tetracycline and Neoplasms

Genetically engineered mouse models (GEMMs) have proven essential to the study of mammalian gene function in both development and disease. However, traditional constitutive transgenic mouse model systems are limited by the temporal and spatial characteristics of the experimental promoter used to drive transgene expression. To address this limitation, considerable effort has been dedicated to developing conditional and inducible mouse model systems. Although a number of approaches to generating inducible GEMMs have been pursued, several have been restricted by toxic or undesired physiological side effects of the compounds used to activate gene expression. The development of tetracycline (tet)-dependent regulatory systems has allowed for circumvention of these issues resulting in the widespread adoption of these systems as an invaluable tool for modeling the complex nature of cancer progression.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Humans; Mice; Neoplasms; Operator Regions, Genetic; Tetracycline; Trans-Activators; Transgenes

Among viral and non-viral gene delivery systems, SV40-based vectors show great promise in the cancer gene therapy field. SV40 vectors very efficiently deliver genes such as anti-viral agents, DNA vaccine, genes for chemoprotection (such as ABC transporters genes), suicide genes and antiangiogenic genes. The recombinant SV40 vectors can infect a wide variety of cells-dividing cells as well as non-cycling ones. Most of the SV40-based vectors can incorporate larger transgenes than the capacity of the SV40 wild-type, which is 5.2 kb; Moreover, in vitro packaged vectors demonstrate efficient delivery of plasmids with a molecular weight of up to 17.7 kb. SV40-based vectors carry some SV40 viral sequences, but the SV40 in vitro-packaged vectors are free of any SV40 wild-type viral DNA sequences. These vectors are prepared with nuclear extracts of SF9 insect cells containing the main viral capsid protein of the SV40 wild-type virus, VP1. This review summarizes different strategies in which SV40 vectors are used to deliver genes in vitro, to living mice, and to tumors growing in nude mice.

Topics: Antineoplastic Agents; Bone Marrow Cells; Cell Line; Gene Transfer Techniques; Genes, MDR; Genetic Vectors; HIV Infections; Humans; Neoplasms; Simian virus 40; Tetracycline

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Drugs, Investigational; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Protease Inhibitors; Pyrazines; Sulfonamides; Tetracycline; Tetracyclines; Thiophenes

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

Topics: Gene Expression Regulation; Gene Targeting; Genetic Therapy; Genetic Vectors; Neoplasms; Recombinant Fusion Proteins; Tetracycline; Viruses

Topics: Biopsy; Bleomycin; Carcinoembryonic Antigen; Chromosome Aberrations; Cytodiagnosis; Drainage; Endoscopy; Humans; Mesothelioma; Neoplasms; Nitrogen Mustard Compounds; Pleural Effusion; Pleural Neoplasms; Quinacrine; Talc; Tetracycline

Tumor scintigraphic localization of neoplasms can be done in two ways: indirectly and directly. The first method shows alternations of the normal structure of the organ, such as "cold lesions" in liver and thyroid. Abnormalities in function as increased permeability of the blood barrier results from abnormal deposition of the radionuclide in the brain scintigram of a patient with neoplasm. Increased focal areas of uptake of bone-seeking radionuclides are very characteristic of metastases. The direct methods depend on preferential uptake of the radionuclide by the neoplastic tissue resulting from altered metabolism (e.g. Se-75). Other agents such as Gallium-67 have affinity for neoplasms. Another approach is to use antineoplastic agents and radioactive antibodies which will localize in the tumor. At this stage the most useful neoplasm seeking agents are Gallium-67 citrate and 111In-Bleomycin, even though infections can give false positives. The possibility should be considered of enhancing the uptake of radionuclides by neoplastic cells using increased O2 concentration.

Topics: Animals; Antibodies, Neoplasm; Bleomycin; Fibrinogen; Gallium Radioisotopes; Humans; Iodine Radioisotopes; Mercury Radioisotopes; Neoplasms; Radionuclide Imaging; Selenomethionine; Tetracycline

Effective control of a recurrent malignant pleural effusion can greatly improve the quality of life of the cancer patient. At least a dozen different techniques have been advocated for controlling this common complication of malignant disease. The present review collects and examines the clinical results of all techniques designed to treat this problem. The pathophysiology and diagnostic evaluation of the effusion are also discussed. On the basis of comparisons involving effectiveness, morbidity, and convenience, we recommend intrapleurally administered tetracycline with thoracostomy drainage as the technique of choice. Instillation of a talc suspension with thoracostomy drainage is also a safe and effective technique and should be employed when tetracycline fails or is contraindicated.

Topics: Drainage; Humans; Intubation; Neoplasm Metastasis; Neoplasms; Nitrogen Mustard Compounds; Pleura; Pleural Effusion; Quinacrine; Radioisotopes; Talc; Tetracycline; Thorax

Several radiopharmaceuticals have recently been shown to have a considerable affinity for malignant tissue. All the tumor-seeking radiopharmaceuticals in current use are nonspecific and may also be picked up by benign tumors and infectious processes, including abscess and granuloma. The sensitivity of the tumor-imaging procedure depends on the radiopharmaceutical employed, the type of tumor, its size and location, and previous or current treatment. Gallium-67 citrate (67Ga), the most widely used tumor-seeking radiopharmaceutical, seems to have its greatest value in detecting bronchogenic carcinomas irrespective of cell type. The sensitivity for lung cancer in 489 studies was 93 per cent. Gallium-67 is also of great value in the staging of Hodgkin's disease, in which its sensitivity is 87 per cent. Non-Hdgkin's lymphomas are detected with only slightly lower sensitivity. There is, in fact, evidence that 67Ga is at least complemenatry, if not more sensitive than lymphangiography, in the staging of lymphoma. However, adenocarcinomas originating in the gastrointestinal tract are detected by 67Ga with a sensitivity of only about 40 per cent, whereas various chelates of bleomycin (including 111In-Bleo, 99mTc-Bleo and 57Co-Bleo) detect adenocarcinoma of the gastrointestinal tract with considerably higher sensitivity. In the few studies available comparing bleomycin chelates, 57Co-Bleo and 99mTc-Bleo appear to be more sensitive in detecting tumor than 111In-Bleo. Other tumor-seeking radiopharmaceuticasl which have been employed with somewhat less success include selenium compounds, labeled pyrimidines, several inorganic cations, lanthanide chelates and labeled proteins. Yet to be evaulated clinically is the efficacy of radiolabeled antibodies which are specific for tumor antigens, such as 131I-anti-CEA (carcinoembryonic antigen).

Topics: Antibodies, Neoplasm; Bismuth; Bleomycin; Carcinoembryonic Antigen; Cesium Radioisotopes; Chelating Agents; Chloroquine; Cobalt Radioisotopes; Copper; Gallium Radioisotopes; Glycerophosphates; Humans; Indium; Mercury Radioisotopes; Metals, Rare Earth; Naphthoquinones; Neoplasms; Porphyrins; Proteins; Pyrimidines; Radioisotopes; Radionuclide Imaging; Selenium; Technetium; Tetracycline

Topics: Fluorescence; Humans; Neoplasm Metastasis; Neoplasms; Stomach Neoplasms; Tetracycline

Topics: Cosmic Radiation; Environmental Exposure; Female; Fetus; Food Contamination, Radioactive; Humans; Iodine Isotopes; Maternal-Fetal Exchange; Neoplasms; Nuclear Energy; Placenta; Pregnancy; Pregnancy Complications; Radiation Injuries; Radioactive Waste; Radiography; Radioisotope Renography; Radioisotopes; Radionuclide Imaging; Serum Albumin, Radio-Iodinated; Terminology as Topic; Tetracycline; Thyroid Diseases

Topics: Chlortetracycline; Humans; Microscopy; Microscopy, Fluorescence; Myocardial Infarction; Neoplasms; Tetracycline; Trichloroacetic Acid; Ultraviolet Rays; Vitamin B 12

Topics: Bone and Bones; Chemical Phenomena; Chemistry; Collagen; Dental Caries; Dental Caries Susceptibility; Dental Enamel Hypoplasia; Dental Pulp; Dentin; Fluorescence; Growth; Humans; Neoplasms; Polysaccharides; Tetracycline; Tetracyclines; Tooth Discoloration

We reviewed 36 cases of symptomatic malignant pericardial effusion managed with pericardiocentesis at our institution from 1982 to 1989. There were 13 men and 23 women, aged 49 +/- 12 years (range, 33-76 years). The commonest underlying tumours were lung cancer (12 cases, 33%) and breast cancer (11 cases, 30%). Pericardiocentesis was successful as the initial management in 34 of 36 patients (94%); one patient died as a result of the procedure and another required subxiphoid incision and tube drainage of the effusion. When intrapericardial sclerotherapy was performed, only three of 28 patients required repeat pericardiocentesis, and when sclerotherapy was not performed initially, four of seven patients had recurrent symptomatic effusions. Median survival following pericardiocentesis in breast cancer patients was 10 months (range, 0-36 months) and in all other malignancies was four months (range, 0-12 months). We conclude that pericardiocentesis with intrapericardial sclerotherapy provides good local control for symptomatic malignant pericardial effusion in the majority of patients. In spite of this, the median survival of such patients is poor, especially in patients with malignancies other than breast cancer, with few patients surviving more than a few months.

Topics: Adult; Aged; Breast Neoplasms; Drainage; Echocardiography; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Palliative Care; Pericardial Effusion; Pericardium; Prognosis; Punctures; Sclerotherapy; Survival Rate; Tetracycline

In a prospective randomized study the effect of pleurodesis using fibrin-glue was compared with pleurodesis using tetracycline in the management of malignant pleural effusions. Intrapleural therapy with fibrin-glue was significantly more effective concerning long-term results as relapse of pleural effusion and improvement of lung function just as time of draining pleural effusion and pain during the application of fibrin glue/tetracycline. Thus, intracavitary therapy with fibrin glue may be recommended in the control of malignant pleural effusions.

