germanium and propagermanium

Inflammation plays an essential role in the development and progression of most cancers. Chemokine C-C motif chemokine 2 (CCL2) and its receptor C-C chemokine receptor type 2 (CCR2) constitute a key signaling axis in inflammation that has recently attracted much interest on the basis of evidence showing its association with cancer progression. Propagermanium (3-oxygermylpropionic acid polymer) is an organogermanium compound that is given for the treatment of hepatitis B in Japan and which inhibits the CCL2-CCR2 signaling pathway. Herein, we review the importance of the CCL2-CCR2 axis as a target in cancer treatment as shown by studies in mice and humans with pharmacological agents including propagermanium.

Topics: Animals; Antineoplastic Agents; Chemokine CCL2; Clinical Trials as Topic; Germanium; Humans; Japan; Mice; Neoplasms; Organometallic Compounds; Propionates; Receptors, CCR2; Signal Transduction; Small Molecule Libraries

This paper reviews the history, chemistry, safety, toxicity, and anticancer effects of the organogermanium compound bis (2-carboxyethylgermanium) sesquioxide (CEGS). A companion review follows, discussing the inaccuracies in the scientific record that have prematurely terminated research on clinical uses of CEGS. CEGS is a unique organogermanium compound first made by Mironov and coworkers in Russia and, shortly thereafter, popularized by Asai and his colleagues in Japan. Low concentrations of germanium occur in nearly all soils, plants and animal life; natural occurrence of the CEGS form is postulated but not yet demonstrated. The literature demonstrating its anticancer effect is particularly strong: CEGS induces interferon-gamma (IFN-gamma), enhances natural killer cell activity, and inhibits tumor and metastatic growth--effects often detectable after a single oral dose. In addition, oral consumption of CEGS is readily assimilated and rapidly cleared from the body without evidence of toxicity. Given these findings, the absence of human clinical trials of CEGS is unexpected. Possible explanations of why the convincing findings from animal research have not been used to support clinical trials are discussed. Clinical trials on CEGS are recommended.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Germanium; Hemodynamics; Humans; Interferon Inducers; Models, Animal; Neoplasms, Experimental; Organometallic Compounds; Propionates

The preceding paper reviewed the anticancer properties and safety of bis (2-carboxyethylgermanium) sesquioxide (CEGS). An examination of those data leads one to question why this information has not stimulated clinical trials in patients with cancer. The answer is discussed in this paper, which traces the history to an error published in the scientific literature in 1987. The reliance by subsequent authors on secondary sources, citing only the error and not the correction published in 1988, constitutes part of the explanation of why CEGS has been neglected. A second factor is also considered: careless reporting about any germanium-based compound as if the many thousands of germanium compounds were all the same. This combination of a publication error, careless writing, and the reliance on secondary sources appears to be responsible for the neglect of the potential clinical use of this unique germanium compound.

Topics: Animals; Antineoplastic Agents; Bias; Ethics, Professional; Germanium; Humans; Interferon Inducers; Models, Animal; Neoplasms, Experimental; Organometallic Compounds; Peer Review; Propionates; Publication Bias; Research Design; Writing

Although antiviral agents have been adopted for the management of chronic hepatitis B, they have only limited efficacy because of the underlying impaired immune status. Propagermanium, a hydrophilic polymer of 3-oxygermyl propionate, has been reported to have potent immune modulatory activity associated with antiinflammatory and antineoplastic properties. For example, propagermanium augments lymphocyte functions in CD4 and CD8 cells, and in natural killer (NK) cells, and induces the production of several cytokines. A controlled pilot study of 16-week treatment with propagermanium for chronic hepatitis B (of moderate and mild grades on hepatic histology) revealed a sustained clearance of hepatitis B e (HBe) antigen and a favorable biochemical response at week 16 of treatment and at week 48 post-treatment. An open study also supported the clearance of hepatitis B virus from the blood and the possible improvement of histologic grading in the liver. There were few adverse events. A postmarketing survey, however, revealed the occurrence of moderate to severe liver damage after the treatment in about 4% of patients. Despite the exact nature of the liver damage being unclear, a putative cause is the swift removal of virus-infected hepatocytes by an immune reaction through the treatment. A subtle balance between host and viral conditions is the factor which most determines hepatitis B virus persistence. The rationale for a nonspecific immune modulator for the treatment of chronic hepatitis B will be the restoration of cellular immune responsiveness to viral infection. Although the cellular immunity for hepatitis B virus prior to the treatment should be studied, adequate observation of hepatic functions and viral markers in the recipients is clinically useful to predict liver failure during the treatment. In summary, the propagermanium regimen offers a potent and safe approach that is cost-effective for appropriate chronic hepatitis B patients with reserve hepatic capacity, and will provide new perspectives for immune therapy in chronic hepatitis B.

