tetracycline and Adenoma

Mutations of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a(-/-) mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.

Topics: Adenoma; Adrenal Cortex Neoplasms; Animals; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; DNA, Antisense; Down-Regulation; Exons; Female; Lymphoproliferative Disorders; Mesoderm; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pregnancy; Promoter Regions, Genetic; Proteins; Tetracycline; Thyroid Neoplasms; Trans-Activators

Adaptive epigenetic changes and toxicity often accompany constitutive expression of a transgene or knockout of an endogenous gene in mice. These considerations potentially limit the usefulness of transgenic technology in studying the in vivo functions of a gene. Using conditional gene expression technology, it is possible to override such restrictions to achieve temporal and tissue-specific manipulation of gene expression in vivo. Based on the tetracycline regulatory system, we established a binary transgenic model in which the conditional expression of two transgenes, SV40 T antigen (TAg) and lacZ, can be tightly regulated in the liver by administration of tetracycline. The mouse albumin or mouse major urinary protein promoter was used to achieve liver-specific expression of the tetracycline-responsive transcriptional activator (tTA) in one set of transgenic mice. These mice were crossed with transgenic mice carrying either TAg or lacZ under the control of the tTA-regulated promoter. Analyses of mice transgenic for both tTA and TAg (or lacZ) revealed that the liver-specific expression of the transgenes could be suppressed to undetectable levels and regulated in a reversible fashion by tetracycline administration and withdrawal. Mice with tTA and TAg transgenes developed hepatocellular adenomas and hyperplasia that could be prevented by continuous tetracycline administration. Our report demonstrates the value of this binary transgenic model in studying the physiological functions of any potential genes of interest in a liver-specific manner.

Topics: Adenoma; Albumins; Animals; Anti-Bacterial Agents; Antigens, Polyomavirus Transforming; Crosses, Genetic; Gene Expression Regulation; Gene Transfer Techniques; Genotype; Hyperplasia; Lac Operon; Liver; Liver Neoplasms; Mice; Mice, Transgenic; Promoter Regions, Genetic; Proteins; Spleen; Tetracycline; Transcriptional Activation; Transgenes

To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b(G12D) under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fall in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging.

Topics: Adenocarcinoma; Adenoma; Animals; Apoptosis; Bromodeoxyuridine; Cyclin-Dependent Kinase Inhibitor p16; DNA Primers; Gene Expression Regulation, Neoplastic; Genes, ras; Genes, Tumor Suppressor; Genotype; In Situ Nick-End Labeling; Lung Neoplasms; Mice; Mice, Knockout; Mice, Transgenic; Models, Genetic; Neoplasm Recurrence, Local; Reverse Transcriptase Polymerase Chain Reaction; Tetracycline; Transgenes; Tumor Suppressor Protein p53

Fine needle biopsy (FNB) has been used as a therapeutic method in different nodular lesions of the thyroid. Between 1989-1995, 295 subjects with thyroid cysts, 235 women and 60 men have been treated by FNB. The treatment of cysts was performed by: one or multiple aspirations in 207 cases, sclerosis by injection with tetracycline in 77 cases and by ethanol washing in 11 cases. 263 (89.11%) cases have been cured and we have lost track of 32 cases in the survey. Of the 207 cases treated by aspiration, 177 (86.5%) have been cured after one or more aspirations. Of the 77 cases treated by injections with tetracycline, 75 (97.26%) displayed sclerosis after one or more injections. All 11 cases treated by ethanol washing method displayed sclerosis. Between 1993-1995 we used percutaneous ethanol injection (PE1) in 6 cases, as an alternative to the classic treatment, in order to induce necrosis of toxic adenoma. After 1 to 9 injections all cases were cured, with the appearance of the entire image of the gland on the scintigram. In 4 cases of cold nodules with benign cytology PEI, induced a significant decrease of volume appreciated by sonography.

Topics: Adenoma; Administration, Cutaneous; Adolescent; Adult; Aged; Biopsy, Needle; Child; Cysts; Ethanol; Female; Humans; Male; Middle Aged; Tetracycline; Thyroid Diseases; Thyroid Neoplasms; Thyroid Nodule

Topics: Adenoma; Adult; Aged; Biopsy; Bone and Bones; Bone Development; Bone Resorption; Child, Preschool; Female; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Hormone; Parathyroid Neoplasms; Ribs; Tetracycline

Topics: Adenoma; Bone Cysts; Female; Humans; Ilium; Metacarpus; Microradiography; Microscopy, Fluorescence; Middle Aged; Parathyroid Neoplasms; Tetracycline

Topics: Adenoma; Anti-Bacterial Agents; Chloramphenicol; Cholesteatoma; Ear Canal; Ear, Middle; Erythromycin; Humans; Pathology; Staphylococcal Infections; Surgical Procedures, Operative; Tetracycline

Topics: Adenoma; Aminosalicylic Acid; Aminosalicylic Acids; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Antitubercular Agents; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Chloramphenicol; Isonicotinic Acids; Leukemia; Leukemia, Experimental; Liver Neoplasms; Neoplasms; Neoplasms, Experimental; Oleandomycin; Pharmacology; Pyrazinamide; Research; Rolitetracycline; Sarcoma; Sarcoma, Experimental; Sarcoma, Yoshida; Streptomycin; Tetracycline