Topics: Female; Fibrin Tissue Adhesive; Follow-Up Studies; Humans; Male; Neoplasms; Palliative Care; Pleura; Pleural Effusion; Tetracycline

Fifty patients with malignant pleural effusion were randomized to receive one or two doses of tetracycline sclerotherapy. We found that a single sclerotherapy treatment with tetracycline at a dose of 20 mg/kg was as effective as two sclerotherapy treatments and provided symptomatic relief in 46 of the 50 patients.

Topics: Humans; Instillation, Drug; Neoplasms; Pleural Effusion; Sclerosing Solutions; Tetracycline

Both bleomycin and tetracycline have been suggested as the sclerosing agent of choice in the management of malignant pleural effusions. To determine if one drug is superior to the other in this role, patients with malignant pleural effusions were randomly assigned to receive either bleomycin or tetracycline in the previously evacuated pleural space through a thoracostomy tube. Following instillation of the assigned agent, the tube was clamped for 8 hours and then reattached to suction. When the chest tube drainage had slowed to less than 40 ml in a 24-hour period or if 7 days had passed, the tube was removed. Pleural sclerosis was attempted 42 times in 34 patients. No statistically significant differences were found between the two treatment groups when prevention of effusion reaccumulation and time to removal of the chest tube (efficiency) were compared. Side effects including pleural pain and fever, occurred with both agents, but were manageable. Since one drug was not clearly superior to the other, and bleomycin is more costly, we suggest that tetracycline rather than bleomycin be used when pleural sclerosis is needed to manage malignant pleural effusions.

Topics: Bleomycin; Humans; Neoplasms; Pleural Effusion; Random Allocation; Sclerosing Solutions; Tetracycline

Eighteen patients with advanced metastatic malignancy who had 21 pleural effusions requiring sclerosis for control were randomly allocated to intrapleural therapy with tetracycline or quinacrine. Tetracycline produced partial or complete control of the effusion in ten of 12 trials for a median duration of 6 months (range 1.5 to 22 months). Partial or complete control was obtained in nine of ten trials with quinacrine, for a median duration of 3 months (range 1 to 13 months). All complete responders who died achieved control of their effusions until their terminal admissions despite clinical evidence of overt systemic tumor progression in the intervening period. Single-dose tetracycline therapy was accompanied by less fever (p less than 0.04) and less pleuritic pain (p = 0.09) than quinacrine. Tetracycline is effective, well tolerated, easily administered, and should be considered as the initial therapy for malignant pleural effusions requiring pleural sclerosis.

Topics: Clinical Trials as Topic; Female; Humans; Intubation; Neoplasms; Pleura; Pleural Effusion; Quinacrine; Tetracycline

Eleven antimicrobial peptides (AMP) based on the incorporation of cyclic tetra substituted C(α) amino acids, as well as other unnatural amino acids were designed, synthesized and screened for in vitro activity against 18 strains of bacteria as well as 12 cancer cell lines. The AMPs discussed herein are derived from the following peptide sequence: Ac-GF(X)G(X)B(X)G(X)F(X)G(X)GB(X)BBBB-amide, X=any one of the following residues, A5c, A6c, Tic or Oic and B=any one of the following residues, Arg, Lys, Orn, Dpr or Dab. A diversity of in vitro inhibitory activity was observed for these AMPs. Several analogs exhibited single digit μM activity against drug resistant bacteria including; multiple drug resistant Mycobacterium tuberculosis, extremely drug resistant Mycobacterium tuberculosis and MRSA. The physicochemical properties of the basic amino acid residues incorporated into these AMPs seem to play a major role in defining antibacterial activity. Overall hydrophobicity seems to play a limited role in defining antibacterial activity. The ESKAPE pathogens were used to compare the activity of these AMPs to another family of synthetic AMPs incorporating the unnatural amino acids Tic and Oic. In most cases similarly substituted members of both families exhibited similar inhibitory activity against the ESKAPE pathogens. In specific cases differences in activity as high as 15 fold were observed between analogs. In addition four of these AMPs exhibited promising IC50 (<7.5μM) values against 12 different and diverse cancer cell lines. Five other AMPs exhibited promising IC50 (<7.5μM) values against selected cancer cell lines.

Topics: Amino Acid Sequence; Amino Acids; Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Bacterial Infections; Cell Line, Tumor; Humans; Models, Molecular; Mycobacterium tuberculosis; Neoplasms; Peptides; Tuberculosis

Successful immunogenic apoptosis in experimental cancer therapy depends on the induction of strong host anti-tumor responses. Given that tumors are often resistant to apoptosis, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. We have developed a genetic model in which direct dimerization of FADD combined with inducible expression of RIPK3 promotes necroptosis. We report that necroptotic cancer cells release damage-associated molecular patterns and promote maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation. Using both FADD-dependent and FADD-independent RIPK3 induction systems, we demonstrate the efficient vaccination potential of immunogenic necroptotic cells. Our study broadens the current concept of immunogenic cell death and opens doors for the development of new strategies in cancer therapy.

Topics: Alarmins; Animals; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Chemokines; Cross-Priming; Dendritic Cells; Immunity; Ligands; Mice; Models, Biological; Necrosis; Neoplasms; NF-kappa B; Phagocytosis; Protein Multimerization; Tetracycline; Vaccination

A quick and efficient synthesis and the biological evaluation of promising antitumor-antibiotics proximicins A, B and C are reported. The characteristic repetitive unit of these molecules, the methyl 4-Boc-aminofuran-2-carboxylate 15, was prepared in three synthetic steps in good yield using an optimised copper-catalysed amidation method. The proximicins were evaluated for their antitumor activity using cellular methods. Proximicin B induced apoptosis in both Hodgkin's lymphoma and T-cell leukemia cell lines and proximicin C exhibited significantly high cytotoxicity against glioblastoma and breast carcinoma cells. The proximicins were also screened against Escherichia coli, Enterococcus faecalis and several strains of methicillin-and multidrug-resistant Staphylococcus aureus. Proximicin B showed noteworthy activity against antibiotic-resistant Gram-positive cocci.

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; Bacterial Infections; Cell Line, Tumor; Enterococcus faecalis; Escherichia coli; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Neoplasms; Netropsin; Staphylococcus aureus

Historically, skin toxicity has been assessed in prospective clinical trials using the clinician-reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The patient-reported Skindex-16 measures symptoms and perceptions of toxicity. This study was designed to compare information provided by these two measures.. Data were compiled from three placebo-controlled North Central Cancer Treatment Group studies (N06C4, N03CB, N05C4) having rash prevention as the primary objective. All used the Skindex-16 and CTCAE at baseline, weekly during treatment and during a minimum 2-week follow-up period. Statistical procedures, including Pearson correlations, were utilized to determine relationships between adverse event (AE) grades and Skindex-16 scores.. Four hundred and twelve individual patients provided data (median age, 61; 134 male). Patients' Skindex-16 score results show a 0.9 overall mean (range 0-6 with 6 being worse symptoms), a 0.4 baseline mean (range, 0-4.3) and a 1.3 end-of-treatment mean (range, 0-5.9). Ninety-three, 142 and 177 patients experienced a grade 0, 1 and 2+ CTCAE skin toxicity, respectively. Baseline Skindex-16 scores had relatively low correlation with CTCAE grades. The correlation of rash grade with Skindex-16 scores ranged from r = 0.49 with the function subscale to r = 0.62 with the symptom subscale. The highest correlations of the maximum grade of any dermatological AE with the Skindex-16 were r = 0.48 for the total score and r = 0.55 for the symptom subscale.. The data reported support the decision to include both measures in a clinical trial to assess the patient experience, as each measure may specifically target varying symptoms and intensities.

Topics: Algorithms; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cetuximab; Erlotinib Hydrochloride; Exanthema; Female; Gefitinib; Humans; Male; Middle Aged; Mometasone Furoate; Neoplasms; Pregnadienediols; Protein Kinase Inhibitors; Protein Synthesis Inhibitors; Quinazolines; Radiodermatitis; Randomized Controlled Trials as Topic; Severity of Illness Index; Sunscreening Agents; Surveys and Questionnaires; Terminology as Topic; Tetracycline

Control of therapeutic gene expression in tumours is a major goal of gene therapy research, as it can restrict cytotoxic gene expression in cancer cells. In addition, the combination of hyperthermia with gene therapy through the application of heat-inducible vectors can result in considerable improvements in therapeutic efficiency. In this study, to combine heat-inducibility with high-level transgene expression, we developed a heat-inducible transgene expression system with transcriptional amplification mediated by a tetracycline-responsive transactivator.. A hybrid promoter was generated by placing the heat shock protein (HSP) 70B' promoter under the tetracycline-repressor responsive element sequence, and a reporter/therapeutic gene expression plasmid was constructed by placing a reporter/therapeutic gene under the control of this hybrid promoter.. When the transactivator expression plasmid harbouring an expression cassette of the tetracycline-responsive transactivator gene was co-transfected with a reporter gene expression plasmid, the reporter gene expression was controlled by heat treatment. With this system, high levels of heat-induced transgene expression were observed compared to that from the HSP promoter alone without the transactivator. Evaluation of in vitro therapeutic effects using cancer cell lines revealed that therapeutic gene expression effectively caused cell death in a greater percentage of the cells.. These findings indicate that this strategy improves the efficacy of cancer gene therapy.

Topics: Cell Line, Tumor; Gene Expression; Genetic Therapy; Hot Temperature; HSP70 Heat-Shock Proteins; Humans; Neoplasms; Promoter Regions, Genetic; Tetracycline; Trans-Activators; Transgenes; Tumor Necrosis Factor-alpha

A series of steroid and azasteroid analogues containing a six-membered ring A with various functionalities were synthesized. Furthermore, the syntheses of tetracyclic analogues bearing a five-membered A-ring and the syntheses of a number of bicyclic secosteroid analogues were carried out. All compounds were tested for their antibacterial, antifungal and cytotoxic activities. Among all tested compounds 7 and 9 showed outstanding cytotoxic activities but were devoid of antimicrobial activities. The cytotoxic activities of compounds 7, 9 and 10 were initially verified by the National Cancer Institute (NCI) in a one-dose 60 cell assay. In accordance with our results 7 and 9 satisfied pre-determined threshold inhibition criteria for progression to the 5-dose NCI screening, which revealed a selective activity profile for both candidates.