Topics: Adjuvants, Immunologic; Alanine Transaminase; Double-Blind Method; Female; Germanium; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunity, Cellular; Interferon Inducers; Liver; Liver Failure, Acute; Male; Organometallic Compounds; Pilot Projects; Product Surveillance, Postmarketing; Propionates; Time Factors

Topics: 2-Aminopurine; Adrenal Cortex Hormones; Antiviral Agents; Famciclovir; Germanium; Hepatitis B; Humans; Immunologic Factors; Interferons; Interleukin-12; Lamivudine; Organometallic Compounds; Propionates; Reverse Transcriptase Inhibitors; Thymosin

Germanium-containing dietary supplements became popular in the 1970s in Japan and later in other countries, as elixirs for certain diseases (e.g., cancer and AIDS). Germanium is not an essential element. Its acute toxicity is low. However, at least 31 reported human cases linked prolonged intake of germanium products with renal failure and even death. Signs of kidney dysfunction, kidney tubular degeneration, and germanium accumulation were observed. Other adverse effects were anemia, muscle weakness, and peripheral neuropathy. Recovery of renal function is slow and incomplete even long after germanium intake was stopped. The total dose of ingested germanium (as dioxide, carboxyethyl germanium sesquioxide, germanium-lactate-citrate, or unspecified forms) varied from 15 to over 300 g; the exposure duration varied from 2 to 36 months. In laboratory animals, elevated germanium in tissues and impaired kidney and liver function were observed in a life-time drinking water (5 ppm germanium) study. Other toxicities associated with ingested germanium products in human cases were also demonstrated in animal studies with germanium dioxide and sometimes other germanium compounds. Based on the evidence of persistent renal toxicity associated with germanium dioxide, the lack of conclusive findings of differential nephrotoxicity of organic germanium compounds, and the possibility of contamination of the organic germanium products with inorganic germanium, it is clear that germanium products present a potential human health hazard.

Topics: Administration, Oral; Adolescent; Adult; Anemia; Animals; Antimutagenic Agents; Antineoplastic Agents; Child; Child, Preschool; Female; Food, Fortified; Germanium; Humans; Kidney; Lethal Dose 50; Liver; Male; Middle Aged; Muscle Weakness; Neurons; Organometallic Compounds; Propionates; Renal Insufficiency; Risk Assessment

Topics: Animals; Germanium; Humans; Organometallic Compounds; Propionates

Topics: Antineoplastic Agents; Germanium; Humans; Organometallic Compounds; Propionates

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow-derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid-derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7-deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose-escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Twelve patients were enrolled in the study. Dose-limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)-6, in agreement with our previous mouse model. Also, IL-6 was downregulated in a PG dose-dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Chemokine CCL2; F-Box-WD Repeat-Containing Protein 7; Female; Germanium; Humans; Interleukin-6; Japan; Macrophages; Middle Aged; Myeloid-Derived Suppressor Cells; Organometallic Compounds; Propionates; RNA, Messenger; Signal Transduction; Young Adult

Interferon (IFN) is one of several drugs effective in treating multiple myeloma (MM), and propagermanium is an IFN inducer. We report on 10 MM patients who were treated with propagermanium at doses from 10 to 40 mg. Two patients achieved complete remission (CR), two patients achieved partial remission (PR), and the condition of four patients was stable (stable disease, SD). After discontinuation of propagermanium, the status of MM progressed in two patients who were in SD and in two patients who had achieved PR. The administration of propagermanium was restarted in one patient resulting in a decrease in her paraprotein.

Topics: Aged; Aged, 80 and over; Disease Progression; Female; Germanium; Humans; Interferon Inducers; Male; Middle Aged; Multiple Myeloma; Myeloma Proteins; Organometallic Compounds; Propionates; Remission Induction; Treatment Outcome

Although antiviral agents have been adopted for the management of chronic hepatitis B, they have only limited efficacy because of the underlying impaired immune status. Propagermanium, a hydrophilic polymer of 3-oxygermyl propionate, has been reported to have potent immune modulatory activity associated with antiinflammatory and antineoplastic properties. For example, propagermanium augments lymphocyte functions in CD4 and CD8 cells, and in natural killer (NK) cells, and induces the production of several cytokines. A controlled pilot study of 16-week treatment with propagermanium for chronic hepatitis B (of moderate and mild grades on hepatic histology) revealed a sustained clearance of hepatitis B e (HBe) antigen and a favorable biochemical response at week 16 of treatment and at week 48 post-treatment. An open study also supported the clearance of hepatitis B virus from the blood and the possible improvement of histologic grading in the liver. There were few adverse events. A postmarketing survey, however, revealed the occurrence of moderate to severe liver damage after the treatment in about 4% of patients. Despite the exact nature of the liver damage being unclear, a putative cause is the swift removal of virus-infected hepatocytes by an immune reaction through the treatment. A subtle balance between host and viral conditions is the factor which most determines hepatitis B virus persistence. The rationale for a nonspecific immune modulator for the treatment of chronic hepatitis B will be the restoration of cellular immune responsiveness to viral infection. Although the cellular immunity for hepatitis B virus prior to the treatment should be studied, adequate observation of hepatic functions and viral markers in the recipients is clinically useful to predict liver failure during the treatment. In summary, the propagermanium regimen offers a potent and safe approach that is cost-effective for appropriate chronic hepatitis B patients with reserve hepatic capacity, and will provide new perspectives for immune therapy in chronic hepatitis B.

