tretinoin and Tongue-Neoplasms

All trans retinoic acid (ATRA) is used as standard of care in promyelocytic leukemia. Not much is known about the gene expression profile in ATRA-treated tongue cancer cells. We performed a genome-wide transcriptional profiling of ATRA-treated tongue cancer cells to understand the pathways that mediate ATRA action in tongue cancer.. We measured the effects of ATRA on the proliferation of SCC-9 human tongue carcinoma cells. The differential gene expression profile was measured by microarray analysis of untreated and ATRA-treated cells and expression of key genes was validated by real-time RT-PCR.. ATRA treatment (24 and 48 hr) significantly inhibited SCC-9 cell proliferation in a dose-dependent manner. SCC-9 cells treated for 48 hr with ATRA showed upregulation of 276 genes, including ANGPTL4, GDF15, ICAM1 and TUSC4, and downregulation of 43 genes, including CXCL10. Validation by real-time PCR showed a significant upregulation of intracellular adhesion molecule 1 (ICAM1) and downregulation of CXCL10 and IL32.. ATRA had an anti-tumor effect in tongue cancer cells. This effect is likely mediated via upregulation of ICAM1 and downregulation of CXCL10 and IL32.

Topics: Antineoplastic Agents; Case-Control Studies; Chemokine CXCL10; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study; Humans; Intercellular Adhesion Molecule-1; Interleukins; Linear Models; Oligonucleotide Array Sequence Analysis; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured

Topics: Aged; Antineoplastic Agents; Carcinoma, Verrucous; Female; Follow-Up Studies; Humans; Laser Therapy; Lasers, Gas; Leukoplakia, Oral; Neoplasms, Second Primary; Tongue Neoplasms; Tretinoin; Wound Healing

Retinoids are known to suppress carcinogenesis in various epithelial tissues. Among them, all-trans-retinoic acid (atRA) is recognized as one such active retinoid. However, despite the known anticarcinogenic activity of atRA, it exhibits its short plasma half-life during repeated oral administration due to the "acute retinoid resistance" in the liver. This has been the major limitation in clinical applications of atRA. Therefore, in order to render atRA more suitable for clinical uses, sustained delivery of atRA using biodegradable microspheres is suggested in this study. When 50 mg atRA/kg of atRA-loaded microspheres were subcutaneously administered to rats once, the atRA concentration in plasma was maintained around 6.5 ng/ml for 7 weeks, with only minor signs of toxicity. When the chemopreventive efficacy of atRA-loaded microspheres was evaluated using a model of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in F344 rats, a single injection of atRA-loaded microspheres significantly suppressed oral carcinogenesis. Additional injections of atRA-loaded microspheres, however, did not indicate further suppression of carcinogenesis.

Topics: 4-Nitroquinoline-1-oxide; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Male; Microspheres; Mouth Neoplasms; Neoplasms, Experimental; Palatal Neoplasms; Polyesters; Polyethylene Glycols; Precancerous Conditions; Rats; Rats, Inbred F344; Solubility; Tongue Neoplasms; Tretinoin

All-trans retinoic acid (atRA) is one of the most potential chemopreventive agents for head and neck squamous cell carcinoma (HNSCC). However, the induced metabolism of atRA by cytochrome P450s in the liver limits its clinical applications. To overcome such limitation, we had developed atRA-loaded microspheres designed to release atRA for a long period. Unfortunately, the atRA-loaded microspheres severely induced inflammatory responses: that is, atRA released from the microspheres significantly induced the proliferation of fibroblasts and collagen deposition, thereby causing a permeability barrier for drugs from entering the blood stream. In the present study, the effects of celecoxib as an anti-inflammatory drug are investigated when it is concurrently used with atRA-loaded microspheres to treat 4-NQO-induced oral carcinogenesis. We investigated if it might influence the plasma concentration of atRA and its metabolism by preventing the fibroblast proliferation and collagen deposition, reduce the toxicity level of atRA, and improve the chemopreventive efficacy of atRA-loaded microspheres. The concurrently administered celecoxib prevented inflammatory responses and suppressed the number of fibroblasts and collagen deposition in the fibrous capsules for 14 days. The atRA concentration in plasma was also increased and the metabolism of atRA was significantly decreased within 2 weeks. In the 4-NQO-induced oral carcinogenesis study, the incidence of invasive SCC was above 44% when F344 rats were treated with atRA-loaded microspheres. However, the treatment using atRA-loaded microspheres and celecoxib concurrently could reduce the incidence of invasive SCC up to 28%, and three of 25 rats were found to have no tongue lesions. In conclusion, the concurrent use of celecoxib could maintain the atRA concentration in plasma at a higher level while reducing its metabolism by preventing inflammatory responses, thereby improving their chemopreventive effects against 4-NQO-induced oral carcinogenesis.