Topics: Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disk Diffusion Antimicrobial Tests; Drug Screening Assays, Antitumor; Female; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Inhibitory Concentration 50; Ketones; Male; Neoplasms; Steroids; Structure-Activity Relationship

In this paper the novel N-cycloalkyl-(cycloalkylaryl)-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetamides synthesis by aminolysis of activated by thionyl chloride or carbonyldiimidazole [(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)-thio]acetic acids and alkylation of the 3-R-6-thio-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts with N-cycloalkyl-(cycloalkylaryl)-2-chloroacetamides are proposed. The structures of compounds are determined by (1)H, (13)C NMR, LC-MS and EI-MS analysis. The in vitro anticancer, antibacterial activity and Photobacterium leiognathi Sh1 bioluminescence inhibition of synthesized compounds were revealed. SAR results were discussed. Compound 4.10 was found to be the most anticancer active one, selectively influenced on the non-small cell lung and CNS cancer cell lines, especially on the HOP-92 (log GI(50) = -6.01) and U251 (log GI(50) = -6.00).

Topics: Acetamides; Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Bacterial Infections; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Microbial Sensitivity Tests; Neoplasms; Quinazolines

CD24 is a cell surface, heavily glycosylated glycosylphosphatidylinositol-anchored mucin-like protein that is overexpressed in various human malignancies. To accurately analyze CD24 function and dissect its biological role in a defined genetic background, it is critical to tightly regulate its expression and be able to turn it on/off in a restricted environment and at a specific time. The tetracycline-induced expression system is most promising as it exhibits such regulation, lack of pleiotropic effects, and high and rapid induction levels. To evaluate the oncogenic and immunotherapeutic potential of CD24 by applying the Tet-On system, the human CD24 gene was cloned downstream to two tetracycline operator sequences, resulting in pCDNA4/TO-CD24, which was then transfected into tetracycline (Tet) repressor-expressing cells (293T-REx), allowing tight on/off regulation, thereby resulting in a very low background or leaky CD24 expression. Selected clones were chosen for further studies and characterized in vitro and in vivo, and several treatment modalities were examined. In addition, the role of CD24 in promoting cell proliferation and tumor growth was studied. The tetracycline-dependent system was successfully implemented. Tetracycline treatment induced CD24 expression in a dose- and time-dependent fashion, which was abrogated following treatment with anti-CD24 monoclonal antibodies (mAbs). CD24-induced expression led to an increased proliferation rate that was inhibited by mAb treatment. In vivo, significantly larger tumors were developed in tetracycline-fed mice. The CD24 Tet-On system is a good model to unravel the role and underlying CD24 pathogenesis in vivo. This valuable tool allows the successful study of novel treatment options, whose effectiveness depends on the CD24 expression level. This set of experiments supports CD24 oncogenic properties.

Topics: Animals; Antibodies, Monoclonal; CD24 Antigen; Cell Proliferation; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Immunotherapy; Mice; Molecular Targeted Therapy; Neoplasms; Oncogenes; Tetracycline

There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Cetuximab; Drug Resistance, Neoplasm; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Humans; Neoplasms; Radiation Tolerance; Tetracycline; Tumor Suppressor Protein p53

The use of conditionally replicative adenoviruses (CRAds) as a promising strategy for cancer gene therapy has been developed to overcome inefficient transduction of solid tumor masses by replication-deficient adenoviruses. Many modifications have been made to CRAds to enlarge tropism, increase selectivity and lytic ability, and improve safety. However, safety is still a concern in the context of future clinical application of CRAds. Particularly, after injection into the body, viral replication cannot be controlled externally. Therefore, we constructed a novel CRAd using a tetracycline-inducible promoter system to realize external pharmacological control of its replication. The effect of this CRAd in vitro was measured at the levels of viral DNA replication, cell death and progeny production. We showed that CRAd replication was tightly controlled by the presence or absence of doxycycline (Dox). Moreover, this system showed a significant gene expression in vivo, in which the viral replication was controlled by the oral administration of Dox. This strategy may help improve the safety of cancer gene therapy.

Topics: Adenoviridae; Cell Line; Cell Line, Tumor; Gene Expression Regulation, Viral; Genetic Therapy; Genetic Vectors; HeLa Cells; Humans; Neoplasms; Promoter Regions, Genetic; Protein Synthesis Inhibitors; Tetracycline; Virus Replication

Activating mutations of the oncogene K-ras are found in one third of all human cancers. Much of our knowledge on K-ras signal transduction and its influence on tumor initiation and progression come from in vitro studies with cell lines. However, mouse models of human cancer allow a much more faithful recapitulation of the human disease, and the in vivo perspective is crucial for our understanding of neoplasia. In recent years, several new murine models for K-ras-induced tumorigenesis have been described. They allow new insights into the specific role that oncogenic K-ras proteins play in different solid tumors, and they permit the molecular dissection of the pathways that are initiated by somatic mutations in subsets of cells. Key advances have been made by the use of tissue-specific and inducible control of expression, which is achieved by the Cre/loxP technology or the tetracycline system. From these sophisticated models, a common picture emerges: the effects of K-ras on tumor initiation depend strongly on the cellular context, and different tissues vary in their susceptibility to K-ras transformation.

Topics: Animals; Crosses, Genetic; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; Genes, ras; Genes, Tumor Suppressor; Intestinal Mucosa; Intestinal Neoplasms; Lung Neoplasms; Mice; Mice, Transgenic; Mutation; Neoplasms; Neoplastic Stem Cells; Organ Specificity; Pancreatic Neoplasms; Protein Synthesis Inhibitors; ras Proteins; Tetracycline; Transgenes

We have previously described oncolytic adenovirus (Ad) vectors KD3 and KD3-interferon (IFN) that were rendered cancer-specific by mutations in the E1A region of Ad; these mutations abolish binding of E1A proteins to p300/CBP and pRB. The antitumor activity of the vectors was enhanced by overexpression of the Adenovirus Death Protein (ADP, E3-11.6K) and by replication-linked expression of IFN-alpha. We hypothesized that the anticancer efficacy of the KD3-IFN vector could be further improved by expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). E1-deleted Ad vectors were constructed carrying reporter genes for enhanced green fluorescent protein or secreted placental alkaline phosphatase (SEAP) and a therapeutic gene for TRAIL under control of the TetON system. Expression of the genes was increased in the presence of a helper virus and the inducer doxycycline such that up to 231-fold activation of expression for the TetON-SEAP vector was obtained. Coinfection with TetON-TRAIL augmented oncolytic activity of KD3 and KD3-IFN in vitro. Induction of TRAIL expression did not reduce the yield of progeny virus. Combination of TetON-TRAIL and KD3-IFN produced superior antitumor activity in vivo as compared with either vector alone demonstrating the efficacy of a four-pronged cancer gene therapy approach, which includes Ad oncolysis, ADP overexpression, IFN-alpha-mediated immunotherapy, and pharmacologically controlled TRAIL activity.

Topics: Adenoviridae; Adenovirus E3 Proteins; Animals; Apoptosis; Cell Line, Tumor; Doxycycline; Gene Expression Regulation, Neoplastic; Genetic Therapy; Genetic Vectors; Humans; Interferon-alpha; Mice; Mutation; Neoplasms; Tetracycline; TNF-Related Apoptosis-Inducing Ligand

Tumor-targeted vectors with controllable expression of therapeutic genes and specific antitumor antibodies are promising tools for the reduction of malignant tumors. Here we describe a new plasmid for the eukaryotic expression of an anti-HER2/neu mini-antibody-barnase fusion protein (4D5 scFv-barnase-His(5)) with an NH(2)-terminal leader peptide. The 4D5 scFv-barnase-His(5) gene was placed downstream of the tetracycline responsive-element minimal promoter in the vector using the Tet-Off gene-expression system. The Bacillus amyloliquefaciens ribonuclease barnase is toxic for the host cells. To overcome this problem, barstar gene under its own minimal cytomegalovirus promoter was used in designed vector. Barstar inhibits the background level of barnase in the cells in the presence of tetracycline in culture medium. The HEK 293T cells were transfected with the designed vector, and the 4D5 scFv-barnase-His(5) fusion protein was identified by anti-barnase antibodies in cell culture medium and after purification from cell lysates using metal-affinity chromatography. The overexpression of the anti-HER2/neu mini-antibody-barnase fusion protein decreased the intensity of fluorescence of HEK 293T cells co-transfected with the generated plasmid and a plasmid containing the gene of enhanced green fluorescent protein (pEGFP-N1), in comparison with the intensity of fluorescence of HEK 293T cells transfected with pEGFP-N1, in the absence of tetracycline in the medium. The effect of the 4D5 scFv-barnase-His(5) on EGFP fluorescence indicates that the introduced barnase functions as a ribonuclease inside the cells. The anti-HER2/neu mini-antibody could be used to deliver barnase to HER2/neu-positive cells and provide its penetration into the target cells, as HER2/neu is a ligand-internalizing receptor. This expression vector has potential applications to both gene and antibody therapies of cancer.

Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; Bacterial Proteins; Cell Line; Gene Expression; Genes, erbB-2; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy; Neoplasms; Recombinant Fusion Proteins; Ribonucleases; Tetracycline; Transfection

Cell cycle arrest at the G2-M checkpoint is an essential feature of the mechanisms that preserve genomic integrity. CDC25 phosphatases control cell cycle progression by dephosphorylating and activating cyclin-dependent kinase/cyclin complexes. Their activities are, therefore, tightly regulated to modulate cell cycle arrest in response to DNA damage exposure. Here, we report that overexpression of CDC25B affects viability, reduces clonogenic efficiency, and increases sensitivity of cancer cells to a genotoxic agent. We show that ectopic expression of CDC25B results in bypass of a genotoxic-induced G2-M checkpoint. In addition, cancer cells constitutively expressing high level of CDC25B are shown to be prone to exit prematurely from the G2-M checkpoint arrest and to enter mitosis. Finally, we show that this exit is dependent on CDC25B expression. Together with previous results, our data strongly support a model in which CDC25B is the key phosphatase that controls entry into mitosis after DNA damage, thus emphasizing the relevance of its overexpression in many human tumors.

