cyclic-gmp and Neoplasms

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.

Topics: Cyclic GMP; Erectile Dysfunction; Humans; Male; Neoplasms; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

The second messenger cyclic guanosine monophosphate (cGMP) is an important regulator of human (patho-)physiology and has emerged as an attractive drug target. Currently, cGMP-elevating drugs are mainly used to treat cardiovascular diseases, but there is also increasing interest in exploring their potential for cancer prevention and therapy. In this review article, we summarise recent findings in cancer-related cGMP research, with a focus on melanoma, breast cancer, colorectal cancer, prostate cancer, glioma, and ovarian cancer. These studies indicate tremendous heterogeneity of cGMP signalling in tumour tissue. It appears that different tumour and stroma cells, and perhaps different sexes, express different cGMP generators, effectors, and degraders. Therefore, the same cGMP-elevating drug can lead to different outcomes in different tumour settings, ranging from inhibition to promotion of tumourigenesis or therapy resistance. These findings, together with recent evidence that increased cGMP signalling is associated with worse prognosis in several human cancers, challenge the traditional view that cGMP elevation generally has an anti-cancer effect. As cGMP pathways appear to be more stable in the stroma than in tumour cells, we suggest that cGMP-modulating drugs should preferentially target the tumour microenvironment. Indeed, there is evidence that phosphodiesterase 5 inhibitors like sildenafil enhance anti-tumour immunity by acting on immune cells. Moreover, many in vivo results obtained with cGMP-modulating drugs could be explained by effects on the tumour vasculature rather than on the tumour cells themselves. We therefore propose a model that incorporates the NO/cGMP signalling pathway in tumour vessels as a key target for cancer therapy. Deciphering the multifaceted roles of cGMP in cancer is not only a challenge for basic research, but also provides a chance to predict potential adverse effects of cGMP-modulating drugs in cancer patients and to develop novel anti-tumour therapies by precision targeting of the relevant cells and molecular pathways.

Topics: Cyclic GMP; Humans; Male; Neoplasms; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Tumor Microenvironment

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self-DNA in the cytoplasm. Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein stimulator of interferon genes (STING), which then activates the kinases IKK and TBK1 to induce the secretion of interferons and other cytokines. Recently, a series of studies demonstrated that the cGAS-STING pathway, a vital component of host innate immunity, might play an important role in anticancer immunity, though its mechanism remains to be elucidated. In this review, we highlight the latest understanding of the cGAS-STING pathway in tumor development and the advances in combination therapy of STING agonists and immunotherapy.

Topics: Cyclic GMP; DNA; Guanosine Monophosphate; Humans; Immunotherapy; Interferons; Membrane Proteins; Neoplasms; Nucleotidyltransferases

Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth. In this review, we describe the rationale for using the sulindac scaffold to design-out COX inhibitory activity, while improving potency and selectivity to inhibit PDE5 and PDE10 that activate cGMP/PKG signaling to suppress Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; beta Catenin; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Humans; Neoplasms; Phosphodiesterase Inhibitors; Signal Transduction; Sulindac; Transcription, Genetic; Wnt Proteins

Delivery systems are a powerful technology for enhancing the effect of cancer immunotherapy. We have been in the process of developing lipid-based delivery systems for controlling the physical properties and dynamics of immunofunctional molecules such as antigens and adjuvants. The lipid nanoparticulation of these molecules improves their physical properties, resulting in a good water dispensability, greater stability, and small size. The cell wall skeleton of bacille Calmette-Guerin (BCG-CWS) could be used to replace live BCG as a drug for treating bladder cancer, but problems associated with the physical properties of BCG-CWS have prevented its use. To overcome such problems, we developed a novel packaging method that permits BCG-CWS to be encapsulated into lipid nanoparticles, which induce antitumor responses against bladder cancer. Lipid nanoparticulation also improves the intracellular trafficking and biodistribution of immunofunctional molecules. Cyclic di-GMP (c-di-GMP) is an adjuvant that is recognized by the cytosolic sensor. However, c-di-GMP cannot pass through the cell membrane. We encapsulated c-di-GMP into lipid nanoparticles containing a pH-responsive lipid that was developed in our laboratory and achieved efficient cytosolic delivery and the induction of antitumor immunity. Furthermore, we are attempting to control the functions of immune cells by RNA interference. We have recently succeeded in the efficient delivery of small interfering RNA into mouse dendritic cells (DCs), which led to the enhancement of antitumor activity of DCs. In this review, our recent efforts regarding cancer immunotherapy using lipid-based nanoparticles are reviewed.

Topics: Adjuvants, Immunologic; Animals; Cell Wall Skeleton; Cyclic GMP; Dendritic Cells; Drug Delivery Systems; Drug Design; Humans; Immunotherapy; Lipids; Mice; Mycobacterium bovis; Nanoparticles; Neoplasms; RNA Interference; Urinary Bladder Neoplasms

Phosphodiesterase 5 (PDE5) inhibitors (PDE5i) have been used clinically for the treatment of erectile dysfunction, acting on the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway. Simultaneously, researchers have elucidated the roles that this pathway plays in the regulation of cell proliferation, tumor development, and progression. As a result, our knowledge of PDE5i and cancer biology has expanded and provides an integration that holds great promise for some, but concern for others.. This review evaluates the role of PDE5i and the NO/cGMP signaling pathway in the pathogenesis and prevention of various malignancies.. A literature review was performed with regard to the role of NO/cGMP pathway in tumor formation and prevention in preclinical and clinical studies. Studies that utilized PDE5i to further explore the involvement of this pathway also were included.. To evaluate whether PDE5i provide a potential benefit for treating and/or preventing malignancies; or if they create potential harm leading to the development of these malignancies.. The best available data suggest that the interactions between PDE5i and cancer are tumor- and tissue-specific. Currently, the effect of PDE5i use on melanoma development is being debated. Further clinical controversy lies in PDE5i use for penile rehabilitation after nerve-sparing prostate cancer surgery. Preclinical studies suggest that PDE5 inhibition could lead to a decreased risk of developing colorectal and breast cancer, leukemia, and myeloma. PDE5i also may provide an additional antitumor immune response. Finally, researchers have demonstrated a synergistic effect from combining PDE5i with current chemotherapeutic regimens.. Currently, there are inadequate data to make any conclusive statements regarding the role of PDE5i in cancer pathogenesis and how to alter clinical management. In order to create appropriate clinical guidelines, further experimental and clinical evidence is required.

Topics: Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Neoplasms; Nitric Oxide; Penis; Phosphodiesterase 5 Inhibitors

Nitric oxide (NO) is one of the 10 smallest molecules found in nature. It is a simple gaseous free radical whose predominant functions is that of a messenger through cGMP. In mammals, NO is synthesized by the enzyme nitric oxide synthase (NOS) of which there are three isoforms. Neuronal (nNOS, NOS1) and endothelial (eNOS, NOS3) are constitutive calcium-dependent forms of the enzyme that regulate neural and vascular function respectively. The third isoform (iNOS, NOS2), is calcium-independent and is inducible. In many tumors, iNOS expression is high, however, the role of iNOS during tumor development is very complex and quite perplexing, with both promoting and inhibiting actions having been described. This review will aim to summarize the dual actions of iNOS-derived NO showing that the microenvironment of the tumor is a contributing factor to these observations and ultimately to cellular outcomes.

Topics: Animals; Antineoplastic Agents; Bystander Effect; Cyclic GMP; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasms; NF-kappa B; Nitric Oxide Synthase Type II; Polymorphism, Genetic; Signal Transduction; Tumor Microenvironment

The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The α1β1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe(2+)) heme at histidine 105 of the β1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC-cGMP signaling in the chromatin-microenvironment.