Topics: 4-Nitroquinoline-1-oxide; Animals; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Celecoxib; Cyclooxygenase Inhibitors; Delayed-Action Preparations; Drug Therapy, Combination; Female; Liposomes; Male; Pyrazoles; Quinolones; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Sulfonamides; Tongue Neoplasms; Tretinoin

Human telomerase, activated in about 90% of cancers, is mainly composed of hTR, hTERT and TP1. The exposed RNA template of hTR is an ideal target for antisense oligonucleotides (As-ODN); while recent findings indicate all-trans retinoid acid (ATRA) could effectively inhibit the expression of catalytic subunit-hTERT. The aim of this study was to investigate the effect of ATRA and As-ODN in oral squamous cell carcinoma and whether telomerase activity could be synergistically inhibited by them and thus therapeutically exploited in the future. As-ODN-hTR was transfected into human tongue squamous cell carcinoma cell line (Tca8113) with or without ATRA. Telomerase activity was examined by PCR-Elisa; viability was compared with growth curve; apoptotic rate was analyzed by Annexin V/PI double staining and hTERT expression was tested with western blot. Tca8113 cells displayed significant growth inhibition during the 9-day exposure to ATRA/As-ODN, especially to a combination of As-ODN-hTR and 5muM ATRA, correlating with the inhibition of telomerase expression. The relative telomerase activity was inhibited during treated with As-ODN-hTR alone, ATRA alone, or a combination of them. While without ATRA, the effect of As-ODN would disappear at 96h after transfection. As-ODN-hTR alone or combined with ATRA also significantly increase the apoptotic rate. Our findings provided direct evidence, in oral squamous cell carcinoma, As-ODN-hTR and ATRA could synergistically inhibit telomerase activity and telomerase protein in human tongue squamous cell carcinoma cells, which correlated with the induction of growth arrest.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; DNA-Binding Proteins; Down-Regulation; Genetic Therapy; Humans; Oligonucleotides, Antisense; Telomerase; Tongue Neoplasms; Transfection; Tretinoin

To investigate the receptor-related mechanism of retinoids inhibiting proliferation and inducing apoptosis of human oral squamous cell carcinoma cell line Tca8113.. The effects of 3 retinoids (namely 9-cis-RA, at-RA and 13-cis-RA), TTNPB (RAR agonist) and methoprene acid (Ma, RXR agonist) on proliferation and cell cycle of Tca8113 cells were analyzed by MTT assay and flow cytometry. The roles of these agents in inducing apoptosis of Tca8113 cells were also evaluated by detecting the expression of Bcl-2/Bax, TUNEL and active caspase-3 analysis.. Both retinoids and TTNPB could inhibit the proliferation of Tca8113 cells, and the effect of TTNPB was the most powerful in all the reagents, but MA had no such effect. At the concentration of 1 x 10(-5) mol/L, all the agents except for Ma could increase the percentage of G(1)/G(0)-stage cells after incubation of the cells for 24 h and 48 h. Retinoids and TTNPB could up-regulate the expression of Bax and down-regulate Bcl-2 expression. The results of TUNEL demonstrated that retinoids and TTNPB, but not Ma, could induce apoptosis of Tca8113 cells as compared with the control group (P<0.05). Except for Ma, all the agents up-regulated caspase-3 expression, and the effect of TTNPB was the strongest (P<0.05).. Retinoids can suppress the proliferation of and induce apoptosis of Tca8113 cells, the effect of which involves activation of RAR but not RXR. caspase-3 pathway is involved in apoptosis-inducing effects of retinoids.