Topics: Antineoplastic Agents, Phytogenic; Blotting, Western; cdc25 Phosphatases; Cell Cycle Proteins; Cell Division; Cell Survival; DNA Damage; Etoposide; Flow Cytometry; Fluorescent Antibody Technique, Indirect; G2 Phase; Humans; Neoplasms; Tetracycline; Tumor Cells, Cultured; Tumor Stem Cell Assay

Stromelysin-3 (ST3, MMP-11) has been shown to be strongly overexpressed in stromal fibroblasts of most invasive human carcinomas. However, the molecular mechanisms leading to ST3 expression in nonmalignant fibroblasts remain unknown. The aim of the present study was to analyze the signaling pathways activated in normal pulmonary fibroblasts after their interaction with non-small cell lung cancer (NSCLC) cells and leading to ST3 expression. The use of selective signaling pathway inhibitors showed that conventional and novel protein kinase Cs (PKC) were required for ST3 induction, whereas Src kinases exerted a negative control. We observed by both conventional and real time confocal microscopy that green fluorescent protein-tagged PKCalpha and PKCepsilon, but not PKCdelta, transfected in fibroblasts, accumulate selectively at the cell-cell contacts between fibroblasts and tumor cells. In agreement, RNAi-mediated depletion of PKCalpha and PKCepsilon, but not PKCdelta significantly decreased co-culture-dependent ST3 production. Finally, a tetracycline-inducible expression model allowed us to confirm the central role of these PKC isoforms and the negative regulatory function of c-Src in the control of ST3 expression. Altogether, our data emphasize signaling changes occurring in the tumor microenvironment that may define new stromal targets for therapeutic intervention.

Topics: Cell Adhesion; Cell Line; Cell Line, Tumor; Cell Membrane; Coculture Techniques; Enzyme Activation; Enzyme Induction; Fibroblasts; Green Fluorescent Proteins; Humans; Isoenzymes; Matrix Metalloproteinase 11; Metalloendopeptidases; Neoplasms; Protein Kinase C; Protein Transport; Signal Transduction; Tetracycline; Tetradecanoylphorbol Acetate

Regulation of transgene expression is a major goal of gene therapy research. Previously, we have developed a complex adenovirus (Ad) vector with tetracycline-regulated expression of a Fas ligand (FasL)-green fluorescent protein (GFP) fusion protein. This vector delivered high levels of activity that was regulated by doxycycline. However, this regulation was limited by the low but significant background activity of the TRE promoter. Recently, the Tet-regulated transcriptional silencer, tTS, was reported to suppress efficiently basal TRE activity without affecting induced expression levels. Here, we report development of Ad vectors that incorporate tTS in combination with that of reverse transactivator (rtTA) coupled with TRE promoter driving transgene expression. Incorporation of tTS improved control of transgene expression in vitro, so that an induction range of over three orders of magnitude was achieved in some cell lines. Effective regulation of transgene expression was also seen in a mouse model in vivo, following systemic vector delivery. In the case of FasL-GFP expression, significant improvement in the control of apoptotic activity both in vitro and in a mouse hepatotoxicity model was demonstrated when using rtTA-tTS vectors. In conclusion, a highly effective transgene regulation system, deliverable by a single adenoviral vector, is now available.

Topics: Adenoviridae; Animals; Anti-Bacterial Agents; Apoptosis; Cell Line; Cell Line, Tumor; Fas Ligand Protein; Gene Expression Regulation; Genetic Therapy; Genetic Vectors; Green Fluorescent Proteins; Humans; Membrane Glycoproteins; Neoplasms; Recombinant Fusion Proteins; Silencer Elements, Transcriptional; Tetracycline; Trans-Activators; Transgenes

RNA interference (RNAi) is a powerful tool for studying gene function. We developed an inducible genetic element for short interfering RNA-mediated gene silencing. This system uses a tetracycline (Tet)-responsive derivative of the H1 promoter and the Tet repressor (TetR) for conditional expression of short hairpin RNA (shRNA) in HeLa cells. Promoter constructs were generated, which contain the Tet operator (TetO) derived from a prokaryotic Tet resistance transposon upstream and/or downstream of the TATA box. To quantify the response of controllable transcription units for shRNA expression, we examined the functional activity of polo-like kinase 1 (PLK1), a key component of mitotic progression, that is overexpressed in many human tumors. Cotransfection of plasmids for the expression of TetR and shRNA/PLK1 under the control of an H1 promoter-variant carrying TetO upstream of the TATA box did not alter PLK1 expression and proliferation properties of HeLa cells in the absence of doxycycline. Addition of the antibiotic led to marked downregulation of endogenous PLK1 accompanied by strong inhibition of cellular proliferation. Our data indicate that an inducible transcription system for shRNAs based on the human H1 promoter could be a versatile tool for controlled gene silencing in vitro.

Topics: Cell Cycle Proteins; Cell Division; Doxycycline; Gene Expression Regulation; Gene Silencing; Humans; Neoplasms; Polo-Like Kinase 1; Promoter Regions, Genetic; Protein Kinases; Protein Serine-Threonine Kinases; Protein Synthesis Inhibitors; Proto-Oncogene Proteins; RNA; Tetracycline

Restricted replication-competent adenoviruses (RRCAs) using tumor- and tissue-specific promoters (ttsP's) are new tools for cancer gene therapy. In this study we investigated viral and nonviral factors affecting "leakiness" of several ttsP's and their relevance for nonspecific ttsP-dependent RRCA (ttsP-RRCA) replication. The leakiness of the ttsP's in nontarget cells was per se highly variable and correlated with levels of nonspecific ttsP-RRCA replication. Transcriptional regulator elements fused to ttsP's showed variable effects: a hypoxic response element reduced leakiness of an alpha-fetoprotein promoter. In contrast, a mouse tyrosinase enhancer increased leakiness of a tyrosinase promoter, although it was not affected by a human tyrosinase enhancer. Furthermore, leakiness of ttsP's was enhanced by 5'-terminal adenoviral E1A enhancers, and adenoviral E1A-13S was found to be a strong transactivator of ttsP's, leading to "autoactivation" of leaky ttsP-RRCAs. In a proof-of-principle study, ttsP-RRCA replication was shown to be inhibited by a tetracycline-controlled transcriptional silencer via direct ttsP silencing. This opens up the prospect of pharmacological regulation of ttsP-RRCAs. Together, these data indicate that leakiness of ttsP's induced by several factors is a major cause of nonspecific ttsP-RRCA replication. Consideration of these factors may help optimize ttsP-dependent RRCA vectors and may thereby improve their safety.

Topics: Adenoviridae; Adenovirus E1A Proteins; alpha-Fetoproteins; Enhancer Elements, Genetic; Gene Expression Regulation; Gene Silencing; Genetic Therapy; Genetic Vectors; Humans; Monophenol Monooxygenase; Neoplasms; Promoter Regions, Genetic; Tetracycline; Transcription Factors; Tumor Cells, Cultured; Virus Replication

Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Separation; DNA; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glutathione Transferase; Humans; Maleimides; Mice; Mice, SCID; Microscopy, Fluorescence; Models, Chemical; Mutation; Neoplasm Transplantation; Neoplasms; Plasmids; Protein Binding; Protein Conformation; Tetracycline; Transcriptional Activation; Tumor Suppressor Protein p53

RNA interference is a powerful method for suppressing gene expression in mammalian cells. Stable knock-down can be achieved by continuous expression of synthetic short hairpin RNAs, typically from RNA polymerase III promoters. But primary microRNA transcripts, which are endogenous triggers of RNA interference, are normally synthesized by RNA polymerase II. Here we show that RNA polymerase II promoters expressing rationally designed primary microRNA-based short hairpin RNAs produce potent, stable and regulatable gene knock-down in cultured cells and in animals, even when present at a single copy in the genome. Most notably, by tightly regulating Trp53 knock-down using tetracycline-based systems, we show that cultured mouse fibroblasts can be switched between proliferative and senescent states and that tumors induced by Trp53 suppression and cooperating oncogenes regress upon re-expression of Trp53. In practice, this primary microRNA-based short hairpin RNA vector system is markedly similar to cDNA overexpression systems and is a powerful tool for studying gene function in cells and animals.

Topics: Animals; Cell Proliferation; Cellular Senescence; Fibroblasts; Genetic Vectors; Mice; MicroRNAs; Neoplasms; Oncogenes; Phenotype; Promoter Regions, Genetic; Protein Synthesis Inhibitors; RNA Interference; RNA Polymerase II; RNA, Small Interfering; Tetracycline; Transcription, Genetic; Tumor Suppressor Protein p53

Aggressive melanoma cells have been shown to overexpress proteins that modify their environment, but these proteins can be inhibited by a chemically modified tetracycline.

Topics: Environment; Humans; Neoplasms; Protein Biosynthesis; Proteins; Tetracycline; Tetracyclines

We describe an approach employing intramuscular plasmid electrotransfer to deliver secretable forms of K1-5 and K1-3-HSA (a fusion of K1-3 with human serum albumin), which span, respectively, five and three of the five kringle domains of plasminogen. A tetracycline-inducible system (Tet-On) composed of three plasmids coding, respectively, for the transgene, the tetracycline transcriptional activator rtTA, and the silencer tTS was employed. K1-3-HSA and K1-5, produced from C2C12 muscle cells, were found to inhibit endothelial cell (HMEC-1) proliferation by 30 and 51%, respectively. In vivo, the expression of the transgene upon doxycycline stimulation was rapid, stable, and tightly regulated (no background expression) and could be maintained for at least 3 months. Blood half-lives of 2.1 and 3.7 days were found for K1-5 and K1-3-HSA, respectively. The K1-5 protein was secreted from muscle into blood at a level of 45 ng/ml, which was sufficient to inhibit MDA-MB-231 tumor growth by 81% in nude mice and B16-F10 melanoma cell lung invasion in C57BL/6 mice by 73%. PECAM-1 immunostaining studies revealed modest tumor vasculature in mice expressing K1-5. In contrast, K1-3-HSA, although secreted into blood at much higher level (250 ng/ml) than K1-5, had no effect on tumor growth.