Topics: Animals; Cyclic GMP; Guanylate Cyclase; Humans; Neoplasms; Signal Transduction; Tumor Microenvironment

The broad role of nitric oxide (NO) and cyclic GMP in biochemistry and biology as important messenger molecules is evident from the numerous publications in this research field. NO and cGMP have been known as components of the key signaling pathway in regulating numerous processes such as vascular dilation, blood pressure, neurotransmission, cardiovascular function, and renal function. In spite of almost 150,000 publications with nitric oxide and cyclic GMP, there are few publications regarding the effects of these messenger molecules on gene regulation, cell differentiation and cell proliferation. Our research data with embryonic stem cells and several cancer cell lines suggest that nitric oxide, its receptor soluble guanylyl cyclase (sGC) and sGC's product cyclic GMP can regulate the processes of proliferation and differentiation. Furthermore, we have found that undifferentiated stem cells and some malignant tumors such as human glioma have decreased levels of sGC and translocation of the sGCβ1 subunit to the nucleus. We propose that sGC and cyclic GMP function as tumor suppressors. An understanding of the mechanisms of the translocation of the sGCβ1 subunit into the nucleus and the possible regulation of gene expression of NO and/or cyclic CMP could lead to novel and innovative approaches to cancer therapy and stem cell proliferation and differentiation.

Topics: Biomedical Research; Cardiovascular System; Cyclic GMP; Guanylate Cyclase; Humans; Neoplasms; Nitric Oxide; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase

The role of NO and cGMP signaling in tumor biology has been extensively studied during the past three decades. However, whether the pathway is beneficial or detrimental in cancer is still open to question. We suggest several reasons for this ambiguity: first, although NO participates in normal signaling (e.g., vasodilation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric-oxide synthase (iNOS or NOS-2). In addition, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumors contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and inflammatory cells) with different NO biology. Thus, the NO/sGC/cGMP signaling molecules in tumors as well as the surrounding tissue must be further characterized before targeting this signaling pathway for tumor therapy. In this review, we focus on the NOS-2 expression in tumor and surrounding cells and summarized research outcome in terms of cancer therapy. We propose that a normal function of the sGC-cGMP signaling axis may be important for the prevention and/or treatment of malignant tumors. Inhibiting NOS-2 overexpression and the tumor inflammatory microenvironment, combined with normalization of the sGC/cGMP signaling may be a favorable alternative to chemotherapy and radiotherapy for malignant tumors.

Topics: Animals; Cell Line, Tumor; Cyclic GMP; Guanylate Cyclase; Humans; Macrophages; Mice; Neoplasms; Nitric Oxide; Nitric Oxide Synthase Type II; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Tumor Microenvironment

The physiology of a wide variety of organisms is organized according to periodic environmental changes imposed by the earth's rotation. This way, a large number of physiological processes present diurnal rhythms regulated by an internal timing system called the circadian clock. As part of the rhythmicity in physiology, drug efficacy and toxicity can vary with time. Studies over the past four decades present diurnal oscillations in drug absorption, distribution, metabolism, and excretion. On the other hand, diurnal variations in the availability and sensitivity of drug targets have been correlated with time-dependent changes in drug effectiveness. In this review, we provide evidence supporting the regulation of drug kinetics and dynamics by the circadian clock. We also use the examples of hypertension and cancer to show current achievements and challenges in chronopharmacology.

Topics: Animals; ARNTL Transcription Factors; Biological Clocks; Blood Pressure; Circadian Rhythm; CLOCK Proteins; Cyclic GMP; Humans; Hypertension; Neoplasms; Nitric Oxide; Pharmacokinetics; Pharmacology; Renin-Angiotensin System; Suprachiasmatic Nucleus

In addition to long-term regulation of angiogenesis, angiogenic growth factor signalling through nitric oxide (NO) acutely controls blood flow and haemostasis. Inhibition of this pathway may account for the hypertensive and pro-thrombotic side effects of the vascular endothelial growth factor antagonists that are currently used for cancer treatment. The first identified endogenous angiogenesis inhibitor, thrombospondin 1, also controls tissue perfusion, haemostasis and radiosensitivity by antagonizing NO signalling. We examine the role of these and other emerging activities of thrombospondin 1 in cancer. Clarifying how endogenous and therapeutic angiogenesis inhibitors regulate vascular NO signalling could facilitate development of more selective inhibitors.

Topics: Angiogenesis Inhibitors; Animals; CD36 Antigens; Cyclic GMP; Hemostasis; Humans; Neoplasms; Nitric Oxide; Radiation Tolerance; Regional Blood Flow; Signal Transduction; Thrombospondin 1

In recent years, several novel approaches have been developed to overcome tumor cell resistance to conventional therapeutics. Such approaches include genetic manipulations, vaccine development and exploitation of the anti-tumor host immune response. The overall development of tumor cell resistance to therapeutics is, in large part, the result of the ability of tumor cells to develop specific mechanisms to overcome cell death or apoptosis. Therefore, the possibility to interfere selectively in the regulation of the apoptotic signaling pathways may result in either the direct induction of cell death and/or sensitization of the cells to cytotoxic stimuli. A novel approach based on modifying gene products that regulate resistance to apoptosis involves nitric oxide (NO). NO is a ubiquitous molecule with diverse cellular effects that depend on the source, concentration, latency, cell type and phenotype. This review describes the role played by NO in cancer including carcinogenesis, pathogenesis, angiogenesis, chemoprevention and as a novel therapeutic to overcome resistance when used alone or as a sensitizing agent used in combination with other therapeutics.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cyclic GMP; Drug Resistance, Neoplasm; Humans; Mitochondria; Neoplasms; Nitric Oxide; Protein Processing, Post-Translational; Signal Transduction

Levels of cyclic guanosine 3',5'-monophosphate (cGMP) are elevated in plasma and urine from patients with some cardiovascular diseases and some types of cancer.. This paper is based on studies of cGMP as a biomarker.. It is well documented that cGMP levels are elevated in plasma in patients with heart failure and various leukaemias and in urine from patients with gynaecological cancers. Because of great interindividual variation in levels, cGMP is less suitable in primary diagnostics, but appears to be a sensitive marker in individual follow up in some diseases.

Topics: Biomarkers; Biomarkers, Tumor; Cardiovascular Diseases; Cyclic GMP; Female; Heart Failure; Humans; Leukemia; Male; Neoplasms

Topics: Asthma; Biomarkers; Cyclic GMP; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hyperparathyroidism; Liver Diseases; Myocardial Infarction; Neoplasms; Nitric Oxide; Radioimmunoassay; Reference Values; Specimen Handling

Since the first article on YC-1 was published in 1994, it has been popularly used as a pharmacological tool to activate soluble guanylate cyclase and to increase cyclic GMP levels in cultured cells or isolated tissues. In terms of the pharmacological actions of YC-1, previous studies tend to be limited to it inhibition of platelet aggregation and vascular concentration. However, recent studies have demonstrated that YC-1 has versatile pharmacological effects other than the anti-platelet and vasodilatory effects. In particular, two recent reports suggest that YC-1 could be developed as a new class of anticancer agent for rapidly growing solid tumors, because it inhibits hypoxia-inducible factor 1 (HIF-1) activity, and has been reported to halt tumor growth in vivo. We here review the cyclic GMP-dependent and independent pharmacological actions of YC-1, and its anti-HIF-1, anticancer effect.

Topics: Animals; Antineoplastic Agents; Cyclic GMP; Guanylate Cyclase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Neoplasms; Platelet Aggregation Inhibitors; Transcription Factors

The vasculature endothelium cells and the nerve cells of several regions of the brain and the autonomous nerve system contain a nitric oxide (NO)-synthase, that forms NO from arginine. The NO-synthase is stimulated by bradykinin, histamine and acetylcholine and is especially active in the coronary and brain vessels. In the vasculature smooth muscle NO activates the guanylate cyclase: The increase in the concentration of cGMP induces a relaxation and in this way a vasodilatation. In the nerve cells NO is active as a neuromodulator. The activation of macrophages by gamma-interferon or by lipopolysaccharides induces the formation of a NO-synthase, that has other properties than the enzyme of the endothelium cells. The macrophages secrete NO and inhibit the metabolism of tumour cells, especially enzymes of the respiratory chain and of the citric acid cycle as well as the DNA-synthesis. Trinitroglycerin and amyl nitrite form with thiol-compounds S-nitroso-compounds, the decomposition of these forms NO.

