on the combined application of two or more kinds of inductors in tumors. Nevertheless, the combination of RA with histone deacetylase inhibitors is rarely reported. This article studied the effects of differentiation for papillary thyroid carcinoma and follicular thyroid carcinoma cell lines induced by RA combined with trichostatin A (TSA), enhancing the effect of induction, while reducing the toxic side effects of a single drug, to provide a theoretical basis for preclinical trials.. After incubation with RA combined with TSA, K1 and FTC-133 were grouped into Group 1 (RA 10(-4) mol/L plus TSA 1.65 x 10(-7) mol/L), Group 2 (RA 1 x 10(-4) mol/L plus TSA 3.31 x 10(-7) mol/L), Group 3 (RA 10(-5) mol/L plus TSA 1.65 x 10(-7) mol/L), Group 4 (RA 1 x10(-5) mol/L plus TSA 3.31 x 10(-7) mol/L) by four varied concentrations and three time points (12 h, 24 h, and 48 h). The cell proliferation, conformation, toxic effect, and induced differentiation on K1 and FTC-133 cell lines were studied microscopically with hematoxylin-eosin (HE) to observe cell quantity and morphology, methyl-thiazolyl-tetrazolium (MTT) to calculate cell survival rates, and electrochemiluminescence analysis measuring in vitro thyroglobulin (Tg) levels.. The research showed that K1 and FTC-133 cells had cell spacing increases, with an outer edge of smooth, nuclear chromatin condensation after RA combined TSA. Survival rate were assessed by an analysis of variance (ANOVA) by concentration and time point, F values of K1 and FTC-133 were 23.52 and 170.14, and 57.09 and 224.35, respectively. There were significant differences for both cells (P < 0.01). The SNK analysis indicated that survival rates were in the order of Group 2 < Group 1 < Group 4 < Group 3. Tg was also assessed by ANOVA, F values of K1 were 69.63 and 101.07, and F values of FTC-133 were 79.77 and 81.72 (P < 0.01). Group 1 was compared with Group 3 of K1 and FTC-133 by the least significant difference (LSD) method, and there was no statistical difference between the two group (P = 0.06, 0.2, respectively; P > 0.05), yet a significant difference was seen between the other Groups.. Lower concentrations of RA combined with lower concentrations of TSA have both inhibited cell proliferation, decreased toxicity of the drugs, and increased the effect of K1 and FTC-133 cell differentiation. The mechanism of action may be that TSA has pretranscription DNA regulation and that RA has posttranscriptional signal regulation to enhance the effects of inhibited proliferation and differentiation of cells by transcription systems.

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Apoptosis; Carcinoma; Carcinoma, Papillary; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Thyroglobulin; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tretinoin

A new human thyroid carcinoma cell line, KTC-1, was established from the malignant pleural effusion of a recurrent thyroid carcinoma patient. Cytogenetic analysis revealed a normal karyotype, and no p53 mutation in exons 5-9 was detected. This cell line is tumorigenic in athymic nude mice. Histological findings by light and electron microscopy, such as the absence of follicular structures and the existence of intranuclear cytoplasmic inclusions and psammoma bodies, indicated transplanted tumors to be a poorly differentiated papillary thyroid carcinoma. A low expression level of thyroglobulin was detected by immunocytochemistry and RT-PCR. Messenger ribonucleic acid (mRNA) expression of thyroid transcription factor-1 and PAX-8 was also detected. No mRNA expression of TSH receptors, thyroid peroxidase, or Na+/I- symporter was detected. Interleukin-6 and leukemia inhibitory factor were secreted into the medium. These findings suggest this cell line to be functionally poorly differentiated. Moreover, all-trans-retinoic acid increased the mRNA expression of thyroglobulin and decreased both the mRNA expression and secretion of interleukin-6 and leukemia inhibitory factor while significantly stimulating growth. RT-PCR analysis of retinoic acid receptors (RARs) revealed that KTC-1 cells express a moderate level of RARalpha and -gamma, but a low level of RARbeta. This cell line may be useful for studying redifferentiation therapy for thyroid carcinoma.

Topics: Animals; Carcinoma, Papillary; Cell Differentiation; Cell Division; Cytokines; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Genes, p53; Growth Inhibitors; Humans; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Mice; Mice, Nude; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Polymorphism, Single-Stranded Conformational; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Thyroid Nuclear Factor 1; Trans-Activators; Transcription Factors; Transcription, Genetic; Transplantation, Heterologous; Tretinoin; Tumor Cells, Cultured

NGF has anti-proliferative and anti-invasive effects in neuroendocrine tumors. In the present work we examined the effects of NGF and retinoic acid on cell proliferation and invasion in thyroid carcinoma cells. We found that NGF and retinoic acid do not affect cell proliferation on their own but in combination they produce a strong inhibition. We also found that retinoic acid regulates the matrix metalloproteinase 2 activity and invasion. In contrast, NGF inhibited invasion and reverted the effect of retinoic acid. This effect of NGF is likely mediated by an increase in adhesion to laminin and collagen IV and the inhibition of cell migration. NGF also induced the expression of the p75 NGF receptor. In conclusion, NGF and retinoic acid in combination inhibit proliferation and invasion of thyroid papillary carcinoma cells. These data open the possibility of a potential combined therapy for thyroid papillary carcinomas.