Topics: Antineoplastic Agents; Apoptosis; Benzoates; Carcinoma, Squamous Cell; Cell Line, Tumor; Humans; Receptors, Retinoic Acid; Retinoids; Tongue Neoplasms; Tretinoin

To investigate the effects of ATRA, acitretin and tazarotene on the growth and apoptosis of human tongue squamous cell carcinoma cell line Tca8113. The effect of retinoids on growth of Tca8113 cells in vitro was examined by MTT assay and Trypan blue exclusion assay. Cell cycle analysis, early apoptosis analysis with double staining with Annexin V-FITC and PI, and active caspase-3 analysis with the staining of FITC-conjugated monoclonal rabbit anti-active caspase-3 antibody were made by flow cytometer. Streptavidin-biotin complex (SABC) immunocytochemical assays were employed for the detections of Bax/Bcl-2 proteins expressions. Our results showed that the retinoids inhibited growth of Tca8113 cells in a dose- and time-dependent manner with maximal inhibition 24 h after treatment of 10(-5) mol/L. 10(-5) mol/L retinoids altered cell cycle distribution of Tca8113 cells, revealing an increase in G0/G1-phase population, a decrease in S-phase population and the inhibition of G1/S switching. 10(-5) mol/L retinoids significantly induced apoptosis of Tca8113 cells (all P < 0.05), elevated the cells population with detectable active caspase-3 (P < 0.05 for all), increased the number of cells forming Bax and decreased the number of cells forming Bcl-2 significantly (all P < 0.05). Acitretin played a most prominent role among the retinoids. It is concluded that the inhibition of cell cycle progress of Tca8113 cells by ATRA, acitretin and tazarotene is one of the possible mechanisms for proliferation arrest of Tca8113 cells elicited by the retinoids. The retinoids mediate apoptosis in Tca8113 cells that may be caspase-dependent through mitochondria pathway. High concentration retinoids inhibit growth of Tca8113 cells in vitro by interfering with proliferation and inducing apoptosis of cells. Acitretin may be an alternative medicine for the prevention and treatment of tongue squamous cell carcinoma.

Topics: Acitretin; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Humans; Nicotinic Acids; Tongue Neoplasms; Tretinoin

To investigate the augmentation effect and mechanism of all-trans retinoic acid (ATRA) on the bystander effect of herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system in the treatment of tongue carcinoma cell line.. Immunocytochemistry and flow cytometry (FCM) were used to analyze the expression of Cx43 protein in Tca8113 cells after treated with ATRA; The bystander effect of HSV-TK/GCV system on tongue carcinoma cells before and after treatment with ATRA was detected by MTT assays. The interaction of ATRA and bystander effect was analyzed by factorial experiment.. After treated by ATRA (10(-7) mol/L - 10(-5) mol/L), the expression of Cx43 protein was up-regulated in Tca8113 cells and the positive rate of Cx43 protein increased from 5.17% (before treatment) to 30.53% (10(-5) mol/L ATRA). There was significant difference between ATRA treated cells and untreated cells (P < 0.01). The bystander effect of HSV-TK/GCV system on Tca8113 cells was poor, but improved after combined with ATRA. There was cooperation effect between ATRA and bystander effect of HSV-TK/GCV (P < 0.05).. ATRA can augment the bystander effect of HSV-TK/GCV system in the treatment of tongue carcinoma cell line. The mechanism might be due to up-regulation of Cx43 gene and restore gap junction intercellular communication.

Topics: Antineoplastic Agents; Bystander Effect; Cell Survival; Connexin 43; Dose-Response Relationship, Drug; Drug Synergism; Ganciclovir; Humans; Simplexvirus; Thymidine Kinase; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured

While retinoids have been demonstrated to inhibit growth of many tumor cells, including SCC cells, the molecular mechanism by which retinoids suppress growth has not been elucidated. We previously found that the growth of SCC cells was significantly inhibited by all-trans-retinoic acid (all-trans-RA) treatment, and this inhibition was dependent on the binding and activation of RARs. These nuclear receptors bind retinoids and alter the rate of transcription of specific genes. To identify targets of the activated RARs which mediate growth inhibition, we growth arrested SCC-25 cells in G-0 and examined the effect of all-trans-RA on synchronized SCC-25 cells. All-trans-RA inhibited G-1 progression in quiescent SCC-25 cells stimulated by FBS. More specifically, we found that the all-trans-RA execution point maps to mid/late G-1, 6 to 10 h after stimulation. Using this synchronized cell system, we examined the expression of cell cycle regulatory genes in quiescent SCC-25 cells stimulated with FBS and treated with all-trans-RA. We found few changes in expression of these genes which could account for all-trans-RA inhibition of SCC-25 cell growth. In order to compare the patterns of expression of a wider selection of genes in all-trans-RA treated and non-treated SCC-25 cells, we have used expression array technology. We successfully performed expression profiling experiments on the Atlas Human cDNA arrays which contain 1176 human genes. We have identified several up-regulated and several down-regulated gene expression changes mediated by all-trans-RA treatment in synchronized SCC-25 cells. This novel information will be useful in defining the mechanism by which retinoids suppress the growth of SCC cells.