Topics: Amino Acid Oxidoreductases; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Humans; Macrophages; Neoplasms; Neurons; Neurotransmitter Agents; Nitric Oxide; Nitric Oxide Synthase; Vasodilation

Topics: Calcium; Cell Differentiation; Cell Division; Cell Membrane; Cell Physiological Phenomena; Cyclic AMP; Cyclic GMP; Growth Substances; GTP-Binding Proteins; Hormones; Humans; Neoplasms; Oncogene Proteins, Viral; Oncogenes; Phosphatidylinositols; Protein Kinases; Proto-Oncogene Proteins; Proto-Oncogenes; Receptors, Cell Surface

Tumor promoters act on carcinogen-initiated tissues to cause phenotypic expression of malignancy. Phorbol ester tumor promoters, like hormones, act on cells and tissues at nanomolar concentrations, often producing "physiological" effects. These promoters also act on cells to produce what appear to be nonphysiologic or toxic effects. One of the major questions regarding these phenomena is, Which action or actions of promoters are important in phenotypic expression of malignancy?

Topics: Animals; Calcimycin; Calcium; Chromosomes; Concanavalin A; Cyclic GMP; DNA; Egtazic Acid; Humans; Myristates; Neoplasms; Potassium; Protein Kinase C; Protons; Sodium; Tetradecanoylphorbol Acetate

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adenylyl Cyclases; Animals; Cyclic AMP; Cyclic GMP; Endotoxins; Extracellular Space; Hormones; Humans; Hypercalcemia; Hypertension; Hypoparathyroidism; Kidney Diseases; Neoplasms; Nucleotides, Cyclic; Parathyroid Hormone; Protein Kinases; Pseudohypoparathyroidism; Rats

Topics: Adenosine Triphosphate; Animals; Biological Transport; Blood Cells; Cell Transformation, Neoplastic; Cyclic AMP; Cyclic GMP; Female; Guanosine Triphosphate; Humans; Kidney; Liver; Male; Neoplasms; Neoplasms, Experimental; Nucleotides, Cyclic; Rats; Receptors, Cell Surface

The understanding of passive transfer of cell mediated-immune responses with transfer factor and other cell free materials has progressed to the point that investigators are seeking the chemical identity of the molecule(s) that are responsible for these effects and are working on their mechanisms of action. In addition, clinical trials are underway that should clarify the potential for use of transfer factor in treatment of infections, neoplastic and autoimmune diseases. This chapter will critically review the past and current data concerning the components of transfer factor and their effects on immunologic and inflammatory reactions. Some of the recently developed animal models will be described and evaluated, and the clinical studies that have provided conclusive data regarding efficacy will be reviewed.

Topics: Animals; Antibody Formation; Antineoplastic Agents; Bacterial Infections; Cattle; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Cytotoxicity, Immunologic; Dermatitis, Contact; Dogs; Guinea Pigs; Haplorhini; Humans; Hypersensitivity, Delayed; Immune System Diseases; Immunoglobulins; Lymphatic System; Lymphocyte Activation; Lymphokines; Macrophages; Mice; Mice, Inbred Strains; Mycoses; Neoplasms; Organ Size; Parasitic Diseases; Rosette Formation; Transfer Factor; Virus Diseases

Topics: Adenylyl Cyclases; Animals; Bucladesine; Carcinogens; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic; Cyclic AMP; Cyclic GMP; Humans; Neoplasms; Neoplasms, Experimental; Organ Specificity

Topics: Animals; Bone Marrow Cells; Calcium; Cell Division; Cyclic AMP; Cyclic GMP; DNA; Female; Humans; Hyperthyroidism; Liver Regeneration; Male; Neoplasms; Rats; Thymus Gland

Calcium, in partnership with cyclic AMP, controls the proliferation of non-tumorigenic cells in vitro and in vivo. While it does not seem to be involved in the proliferative activation of cells such as hepatocytes (in vivo) or small lymphocytes (in vitro), it does control two later stages of prereplicative (G1) development. It must be one of the very many regulatory and permissive factors affecting early prereplicative development, because severe calcium deprivation reversibly arrests some types of cell early in the G1 phase of their growth-division cycle in vitro. However, calcium more specifically and much more often regulates a later (mid or late G1) stage of prereplicative development. Thus, regardless of its severity or the type of cell, calcium deprivation in vitro or in vivo reversibly stops proliferative development at that part of the G1 phase in which the cellular cyclic AMP content transiently rises and the synthesis of the four deoxyribonucleotides begins. The evidence points to calcium and the cyclic AMP surge being co-generators of the signal committing the cell to DNA synthesis. The evidence is best explained so far by the cyclic AMP surge causing a surge of calcium ions which combine with molecules of the multi-purpose, calcium-dependent, regulator protein calmodulin (CDR) somewhere between the cell surface and the cytosol. The resulting Ca-calmodulin complexes then stimulate many different (and possibly membrane-associated) enzymes such as protein kinases, one of which produces the DNA-synthetic initiator. Calcium has little or no influence on the proliferation of tumor cells. Some possible explanations of this very important loss of control are considered.

Topics: Animals; Calcium; Calmodulin; Cell Cycle; Cell Division; Cyclic AMP; Cyclic GMP; DNA; Liver; Lymphocyte Activation; Neoplasms; Protein Kinases; Rats; T-Lymphocytes

Many hormones act by combining with cell surface receptors and stimulating adenylate cyclase activity. The cyclic AMP generated is the mediator of a number of cellular metabolic processes. Other processes may be influenced by changes in cyclic GMP levels. Although much evidence from cultured cells suggested that low cellular levels of cyclic AMP and high levels of cyclic GMP are a feature of rapid cell growth and of malignant transformation, review of the data reveals many inconsistencies. Thus in established tumours growing in vivo, for example, cyclic AMP levels appear to be unrelated to tumour growth rates. It seems that tumour cell cyclic AMP is more likely concerned with the regulation of tumour cell function than of growth. This would have implications for therapy, in that drugs which influence cyclic nucleotide metabolism could influence tumour cell function. The control of cyclic nucleotide production in normal and tumour cells is discussed, together with the possible ways in which abnormalities of this may occur.

Topics: Adenylyl Cyclases; Animals; Cell Line; Cell Transformation, Viral; Cells, Cultured; Cyclic AMP; Cyclic GMP; Hormones; Humans; Neoplasms; Neoplasms, Experimental; Prostaglandins E; Protein Kinases; Receptors, Cell Surface

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Calcium; Chemotaxis; Cyclic AMP; Cyclic GMP; Diabetes Insipidus; Glycogen; Humans; Hypersensitivity; Intestinal Mucosa; Lipid Metabolism; Lymphocytes; Methods; Mice; Neoplasms; Nucleotides, Cyclic; Parathyroid Diseases; Phagocytosis; Rats

Topics: Adenylyl Cyclases; Animals; Anti-Inflammatory Agents; Antiviral Agents; Asthma; Cardiovascular Diseases; Cricetinae; Cyclic AMP; Cyclic GMP; Disease; Enzyme Activation; Extracellular Space; Guanylate Cyclase; Humans; Hypoglycemic Agents; Isoenzymes; Kinetics; Mental Disorders; Mice; Neoplasms; Obesity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Psoriasis; Rats

Topics: Animals; Antibody Formation; B-Lymphocytes; Cyclic AMP; Cyclic GMP; Cytotoxicity Tests, Immunologic; Humans; Hypersensitivity; Immunity, Cellular; Immunosuppression Therapy; Indomethacin; Inflammation; Lymphocyte Activation; Lymphocytes; Macrophages; Neoplasms; Neutrophils; Prostaglandins; Receptors, Prostaglandin; T-Lymphocytes