Topics: Angiogenesis Inhibitors; Electroporation; Gene Expression Regulation; Genetic Vectors; Muscle, Skeletal; Neoplasm Metastasis; Neoplasms; Peptides; Plasmids; Plasminogen; Tetracycline; Time Factors

Cas-family proteins have been implicated as signaling intermediaries in diverse processes including cellular attachment, motility, growth factor response, apoptosis and oncogenic transformation. The three defined Cas-family members (p130Cas, HEF1/Cas-L and Efs/Sin) are subject to multiple forms of regulation (including cell-cycle- and cell-attachment-mediated post-translational modification and cleavage) that complicate elucidation of the function of specific Cas proteins in defined biological processes. To explore the biological role of HEF1 further, we have developed a series of cell lines in which HEF1 production is regulated by an inducible promoter. In this system, HEF1 production rapidly induces changes in cellular morphology and motility, enhancing cell speed and haptotaxis towards fibronectin in a process partially dependent on intact ERK and p38 MAPK signaling pathways. Finally, cDNA expression array analysis and subsequent studies indicate that HEF1 production increases levels of mRNA transcripts encoding proteins that are associated with motility, cell transformation and invasiveness, including several metalloproteinases, MLCK, p160ROCK and ErbB2. Upregulation of such proteins suggests mechanisms through which misregulation of HEF1 may be involved in cancer progression.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Antibodies; Blotting, Western; Breast Neoplasms; Cell Movement; Cell Size; Clone Cells; Female; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Microscopy, Confocal; Microscopy, Video; Mitogen-Activated Protein Kinases; Neoplasms; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases; Phosphoproteins; Promoter Regions, Genetic; Tetracycline; Transcription, Genetic; Transfection

Using a binary adenoviral system, we recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression. However, the strong cytotoxicity of Bax and other pro-apoptotic genes to packaging 293 cells has so far hindered construction of the desired single adenoviral vectors expressing toxic genes. We report here the construction of a single bicistronic adenoviral vector for tumor-specific Bax expression. The vector (Ad/gBax) utilizes the Tet-Off system and expresses a GFP/Bax fusion protein for easy detection. The hTERT promoter drives the expression of tTA, a transactivator capable of binding to TRE (tetracycline-responsive element) in the absence of tetracycline, which in turn induces expression of the GFP-Bax gene. The addition of tetracycline in 293 cells blocks the binding of tTA to TRE and substantially inhibits GFP-Bax expression and toxicity, thus allowing the packaging and production of Ad/gBax. Our data show that Ad/gBax could drive the high expression of GFP-Bax in tumor cells but not in normal cells and mouse tissues. Furthermore, the expression of GFP-Bax fusion protein elicited tumor-specific apoptosis in a variety of human cancer cells in vitro and in vivo at a level comparable to that induced by the binary system. Thus, Ad/gBax may become a potent therapeutic agent for the treatment of cancers.

Topics: Adenoviridae; Animals; Apoptosis; bcl-2-Associated X Protein; Cell Division; DNA-Binding Proteins; Genetic Therapy; Genetic Vectors; Green Fluorescent Proteins; Humans; Indicators and Reagents; Kinetics; Luminescent Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Promoter Regions, Genetic; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Recombinant Fusion Proteins; Telomerase; Tetracycline; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Thymidylate synthase (TS) is responsible for the de novo synthesis of thymidylate, which is required for DNA synthesis and repair and which is an important target for fluoropyrimidines such as 5-fluorouracil (5-FU), and antifolates such as Tomudex (TDX), ZD9331, and multitargeted antifolate (MTA). To study the importance of TS expression in determining resistance to these agents, we have developed an MDA435 breast cancer-derived cell line with tetracycline-regulated expression of TS termed MTS-5. We have demonstrated that inducible expression of TS increased the IC(50) dose of the TS-targeted therapeutic agents 5-FU, TDX, and ZD9331 by 2-, 9- and 24-fold respectively. An IC(50) dose for MTA was unobtainable when TS was overexpressed in these cells, which indicated that MTA toxicity is highly sensitive to increased TS expression levels. The growth inhibitory effects of the chemotherapeutic agents CPT-11, cisplatin, oxaliplatin, and Taxol were unaffected by TS up-regulation. Cell cycle analyses revealed that IC(50) doses of 5-FU, TDX and MTA caused an S-phase arrest in cells that did not overexpress TS, and this arrest was overcome when TS was up-regulated. Furthermore, the S-phase arrest was accompanied by 2- to 4-fold increased expression of the cell cycle regulatory genes cyclin E, cyclin A, and cyclin dependent kinase 2 (cdk2). These results indicate that acute increases in TS expression levels play a key role in determining cellular sensitivity to TS-directed chemotherapeutic drugs by modulating the degree of S-phase arrest caused by these agents. Moreover, CPT-11, cisplatin, oxaliplatin, and Taxol remain highly cytotoxic in cells that overexpress TS.

Topics: Blotting, Northern; Blotting, Western; Camptothecin; CDC2-CDC28 Kinases; Cell Cycle; Cell Division; Cisplatin; Cyclin A; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Fluorouracil; Folic Acid Antagonists; Gene Expression Regulation, Enzymologic; Humans; Irinotecan; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Protein Serine-Threonine Kinases; Quinazolines; RNA, Messenger; Tetracycline; Thiophenes; Thymidylate Synthase; Tumor Cells, Cultured

The purpose of this study was the evaluation of the effectiveness of intrapericardial administration of tetracycline, 5-fluorouracil and cisplatin in patients with recurrent malignant pericardial effusion. In 33 cases with malignant pericardial effusion 46 pericardiocenteses under two-dimensional echo-cardiography were performed. No complications were observed after this procedure. Pericardiocentesis was followed by catheterization of the pericardial space for a mean period of 15 days (range 1-64). In 4 cases bacterial pericarditis was observed during catheterization. The mean volume of the pericardial fluid was 2.41 (range 0.4-13 l). In cases with bloody pericardial fluid the PO2, PCO2 and pH of the fluid were estimated and the results compared with the values for venous blood obtained from the upper limbs. Highly statistically significant differences were documented. Twenty cases of malignant pericardial effusion were treated with direct pericardial administration of cisplatin, 3 with 5-fluorouracil and 2 with tetracycline. Good results (no fluid reaccumulation) were observed only after cisplatin therapy. We conclude that pericardiocentesis performed under two-dimensional echo cardiography, followed by pericardial catheterization and direct pericardial treatment with cisplatin are the methods of choice in cases with malignant pericardial effusion. In cases with bloody pericardial fluid PO2, PCO2 and pH analysis can be useful to differentiate the source of the bloody fluid (blood or bloody fluid).

Topics: Adult; Aged; Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbon Dioxide; Catheterization; Cisplatin; Echocardiography; Female; Fluorouracil; Hemorrhage; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Neoplasms; Oxygen; Pericardial Effusion; Pericarditis; Punctures; Recurrence; Remission Induction; Tetracycline; Ultrasonography, Interventional

All of the 88 episodes of beta-haemolytic streptococcal bacteremia (2.9% of all bacteremias) in adult patients during the years 1987-94 in a university hospital were reviewed. 38 bacteremias (43%) were caused by group A, 24 (27%) by group B, 3 (4%) by group C, and 23 (26%) by group G beta-haemolytic streptococcal. There was a statistically significant increase in group A and decrease in group C and G bacteremias (p < 0.02) compared to an earlier 8-year period in the same hospital, although the total number of streptococcal bacteremias remained the same. The most common T types of group A streptococcal strains were T11 (26%), T28 (14%), T6 and T1 (11% each), and T12 (8%). Cardiovascular disease, skin lesions, malignancy, and alcohol abuse were the most common underlying conditions. The most usual types of infection were skin (47%) and respiratory tract infections (23%). The overall mortality was 16%. It was highest in group A (24%) and lowest in group C (0%), 38% of patients with pneumonia died. All streptococcal strains were sensitive to penicillin, vancomycin, and cephalosporins. 11% of group A and 12% of all the strains had decreased sensitivity to erythromycin, 14 and 38% to tetracycline, and 0 and 2% to clindamycin, respectively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Bacterial Typing Techniques; Cardiovascular Diseases; Clindamycin; Drug Resistance, Microbial; Erythromycin; Female; Finland; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Neoplasms; Retrospective Studies; Skin Diseases; Streptococcal Infections; Streptococcus; Streptococcus agalactiae; Streptococcus pyogenes; Tetracycline

An attractive approach to the therapy of solid tumors would be to target cytotoxic agents or coagulants to the vasculature of the tumor rather than to the tumor cells themselves. This strategy has 3 advantages: (a) it should be applicable to many types of solid tumors because all require a blood supply for survival and growth; (b) the target endothelial cells are directly accessible through the blood and are normal cells, making the outgrowth of resistant mutants unlikely; and (c) there is an in-built amplification mechanism because thousands of tumor cells are reliant on each capillary for nutrients and oxygen. Despite its theoretical attractions, the approach of tumor vascular targeting has not been testable because antibodies that recognize tumor vascular endothelial cell antigens with adequate specificity are currently not available. In this study, we developed a model system in which to investigate the antibody-directed targeting of vascular endothelial cells in solid tumors in mice. A neuroblastoma transfected with the mouse interferon-gamma gene, C1300(Mu gamma), was grown in antibiotic-treated BALB/c nude mice. The interferon-gamma secreted by the tumor induces the expression of major histocompatibility complex Class II antigens on the tumor vascular endothelium. Class II antigens are absent from the vasculature of normal tissues, although they are present on B-lymphocytes, cells of monocyte/macrophage lineage, and some epithelial cells. Anti-Class II antibody administered i.v. strongly stains the tumor vasculature, whereas an antitumor antibody directed against a major histocompatibility complex Class I antigen of the tumor allograft produces classical perivascular tumor cell staining. This model should enable the theoretical superiority of tumor vascular targeting over conventional tumor cell targeting to be tested.