Topics: Aged; Animals; Carcinoma, Squamous Cell; Cattle; Cell Cycle; DNA, Complementary; Fetal Blood; G1 Phase; Gene Expression; Gene Expression Profiling; HSC70 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Male; Mitogen-Activated Protein Kinases; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sulfur Radioisotopes; Time Factors; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured

To study the induction of apoptosis by retinoid acid(RA) in Tca83 cell line and the expression of correlative Fas/FasL gene.. Apoptosis of Tca83 was detected by TUNEL, the expression of Fas/FasL-mRNA was detected by RT-PCR and cell immunohistochemical technique.. The cell apoptosis number of Tca83 in RA group was significantly higher than that in non-RA groupe on day 5(P < 0.05). The expression of Fas-mRNA in RA group was also much higher than that in non-RA group on day 5(P < 0.05), but the level of FasLmRNR had no change. Immunohistochemistry also showed, after RA treatment, the Fas stain was enhanced.. The result suggests that apoptosis induced by RA may be resulted from the enhancement of Fas gene transcription and translation.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Fas Ligand Protein; fas Receptor; Gene Expression Regulation, Neoplastic; Humans; In Situ Nick-End Labeling; Membrane Glycoproteins; Reverse Transcriptase Polymerase Chain Reaction; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured

To elucidate the chemosensitivity of human tongue squamous cell carcinoma Tca83 cell line to all-trans retinoid acid (RA) and to determine the potential genetic factors mediating this sensitivity.. RA in the amounts of 0.1, 1, and 10 microMol/L were used to treat human cell line Tca83 in vitro. Cell apoptosis as well as Fas/FasL expression were analyzed by TUNEL, RT-PCR, and immunohistochemistry approaches.. RA in the amounts of 1 and 10 microMol/L RA began to inhibit cell proliferation at day 3 and had induced cell apoptosis on day 5. Both Fas and FasL could be detected in the treated and untreated cells. RA upregulated Fas mRNA and protein expression at day 5. RA had no obvious effect on FasL expression.. The results suggest that apoptosis induced by RA may result from the enhancement of Fas gene transcription and translation.

Topics: Antigens, Surface; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Division; Cell Survival; Coloring Agents; Fas Ligand Protein; fas Receptor; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Ligands; Membrane Glycoproteins; Protein Biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazolium Salts; Thiazoles; Time Factors; Tongue Neoplasms; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured; Up-Regulation

To develop a more effective induced-differentiation or -apoptosis therapy for treating oral squamous cell carcinomas.. The combination of all trans retinoic acid (ATRA) and interferon-gamma (IFN-gamma) was tested for its antiproliferative activity against human tongue squamous cell carcinoma cell line (Tca8113 cells) in vitro. Clonogenic assay, MTT assay, and microscopic cell analysis were performed in this experiment.. The results show that the combination of ATRA and IFN-gamma can produce synergistic antitumor effects, resulting from induction of apoptosis, on Tca8113 cells.. The combination of ATRA and IFN-gamma is a more effective induced-apoptosis therapy for treating oral squamous cell carcinoma.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Division; Dose-Response Relationship, Drug; Drug Synergism; Humans; Interferon-gamma; Time Factors; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured

All-trans-retinoic acid (ATRA) and interferons (IFNs) have been proven to synergistically amplify growth inhibition and apoptosis in the tongue squamous carcinoma cell line (Tca8113). Nuclear retinoic acid receptor-beta (RAR beta) was the key gene that mediated retinoid activity for squamous carcinoma cells. In order to understand the mechanism of ATRA combined with IFN gamma inhibiting growth of Tca8113 cells, this investigation focused on RAR beta mRNA expression.. In this experiment, RT-PCR method was used to analyze the RAR beta expression level, and viable cell count assay was carried out for growth inhibition studies.. All-trans-retinoic acid (1 microM) and IFN gamma (1000 u/mL) inhibited cell growth by 39.2% and 44.4%, respectively. Synergistic inhibition of cell proliferation by 86.7% was found under combined treatment. The combination of suboptimal concentrations of ATRA (0.1 microM) with IFN gamma (1000 u/mL) showed a much stronger additive inhibitory effect on cell proliferation. ATRA (1 microM) and IFN gamma (1000 u/mL) increased RAR beta expression to 4 times and 3 times, respectively. The expression of RAR beta increased 12 times after treatment with combined ATRA and IFN gamma treatment.. These observations indicated that the use of combined ATRA and IFN may lead to enhanced antitumor effects. These results also suggested that ATRA and IFN mediated upregulating expression of RAR beta may play an important role in synergistic inhibition of proliferation in Tca8113 cells.