Topics: Animals; Calcium; Cell Adhesion; Cell Division; Cell Movement; Cell Transformation, Neoplastic; Culture Techniques; Cyclic AMP; Cyclic GMP; Humans; Lymphocyte Activation; Lymphocytes; Microtubules; Mitogens; Mitosis; Neoplasms; Nucleotides, Cyclic

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenylyl Cyclases; Carcinoma, Hepatocellular; Cell Division; Cell Membrane; Cell Transformation, Neoplastic; Cells, Cultured; Cyclic AMP; Cyclic GMP; Cytosine Nucleotides; DNA; Enzyme Activation; Enzyme Inhibitors; Fibroblasts; Growth Substances; Liver; Liver Neoplasms; Lymphocyte Activation; Lymphocytes; Melanoma; Mitogens; Neoplasms; Skin; Thymus Gland

Topics: Aging; Base Sequence; Caffeine; Carcinogens; Cell Differentiation; Cell Division; Chromatin; Chromosome Aberrations; Cyclic AMP; Cyclic GMP; DNA Nucleotidyltransferases; DNA Repair; DNA Replication; Endonucleases; Environment; Genetic Diseases, Inborn; Humans; Models, Biological; Mutagens; Mutation; Neoplasms; Phenotype; Phorbol Esters; Precancerous Conditions; Recombination, Genetic; Ultraviolet Rays

Topics: Adenylyl Cyclases; Animals; Binding Sites; Cell Membrane; Cyclic AMP; Cyclic GMP; Genes; Guanylate Cyclase; Hormones; Neoplasms; Neoplasms, Experimental; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Phosphoric Monoester Hydrolases; Protein Kinases; Receptors, Cell Surface

Topics: Animals; Binding Sites; Cell Adhesion; Cell Division; Cell Membrane; Cell Transformation, Neoplastic; Chick Embryo; Cricetinae; Cyclic AMP; Cyclic GMP; Erythrocytes; Glycolipids; Glycoproteins; Humans; Intercellular Junctions; Kidney Tubules, Proximal; Lectins; Lipid Metabolism; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Proteins

Autologous chimeric antigen receptor (CAR) T cells targeting the CD19 antigen have demonstrated a high complete response rate in relapsed/refractory B-cell malignancies. However, autologous CAR T cell therapy is not an option for all patients. Here we optimized conditions for clinical-grade manufacturing of allogeneic CD19-CAR T cells using CD45RA-depleted donor memory T cells (Tm) for a planned clinical trial. Tm were activated using the MACS GMP T Cell TransAct reagent and transduced in the presence of LentiBOOST with a clinical-grade lentiviral vector that encodes a 2nd generation CD19-CAR with a 41BB.zeta endodomain. Transduced T cells were transferred to a G-Rex cell culture device for expansion and harvested on day 7 or 8 for cryopreservation. The resulting CD19-CAR(Mem) T cells expanded on average 34.2-fold, and mean CAR expression was 45.5%. The majority of T cells were CD4

Topics: Antigens, CD19; Cyclic GMP; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; T-Lymphocytes

The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (

Topics: Animals; Crystallography, X-Ray; Cyclic AMP; Cyclic GMP; Female; Humans; Immunity, Innate; Immunotherapy; Membrane Proteins; Mice; Mice, Inbred BALB C; Models, Molecular; Neoplasms; Signal Transduction; Small Molecule Libraries

The correlation between cell hydration and proliferation is one of the controversial subjects in the present cancer research because the detailed mechanism(s) of correlation between these two cell parameters are not evaluated yet. The fact that magnetic fields have antitumor effects and our previous data that the effect of 4 Hz pulsing magnetic field (PMF) is realized by the activation of Cyclic guanosine monophosphate (cGMP)-dependent Na/Ca exchange allow us to suggest that through the study of PMF effects on cell hydration and proliferation in soft tissues of sarcoma-180 tumor-carrying mice compared with those of healthy ones will be possible to evaluate the character of correlation between cell hydration and proliferation in norm and pathology. The daily 30-min PMF (0.2 mT) exposed on tumor-carrying mice has lifetime prolongation, time-dependent depression of tumor growth, decrease of thermal threshold, and lactate concentration in blood. In the initial (6 days) period tumorigenesis PMF leads to dehydration in spleen cells, which is accompanied by the activation of cell proliferation, while in late periods of tumorigenesis it leads to cell hydration accompanied with proliferation. We are suggesting that PMF-induced overhydration and the increase of cell proliferation in cancer tissue as a consequence of high [Ca]i-induced activation of Ca-calmoduline-NO-cGMP pathway leads to the activation of FNa/Ca exchange, while its antitumor effect expressed in initial period of tumorigenesis is due to the activation of cGMP-dependent FNa/Ca, where because of low [Ca]i, it brings to cell dehydration as a result of reactivation of Na/K pump.

Topics: Animals; Biological Transport; Cell Proliferation; Cyclic GMP; Lactic Acid; Magnetic Field Therapy; Male; Mice; Neoplasms; Pain Threshold; Potassium; Sodium

The platelet inhibitory effects of the Phase 3 anticancer agent and nitric oxide (NO) donor, RRx-001, (1-bromoacetyl-3,3-dinitroazetidine) were examined ex vivo and compared with the diazeniumdiolate NO donor, diethylenetriamine NONOate (DETA-NONOate), which spontaneously releases nitric oxide in aqueous solution. In the absence of red blood cells and in a dose-dependent manner, DETA-NONOate strongly inhibited platelet aggregation induced by several stimuli (ADP, epinephrine and collagen) whereas RRx-001 only slightly inhibited platelet aggregation under the same conditions in a dose-dependent manner; these antiaggregant effects were blocked when both DETA-NONOate and RRx-001 were co-incubated with carboxy-PTIO (CPTIO 0.01-100 micromol), a widely accepted NO scavenger. However, in the presence of red blood cells from healthy human donors, RRx-001, which binds covalently to haemoglobin (Hb) and catalyses the production of NO from endogenous nitrite, more strongly inhibited the aggregation of platelets than DETA-NONOate in a dose-dependent manner likely because haemoglobin avidly scavenges nitric oxide and reduces its half-life; the RRx-001-mediated platelet inhibitory effect was increased in the presence of nitrite. The results of this study suggest that RRx-001-bound Hb (within RBCs) plays an important role in the bioconversion of

Topics: Adult; Azetidines; Blood Platelets; Collagen; Cyclic GMP; Erythrocytes; Female; Hemoglobins; Humans; Male; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Nitro Compounds; Platelet Aggregation; Thrombophilia

The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment.

Topics: Animals; Cell Survival; Chromatin; Cyclic GMP; Immunohistochemistry; Mice; Mice, Inbred C3H; Neoplasms; Neuroprotective Agents; Photoreceptor Cells, Vertebrate; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Binding; Quantitative Structure-Activity Relationship; Rabbits; Retinal Degeneration

The inducible nitric oxide synthase (iNOS) is expressed constitutively but also induced in a number of epithelial cell types. iNOS regulates a number of cellular processes in these cell types without exerting toxicity. Among these functions is protection from cellular injury mediated by pro-apoptotic signals. We have had long-standing interest in the cell protective roles of iNOS in hepatocytes. We demonstrated that the upregulation of iNOS protects hepatocytes and the liver from TNF-mediated toxicity. This includes the inhibition of caspase activity through s-nitrosation. However, some of the effects are mediated through cGMP. Exploration into the mechanisms of the cGMP-mediated protection identified a role for the iNOS/NO/cGMP pathway in the activation of ADAM17 (TACE), which is a sheddase that cleaves a number of cell surface receptors including TNF receptor type 1 (TNFR1). The activation is associated with the phosphorylation of TACE. The iNOS/NO/cGMP/TACE pathway can be augmented by PDE5 inhibitors and reduce organ injury in the setting of sepsis. The implications go beyond acute pathophysiology and may be important to the mechanisms of iNOS in promoting aggressive cancers.