Topics: Animals; Antibodies; Antibody Specificity; Antigens, Neoplasm; Endothelium, Vascular; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neuroblastoma; Tetracycline; Tissue Distribution

Patients with ARF and haematological malignancy (excluding myeloma), presenting to a single unit over 10 years were analyzed to see if patients likely to benefit from intensive renal supportive therapy could be identified. 31 episodes of ARF were identified in 29 patients (mean age 51 +/- 2.9 yr): 19 were associated with acute leukaemia (13 AML, 6 ALL); 10 with lymphoma. Acute tubular necrosis (ATN) was identified as the cause of ARF in 26 cases, with sepsis (96%) and exposure to nephrotoxic drugs (88%), especially aminoglycosides, being the commonest precipitating factors. Toxic levels of the latter were commonly documented. Patient survival was 45%. Requirement for mechanical ventilation resulted in a universally fatal outcome; age greater than 55 yr and the presence of CNS symptoms or signs were also significantly associated with a poor outcome. Non-ATN causes (urate nephropathy or obstruction) carried a better prognosis. However, only 4 patients (14%) lived for more than 6 months following ARF. Thus, although a subgroup of patients more likely to benefit from treatment can be identified, the overall prognosis is poor and limited by that of the underlying disease. The potential benefit of avoiding nephrotoxic drugs, especially aminoglycosides, in these patients is highlighted by this study.

Topics: Acute Kidney Injury; Adolescent; Adult; Age Factors; Aged; Aminoglycosides; Cyclosporins; Female; Humans; Kidney Tubular Necrosis, Acute; Leukemia, Myeloid; Lymphoma; Male; Middle Aged; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Risk Factors; Tetracycline

Pleurodesis for effective control of malignant pleural effusion can be induced with various methods and agents. In 18 patients with histologically or cytologically proven malignant pleural effusion, 500 mg doxycycline hydrochloride diluted in 30 ml of saline was instilled into the emptied pleural space. Tube drainage was performed using suction or gravity. More than one doxycycline instillation was required in 13 cases. Serial chest radiography showed the response to be complete in 11 of the 18 patients and partial in four, while three did not respond. There was no difference between the results obtained with the two drainage systems. In all of the complete responders who died there was no sign of reaccumulated pleural effusion at terminal admission, despite clinical evidence of systemic tumor progression. Three patients--all with breast carcinoma--are alive after 5-27 months, two as complete responders and one as partial responder. The most common side effect was pleuritic pain, defined as significant if narcotic analgesics were required. A moderate febrile reaction appeared in four patients during the first 24 hours post-instillation. The study showed doxycycline to be an effective sclerosing agent for inducing pleurodesis, with acceptable adverse effects.

Topics: Aged; Aged, 80 and over; Animals; Breast Neoplasms; Doxycycline; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pleural Effusion; Rabbits; Tetracycline

Topics: Administration, Topical; Aged; Female; Humans; Male; Middle Aged; Neoplasms; Pleura; Pleural Effusion; Tetracycline

We retrospectively examined the use of tetracycline pleurodesis for the palliative treatment of malignant pleural effusions. Twenty-five patients (32 procedures) were identified for study. In contrast to higher success rates in prior reports, 13 procedures (40.6%) failed as repeated pleural drainage was required. Only five procedures (15.6%) achieved complete resolution of pleural fluid. In 14 procedures (43.8%) pleural effusions recurred but were not treated. In some of these cases the effusion may have been reduced sufficiently to relieve symptoms, while in others the high short-term mortality rate (29% in 30 days) and the development of loculated effusions (34%) may have led to the decision not to treat. Instillation of a larger dose of tetracycline (greater than or equal to 1 g) was associated with a better outcome. Although adequate pleural drainage and proper technique were used, other factors such as the presence of pleural masses, atelectasis, loculations, and patient performance status were not uniformly controlled. Greater attention to these factors and use of a larger dose of tetracycline (greater than or equal to 1 g) may increase the likelihood of a successful pleural symphysis.

Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Drainage; Female; Humans; Male; Middle Aged; Neoplasms; Palliative Care; Pleural Effusion; Radiography; Retrospective Studies; Tetracycline

Because many patients with malignant pleural effusions could survive for months to years beyond its onset, definitive management must be safe and effective. Chemical pleurodesis with tetracycline has gained general acceptance as the therapy of choice, even though no large series confirming this viewpoint has appeared in the literature. We reviewed 108 procedures involving tube thoracostomy and tetracycline pleurodesis, and report a success rate of 94.4% without serious complications. Considering all patients, 49% were symptom-free at three months, and 13% were alive one year later. Several potentially important changes in technique have emerged since the initial description of this procedure. With adherence to meticulous technique, tetracycline pleurodesis provides rapid, effective, and safe palliation of malignant pleural effusions.

Topics: Adult; Aged; Aged, 80 and over; Drainage; Female; Humans; Male; Methods; Middle Aged; Neoplasms; Palliative Care; Pleura; Pleural Effusion; Retrospective Studies; Rotation; Tetracycline

Fifty-eight patients with malignant pericardial effusion were seen from 1979 to 1986. A Kifa catheter was inserted into the pericardial sac and allowed to drain for 12 to 24 hours during electrocardiographic monitoring. Lidocaine hydrochloride, 100 mg, was instilled intrapericardially, followed by tetracycline hydrochloride, 500 to 1,000 mg, in 20 ml of normal saline solution. The catheter was clamped for 1 to 2 hours and then reopened. This procedure was repeated daily until the net drainage was less than 25 ml/24 hours. There were 22 male and 36 female patients (median age 58 years). The primary malignancy included lung (27 patients), breast (16 patients), stomach (3 patients), adenocarcinoma of unknown primary (7 patients), mesothelioma (2 patients) and chronic granulocytic leukemia, ovary and lymphoma (1 patient each). Fifty-six patients received 1 to 5 tetracycline instillations. In 1 patient, the catheter could not be inserted and in another, clotting occurred within the catheter before injection of tetracycline. Complications included transient atrial arrhythmias (5 patients), pain after injection (9 patients) and temperature higher than 37.5 degrees C (5 patients). One patient had a cardiac arrest during pericardiocentesis. Forty-three patients (74%) had control of their effusions for longer than 30 days (median survival 168 days, range 30 to 1,149+), and 5 patients (9%) died before 30 days without effusion. Eight patients (14%) did not achieve control. One declined further therapy after 1 instillation, and 3 died within 6 days with progressive malignancy. One patient had persistent drainage after 3 instillations, and 3 had reaccumulation of fluid 2, 6 and 27 days after catheter removal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Catheterization; Drainage; Electrocardiography; Female; Humans; Instillation, Drug; Male; Middle Aged; Neoplasms; Palliative Care; Pericardial Effusion; Pericardium; Sclerosing Solutions; Tetracycline

Topics: Female; Humans; Male; Middle Aged; Neoplasms; Odorants; Terminal Care; Tetracycline

Topics: Adult; Aged; Combined Modality Therapy; Drainage; Female; Humans; Male; Middle Aged; Neoplasms; Pleural Effusion; Tetracycline

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Neoplasms; Pleura; Pleural Effusion; Pleurisy; Suction; Tetracycline; Thoracoscopy

Twenty-two patients with malignant pericardial effusion were seen at the Toronto General Hospital between 1979 and 1984. Under ECG monitoring, an indwelling Kifa catheter was inserted into the pericardial sac and then connected to a Hemovac system and allowed to drain for 12 to 24 hours. Xylocaine hydrochloride, 100 mg, was first instilled intrapericardially, followed by tetracycline hydrochloride, 500 to 1,000 mg, dissolved in 20 mL normal saline. The catheter was clamped for one to two hours and then allowed to drain into the Hemovac. This procedure was repeated every 24 to 48 hours until the net drainage was less than 25 mL/24 hours. Nine men and 13 women were treated (median age, 55 years). The primary malignancy included lung in 15 patients, breast in two patients, and carcinoma of the stomach, ovary, pleural mesothelioma, chronic granulocytic leukemia, and adenocarcinoma of unknown primary in one patient each. Twenty patients received one to five instillations of tetracycline. In one patient the catheter could not be inserted into the pericardial sac, and in one patient the catheter clotted before tetracycline instillation. Minor complications included transient arrhythmia in two patients, postinjection pain in four patients, and self-limited temperature elevation greater than 38.5 degrees C in two patients. fifteen patients had good control of their malignant pericardial effusion for more than 30 days (median survival, 160 days; range, 38 to 275 days). Three patients died before 30 days without evidence of effusion, and no patient surviving longer than 30 days developed recurrent effusion or pericardial constriction. Intrapericardial tetracycline instillation is a safe and efficacious treatment for malignant pericardial effusion and should be considered the first treatment modality in this situation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cardiac Catheterization; Drainage; Echocardiography; Electrocardiography; Female; Heart Neoplasms; Humans; Male; Middle Aged; Neoplasms; Pericardial Effusion; Pericardium; Prognosis; Sclerosis; Tetracycline

The treatment of 15 patients with neoplastic pleurisy and 25 with spontaneous pneumothorax occurring for the second time is described. All were given endopleural tetracycline therapy for symphyseal purposes. In the neoplastic pleurisy cases, the treatment reduced the number of thoracenteses required. In only 1 case did spontaneous pneumothorax recur a short time after treatment.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Central Nervous System Diseases; Female; Humans; Injections; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pleura; Pleurisy; Pneumothorax; Rectal Neoplasms; Skin Neoplasms; Tetracycline

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; beta-Glucosidase; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Fluorouracil; Humans; Kinetics; Metabolic Clearance Rate; Neoplasms; Nitrogen Mustard Compounds; Tetracycline; Time Factors

Topics: Drainage; Humans; Neoplasms; Palliative Care; Pleural Effusion; Tetracycline

A pleural effusion is a frequent complication of malignant disease. Essential to the care of oncology patients is a fundamental knowledge of the pathophysiology and treatment of such effusions. This article discusses the current thoughts concerning the occurrence of malignant effusions, outlines the current available methods and agents employed for control, and presents a modification of the thoracostomy procedure that appears to be more effective than the standard procedure.