Topics: Carcinoma, Squamous Cell; Cell Division; Drug Synergism; Gene Expression; Humans; Interferon-gamma; Polymerase Chain Reaction; Receptors, Retinoic Acid; RNA, Messenger; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured; Up-Regulation

To study the inhibitory effects of 8-methoxypsoralen (8-MOP) combining with all trans retinoic acid (RA) on tongue cancer cell line Tca8113 and gingiva cancer cell line Ca9-22, MTT assay (tetrazolium-based colormetric assay) was applied and the changes in morphology were observed with the inverted microscope. The results showed that with 30% growth inhibition of the cell lines, the Combination Indexes (CI30) of the two drugs were no more than 0.82, and with 50% growth inhibition, the Combination Index (CI50) were from 0.9 to 0.95, which indicated synergic combination effects of the two drugs against the two oral squamous cancer cell lines. Apoptosis-body-like structures were observed in the cells treated with RA, 8-MOP, or the combination of RA with 8-MOP. Whether combination of the two drugs at appropriate concentrations has clinical value needs to be investigated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Division; Cell Line, Tumor; Humans; Methoxsalen; Tongue Neoplasms; Tretinoin

Retinoids have shown great promise as chemopreventive against the development of squamous cell carcinomas of the upper aerodigestive tract. However, the exact mechanism by which they block new tumors from arising is unknown. Here, we report that 13-cis- and all-trans-retinoic acid, used at clinically achievable doses of 10(-6) mol/L or less, can directly and specifically affect cell lines cultured from oral squamous cell carcinomas, inducing them to switch from an angiogenic to an anti-angiogenic phenotype. Although retinoic-acid-treated and untreated tumor cells make the same amount of interleukin-8, the major inducer of neovascularization produced by such tumor lines, they vary in production of inhibitory activity. Only the retinoic-acid-treated cells produce a potent angio-inhibitory activity that is able to block in vitro migration of endothelial cells toward tumor cell conditioned media and to halt neovascularization induced by such media in the rat cornea. Anti-angiogenic activity is induced in the tumor cells by low doses of retinoids in the absence of toxicity with a kinetics that suggest that it could be contributing to the effectiveness of the retinoids as chemopreventive agents.

Topics: Animals; Breast Neoplasms; Carcinoma, Squamous Cell; Colonic Neoplasms; Cornea; Endothelium, Vascular; Female; Fibrosarcoma; Humans; Interleukin-8; Keratinocytes; Neovascularization, Pathologic; Neovascularization, Physiologic; Neutralization Tests; Phenotype; Rats; Rats, Inbred F344; Tongue Neoplasms; Transforming Growth Factor beta; Tretinoin; Tumor Cells, Cultured

Several studies have correlated the excessive production of prostaglandins (PGs) with tumor promotion and the suppression of the immune response. Inhibition of PGs by pharmacological agents has been demonstrated to enhance immunocompetence, and to suppress growth of tumors in animals and humans. In this study we examined the effect of retinol (I), all-trans-retinoic acid (II), N-(4-Hydroxyphenyl) retinamide (N-4-HPR) (III), canthaxanthin (CTX) (IV), and beta-carotene (beta-CT) (V) on the bioconversion of 14C-arachidonic acid (AA) to PGE2 by squamous carcinoma cells of the tongue, SCC-25. Agents (I), (II), (III), (IV) inhibited while (V) stimulated PGE2 formation in a dose related manner. N-4-HPR was the most potent inhibitor of PGE2 synthesis. The data suggest that certain retinoids and carotenoids have the potential of inhibition of PG synthesis by oral squamous carcinoma cells. Inhibitory effects such as those described here and antioxidant properties might in part contribute to the antiinflammatory and anticarcinogenic activity of retinoids in vivo.