Topics: ADAM17 Protein; Animals; Cyclic GMP; Hepatocytes; Humans; Neoplasm Proteins; Neoplasms; Nitric Oxide; Nitric Oxide Synthase Type II; Second Messenger Systems; Tumor Necrosis Factor-alpha

Ganoderma atrum polysaccharide (PSG-1) has been commonly suggested as a candidate for prevention and therapy of cancer. We investigated the antitumor effect and the underlying molecular mechanisms of PSG-1. The results showed that PSG-1 inhibited tumor growth and resulted in tumor cell apoptosis in vivo. Here, the data revealed that PSG-1 caused a markedly increase in cAMP and PKA activities, rather than cGMP and PKC. Moreover, the treatment of PSG-1 induced a dramatic increase in the protein level of PKA. In contrast, the expression of PKC and intracellular [Ca(2+)]i were inhibited. Our study also revealed that treatment with PSG-1 increased the spleen and thymus weights, lymphocyte proliferation and macrophage phagocytic activity in tumor-bearing mice. Taken together, we conclude that PSG-1 could inhibit the tumor growth, possibly in part by enhancing the induction of apoptosis through cAMP-PKA signaling pathway and down-regulation of Ca(2+)/PKC signal pathway, activating host immune function in S180-bearing mice.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Disease Models, Animal; Down-Regulation; Female; Ganoderma; Macrophages; Mice; Neoplasms; Polysaccharides; Protein Kinase C; Signal Transduction; Spleen

Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. It is thought that c-di-GMP is recognized by ATP dependent RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers a signal via the tank binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as an adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm. Our group has been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic, pH sensitive lipid that has a high fusogenicity. We utilized this lipid as a carrier to transport c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/cholesterol=40/25/35 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of the STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.

Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Cell Line; Cell Line, Tumor; Cyclic GMP; Female; Immunotherapy; Interferon-beta; Lipids; Liposomes; Mice, Inbred C57BL; Neoplasms; Ovalbumin; Piperidines; T-Lymphocytes, Cytotoxic; Tumor Burden

Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate delivery of the drugs/compounds to the tumor site. Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to administration of such complexes.

Topics: Apoptosis; Cell Cycle Checkpoints; Cyclic GMP; Drug Delivery Systems; Humans; Macromolecular Substances; Models, Biological; Neoplasms; Phosphodiesterase Inhibitors; Ruthenium Compounds; Transferrin

The major constituent of green tea, (-)-epigallocatechin-3-O-gallate (EGCG), has been shown to have cancer-preventive and therapeutic activities. Numerous molecular targets for EGCG have been proposed, but the mechanisms of its anticancer activities are not clearly understood. In this issue of the JCI, Kumazoe et al. report that EGCG activates 67-kDa laminin receptor (67LR), elevates cGMP levels, and induces cancer cell apoptosis. Furthermore, a phosphodiesterase 5 inhibitor, vardenafil, synergizes with EGCG to induce cancer cell death. This is a provocative observation with important implications for cancer therapy. It also raises several issues for further investigation, such as the mechanism by which EGCG specifically activates 67LR.

Topics: Animals; Apoptosis; Cyclic GMP; Female; Humans; Male; Neoplasms; Receptors, Laminin

The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

Topics: Animals; Apoptosis; Caspases; Catechin; Cell Line, Tumor; Cell Proliferation; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Imidazoles; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Molecular Weight; Multiple Myeloma; Neoplasms; Phosphodiesterase 5 Inhibitors; Piperazines; Receptors, Laminin; Signal Transduction; Sulfones; Triazines; Vardenafil Dihydrochloride; Xenograft Model Antitumor Assays

Our previous studies demonstrate a differential expression of nitric oxide (NO) signaling components in ES cells and our recent study demonstrated an enhanced differentiation of ES cells into myocardial cells with NO donors and soluble guanylyl cyclase (sGC) activators. Since NO-cGMP pathway exhibits a diverse role in cancer, we were interested in evaluating the role of the NO-receptor sGC and other components of the pathway in regulation of the tumor cell proliferation. Our results demonstrate a differential expression of the sGC subunits, NOS-1 and PKG mRNA and protein levels in various human cancer models. In contrast to sGC alpha(1), robust levels of sGC beta(1) were observed in OVCAR-3 (ovarian) and MDA-MB-468 (breast) cancer cells which correlated well with the sGC activity and a marked increase in cGMP levels upon exposure to the combination of a NO donor and a sGC activator. NOC-18 (DETA NONOate; NO donor), BAY41-2272 (3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine); sGC activator), NOC-18+BAY41-2272, IBMX (3-isobutyl-1-methylxanthine; phosphodiesterase inhibitor) and 8-bromo-cGMP (cGMP analog) caused growth inhibition and apoptosis in various cancer cell lines. To elucidate the molecular mechanisms involved in growth inhibition, we evaluated the effect of activators/inhibitors on ERK phosphorylation. Our studies indicate that BAY41-2272 or the combination NOC-18+BAY41-2272 caused inhibition of the basal ERK1/2 phosphorylation in OVCAR-3 (high sGC activity), SK-OV-3 and SK-Br-3 (low sGC activity) cell lines and in some cases the inhibition was rescued by the sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). These studies suggest that the effects of activators/inhibitors of NO-sGC-cGMP in tumor cell proliferation is mediated by both cGMP-dependent and independent mechanisms.

Topics: 1-Methyl-3-isobutylxanthine; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Humans; Mitogen-Activated Protein Kinases; Neoplasms; Nitric Oxide; Nitroso Compounds; Phosphorylation; Pyrazoles; Pyridines; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Structure-Activity Relationship

We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT-PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA-ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.

Topics: Aged; Aged, 80 and over; Animals; Cyclic GMP; Dogs; G-Protein-Coupled Receptor Kinase 1; Guanylate Cyclase; HCT116 Cells; HT29 Cells; Humans; Hypoxia; Intracellular Signaling Peptides and Proteins; Middle Aged; Neoplasm Invasiveness; Neoplasms; Osteonectin; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptor, PAR-1; Receptors, Antigen; Receptors, Cytoplasmic and Nuclear; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Soluble Guanylyl Cyclase; Thrombin

Oxygen deficiency in tumors reduces the efficacy of nonsurgical treatment modalities. We tested the hypothesis that electrical stimulation of the sciatic nerve could modify the oxygenation status and the blood flow of tumors implanted in the thigh of mice.. The sciatic nerve was electrically stimulated at 5 Hz. Local transplantable liver tumor (TLT) and fibrosarcoma (FSaII) tumor oxygen pressure (pO(2)) and perfusion measurements were carried out using electron paramagnetic resonance (EPR) oximetry and the OxyLite/OxyFlo technique. The radiosensitizing effect of the protocol was assessed by irradiating FSaII tumors with X-rays.. Tumor pO(2) increased from approximately 3 mm Hg to approximately 8 mm Hg, and relative tumor blood flow was increased by 241% and 162% for TLT and FSaII tumor models, respectively. The effect on the tumor oxygenation was inhibited by a nitric oxide synthase (NOS) inhibitor, and an increase in the tumor nitric oxide (NO) content was observed using EPR spin-trapping. The tumor oxygen consumption rate was decreased after the stimulation protocol. In addition, the electrical stimulation of the host tissue increased regrowth delays by a factor of 1.65.. This increase in tumor oxygenation is due to the temporary increase in tumor blood flow, but particularly to a decrease in the tumor oxygen consumption rate (inhibition of respiration) that is mediated by a local production of NO during the protocol. Those tumor hemodynamic changes resulted in a radiosensitizing effect.