Topics: Bleomycin; Fluorouracil; Gold Radioisotopes; Humans; Mechlorethamine; Methods; Neoplasms; Phosphorus Radioisotopes; Pleura; Pleural Effusion; Quinacrine; Talc; Tetracycline; Thiotepa; Thoracic Surgery; Thorax

Topics: Bacterial Infections; Calymmatobacterium; Diagnosis, Differential; Female; Granuloma; Humans; Middle Aged; Neoplasms; Prognosis; Tetracycline

Tumor-seeking radiopharmaceuticals have been employed in the diagnosis of primary neoplasms, in the detection of distant disease, particularly in the localization of tumor foci to facilitate biopsies and the planning of radiation portals, and in assessing the response to tumor therapy. At the present, there is no ideal tumor-scanning agent. However, several approaches appear to be useful and offer promise for further study. The greatest experience has been with Gallium-67, which has major utility in the staging of Hodgkin's disease, in the diagnosis of bronchogenic carcinoma, in the detection of certain metastatic brain tumors, in the identification of recurrent disease, and in the noninvasive diagnosis of leukemic complications. A number of radiolabeled antibiotic and chemotherapeutic agents have shown promise, including tetracycline and bleomycin. A major drawback, however, of these agents which is shared with Gallium-67 is that they appear to be sequestered by inflammatory as well as neoplastic tissue. A most intriguing approach is the use of radiolabeled antibodies to tumor-associated antigens. Animal and clinical experiments have employed antifibrin, antifibrinogen, anticarcinoembryonic antigen, and antiferritin. Theoretically, agents such as these should allow for greater tumor specificity.

Topics: Antibodies, Neoplasm; Bleomycin; Brain Neoplasms; Carcinoembryonic Antigen; Carcinoma, Bronchogenic; Gallium Radioisotopes; Hodgkin Disease; Humans; Indium; Leukemia; Lung Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Radiography; Radioisotopes; Radionuclide Imaging; Technetium; Tetracycline

Iodine-131-tetracycline (131I-TET) was prepared by allowing tetracycline hydrochloride to react with radioiodide in acidic methanol (labeling efficiency greater than 85%). This preparation was found to be stable at--4 degrees C for at least 72 hr. Some minimal in vivo breakdown did occur. The 131I-TET, 67Ga, and several 99mTc compounds were studied in a rat hepatoma model. The incorporation of the radiopharmaceuticals into the tumor occurred rapidly, with peak levels at 0.5 and 24 hr after injection for 131I-TET and 67Ga, respectively. The clearnace of the radiopharmaceutical from nonviable tumor was slower than for viable tumor, and by 72 hr after injection the greatest concentration of radioactivity appeared in the nonviable fraction. All normal tissues showed faster clearance than did tumor tissue, regardless of viability. Decreasing the quantity of 131I-TET injected increased the percent of uptake in the nonviable tumor tissue but had no effect on the viable tumor uptake. Of the 99mTc compounds studied, the phosphates developed the highest tumor-to-background ratios. Unfortunately these ratios were not as high as those achieved for 67Ga or 131I-TET.

Topics: Animals; Disease Models, Animal; Gallium; Gallium Radioisotopes; Iodine Radioisotopes; Isotope Labeling; Liver Neoplasms; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Phosphates; Potassium Iodide; Radionuclide Imaging; Rats; Sugar Acids; Technetium; Tetracycline

Topics: Abnormalities, Drug-Induced; Alkylating Agents; Amphetamine; Androgens; Anticonvulsants; Antithyroid Agents; Carcinogens; Cerebral Palsy; Diethylstilbestrol; Estrogens; Female; Fetus; Folic Acid Antagonists; Gestational Age; Humans; Lead; Maternal-Fetal Exchange; Methylmercury Compounds; Neoplasms; Polychlorinated Biphenyls; Pregnancy; Progesterone; Streptomycin; Tetracycline; Thalidomide; Tooth; Transposition of Great Vessels; Warfarin

Topics: Animals; Basement Membrane; Cell Nucleus; Creatinine; Dogs; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Hematuria; Injections, Intraperitoneal; Kidney; Kidney Concentrating Ability; Kidney Cortex; Kidney Tubules, Distal; Kidney Tubules, Proximal; Mitochondria; Neoplasms; Organoids; Osmolar Concentration; Proteinuria; Pyuria; Tetracycline; Urine

Topics: Androgen Antagonists; Antibiotics, Antineoplastic; Bleomycin; Coumarins; Cyproterone; Endocarditis; Humans; Male; Neoplasms; Paraphilic Disorders; Pneumonia; Pregnadienes; Structure-Activity Relationship; Tetracycline; Urinary Tract Infections; Vitiligo

Topics: Adolescent; Child; Colectomy; Colitis, Ulcerative; Humans; Hydrocortisone; Male; Neoplasms; Prednisolone; Sulfasalazine; Tetracycline

Topics: Bacteria; Bacterial Infections; Doxycycline; Humans; Leukemia; Minocycline; Neoplasms; Tetracycline

Topics: Adult; Aged; Ascitic Fluid; Bone Neoplasms; Breast Neoplasms; Cardiovascular Diseases; False Negative Reactions; False Positive Reactions; Female; Filtration; Gastrointestinal Neoplasms; Humans; Male; Membranes, Artificial; Methods; Middle Aged; Neoplasms; Ovarian Neoplasms; Pleural Effusion; Prostatic Neoplasms; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Testicular Neoplasms; Tetracycline; Tuberculosis

Topics: Chloramphenicol; Culture Media; Humans; Neoplasms; Penicillin Resistance; Penicillins; Staphylococcus; Sulfonamides; Tetracycline

Topics: Chloramphenicol; Erythromycin; Genetics, Microbial; Genotype; Neoplasms; Penicillin G; Penicillin Resistance; Staphylococcus; Streptomycin; Sulfathiazoles; Tetracycline

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteroides; Bacteroides Infections; Breast Neoplasms; Child; Colonic Neoplasms; Female; Genital Neoplasms, Female; Hospitals, Special; Humans; Leukemia; Lymphoma; Male; Middle Aged; Neoplasms; Pressure Ulcer; Sepsis; Surgical Wound Infection; Tetracycline; Time Factors

Topics: Ampicillin; Anti-Bacterial Agents; Drug Combinations; Gentamicins; Humans; Neoplasms; Respiratory Tract Infections; Sepsis; Tetracycline; Urinary Tract Infections

Topics: Ampicillin; Anti-Bacterial Agents; Bacteria; Carbenicillin; Cephalothin; Chloramphenicol; Enterobacteriaceae; Escherichia coli; Gentamicins; Humans; Kanamycin; Klebsiella; Microbial Sensitivity Tests; Neoplasms; Polymyxins; Proteus; Pseudomonas aeruginosa; Pseudomonas Infections; Tetracycline

Topics: Ampicillin; Anti-Bacterial Agents; Carbenicillin; Chloramphenicol; Colistin; Drug Combinations; Drug Interactions; Drug Synergism; Enterobacteriaceae Infections; Erythromycin; Gentamicins; Glycosides; Humans; Hydrogen-Ion Concentration; Infections; Neoplasms; Novobiocin; Penicillins; Polymyxins; Streptomycin; Sulfonamides; Tetracycline; Trimethoprim

Topics: Adolescent; Adult; Aged; Bacteroides Infections; Child; Child, Preschool; Digestive System; Drug Resistance, Microbial; Female; Fusobacterium; Georgia; Humans; Infant; Male; Middle Aged; Neoplasms; Sepsis; Sulfonamides; Tetracycline; Vascular Diseases

Topics: Boron; Cell Line; Cells, Cultured; Conjunctiva; Endoplasmic Reticulum; Female; HeLa Cells; Humans; Leukemia, Myeloid; Lung; Microscopy, Fluorescence; Neoplasms; Tetracycline; Uterine Cervical Neoplasms

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Chloramphenicol; Conjugation, Genetic; Culture Media; Depression, Chemical; Drug Resistance, Microbial; Erythromycin Ethylsuccinate; Escherichia coli; Fluorouracil; Folic Acid Antagonists; Humans; Kanamycin; Neomycin; Neoplasms; Staphylococcus; Stimulation, Chemical; Streptococcus; Streptomycin; Sulfonamides; Tetracycline; Time Factors; Transduction, Genetic

Topics: Adolescent; Adult; Aged; Ampicillin; Bacteroides Infections; Chloramphenicol; Diagnosis, Differential; Erythromycin; Female; Humans; Male; Middle Aged; Neoplasms; Sepsis; Staphylococcal Infections; Tetracycline

Topics: Antineoplastic Agents; Cytopathogenic Effect, Viral; Enzyme Induction; Feedback; Infections; Lysogeny; Neoplasms; Nucleic Acids; Penicillins; Rickettsia; Rifampin; Tetracycline; Virus Diseases

Topics: Fluorescence; Glycosuria; Humans; Neoplasms; Tetracycline

Topics: Cytodiagnosis; Fluorescence; Humans; Neoplasms; Tetracycline

Topics: Fluorescence; Humans; Neoplasms; Tetracycline

Topics: Cytodiagnosis; Exudates and Transudates; Fluorescence; Gastric Juice; Humans; In Vitro Techniques; Intestinal Secretions; Microscopy, Fluorescence; Neoplasms; Pleural Effusion; Sputum; Tetracycline

Topics: Acridines; Cystoscopy; Fluorescence; Humans; Neoplasms; Tetracycline; Ultraviolet Rays