Topics: beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Chromatography, Thin Layer; Fenretinide; Humans; Indomethacin; Prostaglandins; Retinoids; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured; Vitamin A

The aim of this study was to evaluate the effect of four natural and synthetic retinoids: Ro 12-7310 (I), Ro 13-7410 (II), 13-cis-retinoic acid (III), and Ro 13-7652 (IV) on the synthesis of PGE2 in human squamous cell carcinoma (SCC) of the tongue (SCC-25). 5 X 10(6) cells were plated and labeled with 0.2 microCi of (14C)-arachidonic acid (AA) in 2 ml of DMEM/F12 containing 0.1% BSA for 4 h. The cells were then washed, and incubated in serum-free medium with the retinoids (10,20,30,40 microM) for 1 h. The cells were further stimulated with melittin an additional hour. Radioactive metabolites released in media were then extracted with diethyl ether. The ether extracts were separated by TLC and radioactive PGE2 zone was quantitated by means of liquid scintillation counting. The rank order of percent inhibition of PGE2 synthesis by retinoids at four concentration levels was (I) greater than (II) greater than (III) greater than (IV). Since inhibition of PG production has been demonstrated to suppress growth of tumors in animal models and humans, further study on the effect of retinoids on growth of SCC in vitro as well as in vivo seems warranted.

Topics: Acitretin; Arachidonic Acid; Arachidonic Acids; Benzoates; Carcinoma, Squamous Cell; Dinoprostone; Dose-Response Relationship, Drug; Etretinate; Humans; Prostaglandin-Endoperoxide Synthases; Retinoids; Tongue Neoplasms; Tretinoin; Tumor Cells, Cultured

In five lines of cultured human squamous carcinoma cells, transglutaminase activity and envelope competence were highly sensitive to retinoic acid and calcium levels in the growth medium. In cells grown in low calcium medium, these measures of keratinocyte differentiation were reduced. Retinoic acid suppressed envelope competence but total transglutaminase activity was markedly reduced, slightly affected, or greatly stimulated depending upon the cell line and whether the cells were grown in low calcium or 1.8 mM calcium-containing medium. Examination by anion exchange chromatography of the transglutaminase activity in SCC-12B2 cultures showed that expression of the particulate form (type I) of the enzyme was greatly stimulated by calcium. The increase in this activity to high levels that occurs at confluence could be almost completely suppressed by retinoic acid in the medium. The soluble form (type II) in the SCC-12B2 cells was induced in growing or confluent cultures by retinoic acid independent of the calcium concentration in the medium, but the 50% effective concentration (100 nM) for its stimulation was approximately 50-fold higher than the 50% effective concentration for suppression of the type I enzyme (2 nM). Thus, these enzymes appear to be distinct and independently regulated. This conclusion is supported by the finding that SCC-4 and SCC-9 almost exclusively expressed types II and I forms, respectively. In contrast to the results with neoplastic cells, in cultured normal epidermal cells type I enzyme comprised the overwhelming majority of activity and was only partially (75-90%) suppressible by retinoic acid, while type II enzyme seemed poorly if at all stimulable. Thus, the SCC lines appear appropriate for studying biochemical mechanisms of action of certain physiological agents, the molecular basis for altered regulation of differentiated function in neoplastic cells, and the origin of diversity within tumors.

Topics: Calcium; Carcinoma, Squamous Cell; Cell Differentiation; Cell Membrane; Cells, Cultured; Epidermis; Humans; Tongue Neoplasms; Transglutaminases; 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 golden hamsters (Mesocricetus auratus) were divided into 4 equal groups. Group 1 animals had the posterior lateral borders of their tongues painted three times weekly with a 0.5% solution of 7,12-dimethylbenz[a]anthracene (DMBA) in acetone. Group 2 animals were painted with DMBA and also received 10 mg of 13-cis-retinoic acid in peanut oil administered orally by pipette twice weekly. Group 3 animals received only retinoid, and group 4 animals were untreated controls. Four animals in each group were killed at 12, 14, 16, and 18 weeks. In the DMBA-painted animals receiving 13-cis-retinoic acid, the leukoplakia and epidermoid carcinomas developed more slowly and were better differentiated microscopically. The better degree of differentiation was demonstrated by ultrastructural studies. Less cellular separation and fewer microvilli-like structures were evident. No tubular mitochondria were observed. Less dispersion of heterochromatin occurred throughout nuclei, and the basal lamina tended to be regular and continuous.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Basement Membrane; Carcinoma, Squamous Cell; Cell Nucleus; Cricetinae; Cytoplasm; Female; Male; Tongue Neoplasms; Tretinoin

Topics: Adolescent; Aged; Anti-Bacterial Agents; Child; Cryosurgery; Darier Disease; Elastic Tissue; Epidermolysis Bullosa; Female; Humans; Impetigo; Larva Migrans; Lichen Planus; Male; Middle Aged; Papilloma; Pemphigus; Skin Diseases; Tongue Neoplasms; Tretinoin