Topics: Animals; Cell Hypoxia; Cyclic GMP; Electric Stimulation; Flow Cytometry; Laser-Doppler Flowmetry; Mice; Muscle, Skeletal; Neoplasm Transplantation; Neoplasms; Nitric Oxide; Oximetry; Oxygen Consumption; Partial Pressure; Physical Exertion; Radiation Tolerance; Regional Blood Flow; Sciatic Nerve; Spin Trapping

Topics: Apoptosis; Cell Division; Cyclic GMP; Free Radical Scavengers; Humans; Neoplasms; Nitrates; Nitric Oxide; Superoxides; Vasodilation

We measured concentrations of guanosine 3',5'-monophosphate (cGMP) in plasma and urine of healthy subjects and patients with congestive heart failure, renal impairment, neoplastic disease, and hepatic cirrhosis. There was no correlation between cGMP concentrations in urine and in plasma. In all patients except those with renal impairment, urinary cGMP concentrations were significantly higher than in healthy persons. Only patients with heart failure or renal impairment showed significantly increased plasma cGMP concentrations. In contrast, cGMP in urine does not relate to the clinically assessed severity of heart failure (New York Heart Association functional classes). Determination of cGMP in plasma results in higher sensitivity and specificity for diagnosing heart failure than measurement of cGMP in urine.

Topics: Adult; Aged; Cyclic GMP; Female; Heart Failure; Humans; Kidney Diseases; Liver Cirrhosis; Male; Middle Aged; Neoplasms; Reference Values; Ventricular Function, Left

Topics: Asthma; Cyclic GMP; Humans; Liver Diseases; Myocardial Infarction; Neoplasms; Radioimmunoassay

The magnesium interaction with the mononucleotide guanosine-5'-monophosphate disodium salt (5'-GMP Na2 or G5'p) has been studied by Fourier transform infrared spectroscopy. The results have been compared with previously obtained proton nuclear magnetic data on the same system as well as other similar systems. The spectra here show that the natural conformation of the mononucleotide changes significantly in the presence of normal concentrations of magnesium chloride (approximately 10(-3) M) from the predominantly C2'-endo,anti into C3'-endo,anti conformation of the sugar ring, and the phosphate group becomes virtually gauche-gauche. The marker bands for C2'-endo,anti and C3'-endo,anti are shown near 820 cm-1 and 803 cm-1, respectively. The infrared spectroscopic results found here indicate that the unit Mg(H2O)2+5 is coordinated at the N7 site of the base guanine and hydrogen bonded via the water molecules to the carbonyl C6 = O and to the phosphate negative oxygens. This type of bonding is very similar to the binding of the antitumor drug cis-platinum, which is chemically (covalently) bound to the N7 site of guanine in the same molecule or in nucleic acids.

Topics: Cyclic GMP; DNA; Fourier Analysis; Magnesium; Magnesium Chloride; Magnetic Resonance Spectroscopy; Neoplasms; Nucleic Acid Conformation; Spectrophotometry, Infrared

Pain-alleviating effects of epidural spinal cord stimulation (ESCS) were assessed in patients with chronic intractable pain including cancer pain, and some aspects concerning its mechanisms were discussed. The temporary ESCS with percutaneously inserted electrodes was employed in 105 patients, and the implantable systems for long-term use in 19 patients. The ESCS had satisfactory effects especially in patients suffering from cancer pain, causalgia, facial and nape pain. The conditioning stimuli applied to the cervical dorsal cord exhibited interactions with the segmentally evoked spinal cord potential (SCP). The N1 wave of the SCP was inhibited up to 120 ms, while the P2 wave was facilitated for more than 100 ms, suggesting that the presynaptic inhibitory action at the dorsal horn is responsible for mechanism of the ESCS. CSF concentration of norepinephrine was significantly decreased by the ESCS therapy, indicating the existence of the relationship between norepinephrinergic descending inhibitory system and the ESCS in pain-alleviating mechanism.

Topics: Adult; Aged; Cerebral Palsy; Cyclic GMP; Electric Stimulation Therapy; Electrodes, Implanted; Female; Humans; Male; Middle Aged; Neoplasms; Neuralgia; Norepinephrine; Pain, Intractable; Pain, Postoperative; Spinal Cord; Spinal Cord Diseases; Spinal Cord Injuries

Plasma and/or urine cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) levels were measured in 67 normal subjects, 55 patients with nonneoplastic diseases, and 324 patients with ten different types of cancer. There were no significant differences in plasma and urine cyclic nucleotide levels between normal subjects and patients with non-neoplastic diseases. In untreated cancer patients, plasma and urine cAMP levels were similar to those of normal subjects, whereas plasma and urine cGMP levels were markedly higher. This pattern was common to all the cancer groups studied. Chemotherapy per se did not seem to influence cyclic nucleotide levels in cancer patients. However, plasma and urine cGMP levels normalized in all patients who attained complete remission. Moreover, in acute leukemia patients who relapsed, plasma cGMP levels increased significantly with respect to the complete remission values, thus suggesting that this parameter may be useful in monitoring the response of cancer patients to treatment.

Topics: Adolescent; Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Neoplasms; Nucleotides, Cyclic

The double-zone fluorescein fluorescence polarization (FFP) "cancer" test was used to study 540 blood lymphocyte samples from 341 donors, of whom 158 had confirmed cancer: The other donors were noncancer patients, pregnant women, and normal individuals. The FFP response in cancer patients was the reverse of that in normal individuals, but an abnormal response was also obtained in some noncancer conditions, including the chronic inflammatory disorders--rheumatoid arthritis, cholecystitis, and diverticulitis--and in early pregnancy or pregnancy-induced hypertension. Thus the cancer discriminatory value of the test is limited. Examination of its biologic basis suggests that the positive FFP response in cancer and other conditions is due to altered immune status of blood lymphocytes, with associated change in cytoplasmic fluidity affecting the polarization of fluorescence. Incubation of normal blood lymphocytes with cyclic GMP induced an abnormal, cancer-like FFP response.

Topics: Cyclic AMP; Cyclic GMP; Female; Fluorescein; Fluoresceins; Fluorescence Polarization; Humans; In Vitro Techniques; Lymphocytes; Male; Neoplasms; Phytohemagglutinins; Pregnancy

C 1821 is a purified glycoprotein extract from Klebsiella pneumoniae serotype 2 with a molecular weight of about 350,000. It enhances immune responses in animals when given orally and the oral route of administration is devoided of any toxicity even in humans. The present controlled trial showed that C 1821 given per os at the single daily dose of 4 mg for 14 days in untreated cancer patients (mostly lymphomas) significantly enhanced delayed cutaneous hypersensitivity to recall antigens using the Multitest system (7 antigens). It also increased basal levels of lymphocyte cAMP and particularly of cGMP which were decreased in these patients. When incubated in vitro with lymphocytes from either normal controls or patients, C 1821 showed a dose-dependent stimulation of cAMP synthesis which was more pronounced in patients than in controls.

Topics: Adult; Cyclic AMP; Cyclic GMP; Female; Glycoproteins; Humans; Hypersensitivity, Delayed; Immunotherapy; Klebsiella pneumoniae; Lymphocytes; Male; Middle Aged; Neoplasms; Skin Tests

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Blood; Carcinogens; Cell Communication; Cell Cycle; Cell Division; Cells, Cultured; Cyclic AMP; Cyclic GMP; DNA; Fibroblasts; Mice; Neoplasm Metastasis; Neoplasms; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Xanthines

Cyclic guanosine 3',5' monophosphate (cyclic GMP) and cyclic adenosine 3',5' monophosphate (cyclic AMP) have been determined in random urine specimens from 95 healthy individuals, 60 patients with non-cancerous conditions, 52 patients with benign tumours, and 74 patients with malignant tumours. Concentrations of cyclic GMP have also been determined in a number of other groups, including some undergoing cancer treatment. Ninety-three per cent of cancer patients had raised urinary cyclic GMP concentrations compared to the reference range for healthy subjects. For the non-cancerous and benign groups, 33% and 42% respectively had raised concentrations. The urine cyclic AMP concentrations were similar in all groups. Urine cyclic GMP appeared to rise early in the onset of malignant growth. Successful cancer treatment was accompanied by a dramatic fall in the urine cyclic GMP concentrations, whereas if the treatment was unsuccessful the level did not change. It is concluded that urine cyclic GMP may have important applications in the monitoring of cancer treatment.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Uterine Cervical Neoplasms; Uterine Prolapse

Cancer is characterized by a relatively autonomous growth of cells due to a reduced responsiveness to normal controls of proliferation and differentiation. The proliferation of normal cells is regulated at arrest (restriction) points in the cell cycle. Relatively autonomous growth (tumors) can result from various mechanisms which circumvent the normal regulatory controls of the cell cycle.