Topics: Antineoplastic Agents; Carcinoma, Papillary; Cell Adhesion; Cell Division; Cell Movement; Humans; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Nerve Growth Factor; Receptor, Nerve Growth Factor; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

The present study reports light and electron microscopic observations of hamster cheek pouch epithelium exposed to 25 micrograms DMBA (DMBA = 9,10 Dimethyl, 1,2 Benz(a)-nthracene, RA = Retinoic Acid) and 25 micrograms DMBA along with 25 micrograms, 50 micrograms and 100 micrograms retinoic acid. Significant delay in tumour induction was observed in the animals treated with DMBA + retinoic acid. DMBA + retinoic acid treated cheek pouch developed papillary epidermoid carcinomas which were less invasive and less keratinized than only DMBA treated animals. At cellular level DMBA treated animals showed keratinized cells with thick bundles of tonofilaments, broken basement membrane, wide intercellular spaces and loss of desmosomal attachments, whereas animals treated with DMBA + retinoic acid showed decrease in the intercellular spaces, maintenance of basement membrane and intracellular organelles with suppression of keratinization, indicating the differentiating effect of retinoic acid on DMBA transformed cells of hamster cheek pouch.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cell Nucleus; Cell Transformation, Neoplastic; Cheek; Cricetinae; Cytoplasm; Epithelium; Female; Male; Mesocricetus; Microscopy, Electron; Mouth Mucosa; Mouth Neoplasms; Neoplasm Invasiveness; Tretinoin

A 59-year-old woman with a history of papillary carcinoma of the thyroid gland developed three reddish nodules on the scalp. A skin biopsy showed a dermal tumor composed of sheets of clearly differentiated thyroid vesicles. Cutaneous metastases of thyroid carcinoma are very rare and this case is the first case confirmed by immunoperoxidase studies using monoclonal antithyroglobulin antibody. Positive reactions were obtained in colloid and at apices of thyrocytes. Monoclonal antibodies to human thyroglobulin may offer a unique opportunity to confirm the tissue origin of cutaneous metastasis.

Topics: Acitretin; Antibodies, Monoclonal; Carcinoma, Papillary; Female; Humans; Immunoenzyme Techniques; Immunohistochemistry; Middle Aged; Skin Neoplasms; Thyroglobulin; Thyroid Neoplasms; Tretinoin

The cellular content of receptors for retinol (CRBP) and retinoic acid (CRABP) was measured in 148 human mammary carcinomas. High levels of CRABP were found in lobular carcinomas while those of the papillary subgroup had low levels of the receptor. Intermediate values for CRABP were observed for ductal, colloid and medullar carcinomas. The cellular levels of CRBP were high in ductal carcinomas and low in papillar carcinomas. A positive correlation was observed between the receptor for estradiol and CRABP. However, no significant correlation was found between the tumor cell DNA pattern and the content of CRABP and CRBP respectively. Recurrence of disease could be predicted by the nodal status and the level of estradiol receptor while the DNA pattern and the content of receptors for retinoic acid and retinol failed.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Breast Neoplasms; Carcinoma; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; Carrier Proteins; DNA, Neoplasm; Female; Humans; Middle Aged; Neoplasm Proteins; Receptors, Cell Surface; Receptors, Estrogen; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Tretinoin

Sixty-four male and female Syrian hamsters, 3 months of age and weighing 90 to 120 grams, were divided into four equal experimental groups. In animals of Groups 1 and 2 the right posterior lateral border of the tongue was painted three times weekly with a 0.5 percent solution of DMBA in acetone. Group 2 animals also received 10 mg. of 13-cis-retinoic acid in peanut oil administered orally twice weekly by pipette. Carcinogen and retinoid were administered on alternate days. Group 3 animals received only 13-cis-retinoic acid. Group 4 animals served as untreated controls. Four animals in each group were killed at 12, 14, 16, and 18 weeks. The Group 2 animals, receiving 13-cis-retinoic acid, exhibited a significant delay in the development of lingual tumors, both grossly and microscopically. At 14 weeks carcinomas were found in the DMBA animals, but only dysplasia and areas of carcinoma in situ were found in the DMBA-retinoid animals. After 18 weeks the DMBA animals exhibited large lingual tumors with surfacenecrosis, while the DMBA-retinoid animals presented smaller tumors with less invasion of underlying tissue.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cricetinae; Female; Isotretinoin; Leukoplakia, Oral; Male; Mesocricetus; Neoplasms, Experimental; Tongue; Tongue Neoplasms; Tretinoin

Sixty-four male and female Syrian hamsters, 3 months of age and weighing 90 to 120 grams, were divided into four equal experimental groups. In animals of Groups 1 and 2 the left buccal pouch was painted three times weekly with a 0.5% solution of DMBA in heavy mineral oil. Group 2 animals also received 10 mg. of 13-cis-retinoic acid in peanut oil administered orally twice a week by pipette. Carcinogen retinoid were administered on alternate days. Group 3 animals served as controls, receiving only 13-cis-retinoic acid. Group 4 animals served as untreated controls. Four animals in each group (two males and two females) were killed at 10, 12, 14, and 16 weeks. The Group 2 animals, which received 13-cis-retinoic acid, exhibited a significant delay in DMBA carcinogenesis of buccal pouch mucosa, as studied both grossly and histologically. Both groups eventually demonstrated well-differentiated epidermoid carcinomas, but the tumors were smaller in the DMBA-retinoid animals.

Topics: Animals; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cheek; Cricetinae; Female; Isotretinoin; Keratosis; Leukoplakia, Oral; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasms, Experimental; Tretinoin