Topics: Adult; Aged; Fatty Liver; Female; Humans; Jaundice; Middle Aged; Neoplasms; Pancreatitis; Postoperative Complications; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Adult; Aged; Biological Assay; Blood Urea Nitrogen; Bronchopneumonia; Cachexia; Cerebrovascular Disorders; Creatine; Female; Heart Failure; Humans; Laryngeal Neoplasms; Male; Mastectomy; Methacycline; Middle Aged; Neoplasms; Prostatic Neoplasms; Tetracycline; Urinary Tract Infections

Topics: Bone Marrow; Child; Electrons; Kanamycin; Leukemia; Leukemia, Myeloid; Lupus Erythematosus, Systemic; Microscopy; Microscopy, Electron; Mycoplasma; Neoplasms; Neutralization Tests; Oncogenic Viruses; Sarcoma; Tetracycline; Tissue Culture Techniques; Virus Cultivation

Topics: Adenocarcinoma; Animals; Formaldehyde; Injections, Intraperitoneal; Leukemia; Leukemia, Experimental; Mice; Mustard Plant; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Research; Sarcoma 180; Tetracycline

Topics: Colonic Neoplasms; Colostomy; Drug Therapy; Humans; Ileostomy; Kanamycin; Neomycin; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Postoperative Complications; Preoperative Care; Rectal Neoplasms; Rectum; Sulfonamides; Surgical Procedures, Operative; Sutures; Tetracycline

Topics: Carcinoma; Carcinoma, Bronchogenic; Clinical Laboratory Techniques; Fluorescence; Humans; Lung Diseases; Microscopy; Microscopy, Fluorescence; Neoplasms; Sputum; Tetracycline; Ultraviolet Rays

Topics: Blood Circulation; Bone Neoplasms; Carotid Arteries; Coloring Agents; Fluorescence; Fluorescent Dyes; Humans; Injections, Intra-Arterial; Lip Neoplasms; Neoplasms; Tetracycline

Topics: Biomedical Research; Cystitis; Fluorescence; Humans; Kidney Neoplasms; Male; Neoplasms; Prostatic Neoplasms; Tetracycline; Urinary Bladder Neoplasms; Urinary Diversion; Urine

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Lung Neoplasms; Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Bronchial Neoplasms; Carcinoma, Bronchogenic; Early Diagnosis; Fluorescence; Humans; Neoplasms; Sputum; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; Tetracycline; Tetracyclines

Topics: Anti-Bacterial Agents; Female; Fluorescence; Fluoroscopy; Humans; Neoplasms; Protein Synthesis Inhibitors; Tetracycline; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Cytodiagnosis; Fluorescence; Gastric Lavage; Humans; Leiomyosarcoma; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Fluorescence; Neoplasms; Radiography; Radiology; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Neoplasms; Stomach Neoplasms; Tetracycline

Topics: Humans; Melphalan; Neoplasms; Tetracycline

Topics: Fluorescence; Neoplasms; Nursing; Nursing Care; Tetracycline

Topics: Fluorescence; Humans; Neoplasms; Nursing Care; Tetracycline

Topics: Aged; Female; Humans; Male; Microscopy, Fluorescence; Middle Aged; Neoplasms; Tetracycline

Topics: Exudates and Transudates; Fluorescence; Humans; Neoplasms; Sputum; Tetracycline

Topics: Aged; Agranulocytosis; Anti-Bacterial Agents; Bacteroides; Brucella; Chloramphenicol; Complement System Proteins; Endotoxins; Erythromycin; Hodgkin Disease; Humans; Leukemia; Leukopenia; Lymphadenitis; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Multiple Myeloma; Neoplasms; Penicillins; Primary Myelofibrosis; Properdin; Research; Sarcoma; Streptomycin; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; 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

Topics: Anti-Bacterial Agents; Equipment and Supplies; Fluorescence; Fluorescent Antibody Technique; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; Tetracycline; Ultraviolet Rays

Topics: Anti-Bacterial Agents; Fluorescence; Gastric Juice; Gastric Lavage; Geriatrics; Humans; Neoplasms; Stomach Neoplasms; Tetracycline; Ultraviolet Rays

Topics: Adenocarcinoma; Diagnosis, Differential; Fluorescence; Gastritis; Humans; Neoplasms; Sarcoma; Stomach Neoplasms; Stomach Ulcer; Tetracycline

Topics: Anti-Bacterial Agents; Demeclocycline; Early Diagnosis; Fluorescence; Gastric Lavage; Humans; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Achlorhydria; Ascites; Bile; Biomedical Research; Body Fluids; Duodenal Ulcer; Fluorescence; Gastric Lavage; Hernia, Diaphragmatic; Humans; Leiomyosarcoma; Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms; Pancreatic Juice; Pleural Effusion; Polyps; Secretin; Stomach; Stomach Neoplasms; Stomach Ulcer; Tetracycline

Topics: Anti-Bacterial Agents; Granulomatosis with Polyangiitis; Humans; Neoplasms; Pathology; Prednisolone; Radiography, Thoracic; Radiology; Tetracycline

Topics: Anemia; Anemia, Pernicious; Biomedical Research; Fluorescence; Humans; Neoplasms; Pancreatic Neoplasms; Saliva; Stomach Neoplasms; Stomach Ulcer; Tetracycline

Topics: Anti-Bacterial Agents; Coloring Agents; Fluorescent Dyes; Humans; Neoplasms; Skin Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Neoplasms; Stomach Neoplasms; Tetracycline

Topics: Breast Neoplasms; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; Rectal Neoplasms; Stomach Neoplasms; Tetracycline; Ultraviolet Rays

Topics: Anti-Bacterial Agents; Coloring Agents; Cytodiagnosis; Fluorescence; Humans; Neoplasms; Staining and Labeling; Tetracycline

Topics: Animals; Bone and Bones; Cytoplasm; Fluorescence; Gastric Mucosa; Histocytochemistry; Liver; Methylcholanthrene; Mice; Microscopy; Microscopy, Fluorescence; Microscopy, Phase-Contrast; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Pathology; Research; Stomach Neoplasms; Tetracycline; Tooth

Topics: Animals; Anti-Bacterial Agents; Carcinoma; Carcinoma, Ehrlich Tumor; Fluorescence; Fluorescent Dyes; Humans; Mice; Microscopy; Microscopy, Fluorescence; Neoplasms; Neoplasms, Experimental; Oxytetracycline; Rats; Research; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Geriatrics; Humans; Neoplasms; Pathology; Surgical Procedures, Operative; Tetracycline; Ultraviolet Rays; Urinary Bladder Neoplasms

Topics: Anti-Bacterial Agents; Cytodiagnosis; Fluorescence; Gastric Lavage; Humans; Microscopy; Microscopy, Fluorescence; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Photography; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Fluorescent Dyes; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Anti-Bacterial Agents; Demeclocycline; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Animals; Animals, Laboratory; Metabolism; Neoplasms; Neoplasms, Experimental; Protein Synthesis Inhibitors; Research; Tetracycline

Topics: Cytodiagnosis; Fluorescence; Humans; Microscopy; Microscopy, Fluorescence; Neoplasms; Tetracycline

Topics: Cytodiagnosis; Fluorescence; Fluorescent Antibody Technique; Humans; Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Humans; Neoplasms; Tetracycline

Topics: Bone Neoplasms; Fluorescence; Humans; Neoplasms; Osteosarcoma; Sarcoma; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Anti-Bacterial Agents; Cytodiagnosis; Fluorescence; Humans; Neoplasms; Stomach Neoplasms; Tetracycline

Topics: Carcinoma; Demeclocycline; Fluorescence; Fluorescent Dyes; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Citrus sinensis; Fluorescence; Gastric Juice; Humans; Neoplasms; Research; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Neoplasms; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Burns; Fluorescence; Humans; Inflammation; Ischemia; Myocardial Infarction; Necrosis; Neoplasms; Tetracycline

Topics: Animals; Anti-Bacterial Agents; Dogs; Iodine Isotopes; Metabolism; Mice; Neoplasms; Neoplasms, Experimental; Research; Tetracycline; Tetracyclines

Topics: Bronchiectasis; Bronchitis; Carcinoma, Bronchogenic; Fluorescence; Humans; Lung Diseases; Neoplasms; Oxytetracycline; Pulmonary Emphysema; Tetracycline

Topics: Anti-Bacterial Agents; Calcification, Physiologic; Calculi; Kidney Diseases; Muscles; Myocardium; Neoplasms; Pancreatitis; Tetracycline

Topics: Cytodiagnosis; Fluorescence; Neoplasms; Pharmacology; Protein Synthesis Inhibitors; Reproducibility of Results; Stomach Neoplasms; Tetracycline; Ultraviolet Rays

Topics: Bone Neoplasms; Colon; Fluorescence; Intestinal Neoplasms; Neoplasms; Protein Synthesis Inhibitors; Stomach Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Anti-Bacterial Agents; Bone and Bones; Fluorescence; Humans; Neoplasms; Tetracycline; Tetracyclines; Tooth

Topics: Bone and Bones; Bone Neoplasms; Fibrosarcoma; Humans; Neoplasms; Osteosarcoma; Tetracycline

Topics: Bone and Bones; Humans; Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Humans; Inactivation, Metabolic; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Protein Synthesis Inhibitors; Tetracycline; Ulcer

Topics: Anti-Bacterial Agents; Humans; Neoplasms; Protein Synthesis Inhibitors; Radioactivity; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Tetracycline

Topics: Anti-Bacterial Agents; Fluorescence; Humans; Neoplasms; Tetracycline

Topics: Animals; Anti-Bacterial Agents; Fluorescence; Fluorescent Dyes; Mice; Neoplasms; Protein Synthesis Inhibitors; Tetracycline

Topics: Humans; Neoplasms; Tetracycline

Topics: Animals; Antineoplastic Agents; Neoplasms; Neoplasms, Experimental; Tetracycline; Tissue Culture Techniques; Triethylenemelamine

Topics: Animals; Characidae; Diphosphates; Humans; Ions; Naphthoquinones; Neoplasms; Sodium; Tetracycline