Topics: Animals; Cell Cycle; Cell Division; Cyclic AMP; Cyclic GMP; Fibronectins; Growth Inhibitors; Growth Substances; Humans; Interferons; Models, Biological; Neoplasms

Topics: Animals; Cell Division; Cell Line; Culture Techniques; Cyclic AMP; Cyclic GMP; Humans; Interferons; Kinetics; Leukemia L1210; Neoplasms; Ribonucleotides

The present study shows an increased urinary cyclic guanosine 3'.5'-monophosphate (cyclic GMP) excretion rate in children of all age groups bearing malignant tumours or lymphomas. The incidence of increased cyclic GMP excretion was highly significant (79%). Follow-up studies of up to three years have revealed that during periods of remission of malignant disease the urinary cyclic GMP excretion drops to near normal values, whereas recurrences are accompanied by a new increase of cyclic GMP excretion.

Topics: Age Factors; Child; Child, Preschool; Cyclic GMP; Female; Fetus; Follow-Up Studies; Humans; Infant; Infant, Newborn; Leukemia; Lymphoma; Neoplasms; Pregnancy

1. Urinary cyclic nucleotide excretion was studied in 51 patients with malignant tumours and in 24 control subjects. 2. Adenosine 3':5'-cyclic monophosphate excretion was normal in patients with tumours. 3. Urinary excretion of guanosine 3':5'-cyclic monophosphate was significantly greater than normal in patients with lymphoid tumours (both sexes) and in male patients with myeloid tumours or malignant melanoma. 4. Guanosine 3':5'-cyclic monophosphate excretion was normal in patients with breast carcinoma or colonic adenocarcinoma.

Topics: Adolescent; Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Neoplasms

The plasma and 24-hr urinary levels of cyclic adenosine 3':5'-monophosphate and of cyclic guanosine 3':5'-monophosphate (cGMP) were determined for 19 healthy normal patients, 54 patients with six types of nonneoplastic diseases (cholelithiasis, peptic ulcer, coronary heart disease, hypertension, regional ileitis, and cirrhosis), and 54 patients with five types of neoplastic disease (cancers of the lung, colon, and breast, acute myelocyte leukemia, and Hodgkin's disease). The cyclic adenosine 3':5'-monophosphate levels of urine and plasma in normal subjects, in noncancer subjects, and in cancer subjects did not differ significantly. The cGMP levels in the noncancer group were similarly unchanged from those in the normal group. However, mean cGMP levels in the urine and plasma of patients with neoplastic diseases were, respectively, 2- and 3-fold greater than the normal values (p less than 0.005 for urine and p less than 0.05 for plasma). Pharmacokinetic studies with [3H]cGMP in nine healthy controls and 15 patients with neoplasia showed that the mean production rate of this nucleotide in patients with metastatic cancer was elevated when compared to normal patients, but many values fell within the normal range. In acute leukemia, the production rate was seven times normal, with four of five patients having values clearly outside the normal range. The plasma clearance rate in patients with neoplasia was not decreased when compared to that in normal patients. It is proposed that an increased production rate, rather than any change in plasma clearance, accounts for the increased levels of cGMP in the plasma and urine of some patients with neoplastic disease.

Topics: Cyclic AMP; Cyclic GMP; Extracellular Space; Humans; Kinetics; Metabolic Clearance Rate; Neoplasms

Thymosin fraction 5 contains a family of polypeptides with varying biological activities. Current efforts in the thymosin research program are involved in further chemical characterization of thymosin peptides and evaluation of clinical immunotherapeutic protocols. Recent clinical studies with thymosin fraction 5 have shown therapeutic potentials for treatment of patients with primary immunodeficiency diseases and cancer.

Topics: Cyclic GMP; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; Neoplasms; Thymosin; Thymus Hormones

Topics: Aging; Animals; Concanavalin A; Cyclic AMP; Cyclic GMP; Kinetics; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasms; Spleen

Topics: Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Neoplasms; Nucleotides, Cyclic; Polycythemia Vera; Remission, Spontaneous

Guanosine 3'5'-cyclic monophosphate (cGMP) in the plasma of normal persons and patients with lung or breast cancer and other kinds of neoplasma or other diseases was determined using radioimmunoassay. In comparison with normal persons, significant elevation occurred in the cGMP in the plasma of patients with various kinds of cancer or renal insufficiency. The average cGMP values in the plasma of eight normal persons, 16 patients with lung cancer, 16 patients with breast cancer, five patients with oesophagus cancer, three patients with liver cancer, three patients with stomach cancer, ten patients with renal insufficiency and two patients with myocardial infarction, were respectively 3.46, 9.05, 5.39, 5.42, 7.33, 11.66, 19.55, and 8.0 pmol per ml of plasma. There was no elevation in the cGMP in the plasma of the patients with other diseases studied.

Topics: Cyclic GMP; Disease; Humans; Kidney Diseases; Neoplasms; Radioimmunoassay

Implantation of MtT-F4 tumor, a mammotropic tumor that secretes large quantities of ACTH, GH and prolactin, into male Fisher rats induced the development of hyperlipidemia. Free fatty acid, triglyceride and cholesterol levels in the plasma were significantly increased at 31 days after tumor implantation. Blood glucose and glycerol levels remained normal, while uric acid concentration in the blood was significantly decreased. The concentrations of the serum lipoproteins were significantly increased, while, only small changes in the distribution of the serum lipids and the composition of the lipoproteins were observed. Following stimulation of isolated adipose tissue cells with ACTH, the lipolytic response and the accumulation of cyclic AMP was higher in cells derived from the rats with the tumor, although the accumulation of cyclic GMP was not different from control adipocytes. Further, when the isolated adipose tissue cells were stimulated with dibutyryl cyclic AMP no difference was observed between the control and tumor bearing groups. Clofibrate administered in the diet resulted in a complete elimination of the tumor effect on serum triglycerides and to a great extent prevented the rise in serum cholesterol. The tumor-induced increase in the concentration of the high density lipoproteins was not affected, but the elevation of the d less than 1.063 lipoproteins was not affected, but the elevation of the d less than 1.063 lipoproteins was partially reversed. The increased lipolytic response and accumulation of cyclic AMP following stimulation by ACTH was not altered in adipocytes derived from tumor bearing rats. However, clofibrate treatment resulted in a significantly greater accumulation of cyclic GMP in fat cells stimulated with ACTH from both control and tumor bearing rats. Clofibrate in the diet did not alter the levels of GH or prolactin or serum lipids in the control rats nor were the elevated hormone levels of the tumor bearing rats changed.

Topics: Adipose Tissue; Adrenocorticotropic Hormone; Animals; Blood Pressure; Cholesterol; Clofibrate; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Fatty Acids; Growth Hormone; Hyperlipidemias; Lipoproteins; Male; Neoplasm Transplantation; Neoplasms; Prolactin; Rats; Triglycerides

Plasma and 24-h urinary adenosine 3':5'-monophosphate (cyclic AMP) and guanosine 3':5'-monophosphate (cyclic GMP) were measured by radioimmunoassay in 12 normal subjects, 33 patients with six types of non-neoplastic disease (cholelithiasis, peptic ulcer, coronary heart disease, hypertension, regional ileitis, and cirrhosis), and 34 patients with five types of disseminated neoplastic disease (acute myelocytic leukemia; Hodgkin's disease; and metastatic cancer of the lung, colon, and breast). In patients with non-neoplastic disease, cyclic nucleotide values in plasma and urine did not differ significantly (P greater than 0.05) from those in normal subjects. In patients with disseminated cancer, cyclic AMP values in plasma and urine likewise did not differ significantly from those in normal subjects. Plasma cyclic GMP, in contrast, was significantly elevated in all five types of cancer patients, and urinary cyclic GMP was significantly elevated (five times the normal mean) in patients with acute myelogenous leukemia and Hodgkin's disease.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Metastasis; Neoplasms

Plasma and 24-hour urinary cyclic AMP and cyclic GMP levels were determined by saturation analysis in specimens from normal subjects and from 101 patients with tumours of the gastrointestinal tract, breast, lung, bladder or prostate, or with cirrhosis of the liver. Relative to 46 control subjects, plasma cyclic GMP concentrations were significantly elevated in seven patients with gastric tumours, 20 patients with cancer of the breast, six patients with lung cancer, and 12 patients with cirrhosis of the liver. Urinary cyclic GMP/creatinine ratios were significantly increased in cirrhotic patients and in the lung and oesophageal cancer groups. In no cancer group were increases in plasma or urine cyclic GMP levels sufficiently consistent to be of value in the diagnosis of human malignant disease. Changes in extracellular fluid cyclic nucleotide levels in the cirrhotic group were very similar to those that have been reported for primary hepatoma patients.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Neoplasms

Changes in the concentration of cyclic AMP as well as cyclic GMP were measured in different murine tumors and in human tumors of varying malignancy. The quotient of cAMP and cGMP seems to be an important parameter for the molecular-biological derangement. Because of the recently much discussed importance of cAMP and cGMP in the immune defence the changes in the concentration of both nucleotides were measured in the T-lymphocytes of tumor patients. Significant changes occurred in patients with malignant melanoma. Investigations of the stimulatibility of the cAMP and cGMP levels revealed a diminished activatibility of the cAMP level and a higher stimulatibility of the cGMP level in the T-lymphocytes of patients with malignant melanoma as compared with those of the controls. On the basis of the working hypothesis that there is a causal relationship between the deranged dualism of cAMP and cGMP in the T-lymphocytes and the failure of the immunological tumor cell defence, an increase in the cAMP level is offered as a possible therapy. Therapeutic results in tumor-bearing mice and first results in melanoma patients are discussed.

Topics: Animals; Carcinoma, Ehrlich Tumor; Cyclic AMP; Cyclic GMP; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Melanoma; Mice; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Nevus; Skin; Skin Neoplasms; T-Lymphocytes; Time Factors

The author suggests an interpretation of the recently recognized significant enzymatic imbalance in cancer cell as a result of the shift in the balance of cell memrane adenyl- and guanylcyclase activities in favour of the former. The alternative patterns of the development of hypothetical central and peripheral regulatory disturbances are dealt with. The prospective new therapeutic approaches offered by the pathomechanism under study are pointed out.

Topics: Adenylyl Cyclases; Cell Membrane; Cyclic AMP; Cyclic GMP; Enzyme Activation; Guanylate Cyclase; Humans; Neoplasms; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

The urinary excretion of cyclic adenosine 3',5'-monophosphate (cAMP), corrected for urinary creatinine, was determined in 177 patients with primary or metastatic tumours and in 149 normal subjects. In 26 patients with malignancy and in 10 control subjects the excretion of cyclic guanosine 3',5'-monophosphate (cGMP) was also evaluated. The urinary cAMP/Cr ratio in human neoplasms of epithelial origin was often significantly lower than normal, irrespective of the extension of malignancy. Surgical resection of the tumour, radiotherapy, or theophylline treatment increased urinary excretion of the nucleotide. In patients with malignancy, intravenous infusion of glucagon failed to produce the degree of elevation of plasma cAMP seen in normal subjects. Urines from patients with malignant neoplasms had low values of cAMP/Cr ratio with increased values of cGMP/Cr ratio. These findings could be the result of systemic alteration in synthesis or breakdown of the nucleotides.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Glucagon; Humans; Male; Middle Aged; Neoplasms; Theophylline

Our current research program centers around the biologic and chemical characterization of the family of polypeptides present in thymosin fraction 5. A system of nomenclature has been developed and the peptides are being systematically isolated and chemically characterized. Thymosin fraction 5 and its component parts influence a variety of lymphocyte properties including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production, and expression of certain surface markers. Thymosin is being used in clinical trials to investigate its effects on immunodeficiency diseases, malignant diseases, and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Chemical Phenomena; Chemistry; Cyclic AMP; Cyclic GMP; Drug Evaluation; Guinea Pigs; Humans; Immunologic Deficiency Syndromes; In Vitro Techniques; Lymphocytes; Neoplasms; T-Lymphocytes; Thymosin; Thymus Hormones

In human tumor tissues of different degrees of differentiation--nevus-cell-nevus, basalioma, malign melanoma--the cAMP and cGMP content was determined and compared with the corresponding normal values. It is demonstrated that the quotient of the cAMP to the cGMP values is of importance rather than the latter values for themselves. For the benign tumor, this quotient differs only slightly from that of the adjacent normal, sound tissue. On the other hand, for the two malign tumors a drastic decrease of the quotient as compared to that of the normal tissue was found to occur.

Topics: Carcinoma, Basal Cell; Cyclic AMP; Cyclic GMP; Humans; Melanoma; Neoplasms; Nevus; Reference Values

Immunofluorescent localization of prostaglandin-E (PGE), cyclic AMP (CAMP), and cyclic GMP (cGMP) was studied in tumor tissues from 40 patients with a variety of solid tumors. Representative normal tissues served as controls. Rabbit antisera specific for PGE or the cyclic nucleotides were used, and the reactions observed were correlated with the degree and type of lymphocytic reaction at the tumor margins. Strong PGE immunofluorescence was detected in tumor cells in 27 of 42 malignancies; by contrast nine of 13 normal tissues showed weak PGE reactions, cAMP was detected in 30 of the 42 malignancies; cGMP was noted in only seven of the 42 malignant tissues and in none of the normal tissues studied. The most common malignant tumor profile (17/42) was that of positive PGE and cAMP and negative cGMP staining. Tumors showing strong staining with anti-PGE or cAMP demonstrated a distinct trend towards heavier lymphocytic infiltration with a predominance of T cells at their margins, although this association did not reach statistical significance in the present material.

Topics: B-Lymphocytes; Cyclic AMP; Cyclic GMP; Fluorescent Antibody Technique; Humans; Neoplasms; Prostaglandins E; T-Lymphocytes

A survey of the available literature on the role of cyclic nucleotides (cyclic adenosine 3,5-monophosphate and cyclic guanosine 3,5-monophosphate) in the control over various aspects of cellular activity: regulation of growth and morphology of normal and tumorous cells, participation in differentiation of cells, blast-transformation, regulation of inflammatory and immunological processes governed by lymphocytes, is presented. A presumable mechanism of action of cyclic nucleotides is considered.

Topics: Animals; Antineoplastic Agents; Calcium; Cell Differentiation; Cell Transformation, Neoplastic; Cyclic AMP; Cyclic GMP; DNA; Enzyme Activation; Hormones; Humans; In Vitro Techniques; Liver Glycogen; Lymphocyte Activation; Mitosis; Neoplasms; Prostaglandins; Protein Kinases

Topics: Breast Neoplasms; Bucladesine; Cell Migration Inhibition; Colonic Neoplasms; Culture Media; Culture Techniques; Cyclic AMP; Cyclic GMP; Drug Synergism; Humans; Leukocytes; Lung Neoplasms; Neoplasms; Proteins; Theophylline; Tuberculin Test