Topics: Adjuvants, Immunologic; Alanine Transaminase; Double-Blind Method; Female; Germanium; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunity, Cellular; Interferon Inducers; Liver; Liver Failure, Acute; Male; Organometallic Compounds; Pilot Projects; Product Surveillance, Postmarketing; Propionates; Time Factors

Domestication begins with the selection of animals showing less fear of humans. In most domesticates, selection signals for tameness have been superimposed by intensive breeding for economical or other desirable traits. Old World camels, conversely, have maintained high genetic variation and lack secondary bottlenecks associated with breed development. By re-sequencing multiple genomes from dromedaries, Bactrian camels, and their endangered wild relatives, here we show that positive selection for candidate genes underlying traits collectively referred to as 'domestication syndrome' is consistent with neural crest deficiencies and altered thyroid hormone-based signaling. Comparing our results with other domestic species, we postulate that the core set of domestication genes is considerably smaller than the pan-domestication set - and overlapping genes are likely a result of chance and redundancy. These results, along with the extensive genomic resources provided, are an important contribution to understanding the evolutionary history of camels and the genomic features of their domestication.

Topics: Animals; Camelus; Domestication; Genetic Variation; Genetics, Population; Genome; Germanium; Organometallic Compounds; Polymorphism, Single Nucleotide; Propionates; Selection, Genetic; Whole Genome Sequencing

Reactive oxygen species (ROS) are very harmful to dermal cells, and it is thus important to develop cosmetics that protect the skin from ROS and other stimuli. Repagermanium is a synthetic water-soluble organogermanium polymer, and in this study, we attempted to visualize the incorporation of germanium into normal human dermal fibroblasts (NHDFs) using isotope microscopy. In addition, the content of 3-(trihydroxygermyl)propanoic acid (THGP), a hydrolyzed monomer of repagermanium, in NHDFs was determined through liquid chromatography mass spectrometry (LC-MS/MS), and the dose-dependent incorporation of THGP was confirmed. We then evaluated the preventive effects of THGP against ROS-induced NHDF death and confirmed the observed preventive effects through gene profiling and expression analysis. The addition of 0.59-5.9 mM THGP reduced cell death resulting from ROS damage caused by the reaction between xanthine oxidase and hypoxanthine and the direct addition of H

Topics: Cell Death; Cells, Cultured; Chromatography, Liquid; Dose-Response Relationship, Drug; Fibroblasts; Gene Expression Regulation; Germanium; Humans; Hydrolysis; Hypoxanthine; Interleukin-6; Isotope Labeling; Microscopy; Nuclear Receptor Subfamily 4, Group A, Member 2; Organometallic Compounds; Oxidative Stress; Propionates; Skin; Tandem Mass Spectrometry; Xanthine Oxidase

CCR2 could recruit immune cells migrating into brain after ischemic stroke. It is unclear whether and why Propagermanium (PG, a CCR2 inhibitor) is able to protect against ischemic injury. Middle cerebral artery occlusion (MCAO) and reperfusion injury in C57BL/6 J male mice were performed in vivo to mimic ischemic stroke. Cultured BV2 microglia exposed to oxygen and glucose deprivation (OGD)/reoxygenation injury, LPS or IL-4 incubation were served in vitro. TTC staining, neurological score, brain water content, and MRI scan were performed to evaluate stroke outcome. Real time PCR, ELISA, and immunofluorescence were used to estimate inflammatory cytokines expression and releasing. Western blot was utilized to detect pSTAT1/STAT1 expression. Compared with MCAO mice, PG treatment significantly reduced infarction size and brain edema, improved neurological behavior at 72 h after MCAO. For inflammatory response, PG treatment inhibited inflammatory cytokines releasing, such as TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and IL-23. Further studies indicated that PG treatment downregulated mRNA expression of pro-inflammatory iNOS and CD86, and inhibited CD16 expressed in microglia. In vitro, PG incubation inhibited BV2 polarized to pro-inflammatory phenotype through STAT1 downregulation, while had no obvious effect on anti-inflammatory phenotype. Our observations suggest that CCR2 inhibitor PG downregulated pro-inflammatory microglia polarization for decreasing pro-inflammatory microglia phenotype marker, and thereafter inhibited inflammatory responses after MCAO in a STAT1-dependent manner.

Topics: Animals; Brain Ischemia; Cell Line; Germanium; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Microglia; Organometallic Compounds; Propionates; Random Allocation; Receptors, CCR2; Reperfusion Injury

Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) is a water-soluble organogermanium compound that exerts various physiological effects, including anti-inflammatory activity and pain relief. In water, Ge-132 is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP), which in turn is capable of interacting with cis-diol compounds through its trihydroxy group, indicating that this compound could also interact with diol-containing nucleic acid constituents. In this study, we evaluated the ability of THGP to interact with nucleosides or nucleotides via nuclear magnetic resonance (NMR) analysis. In addition, we evaluated the effect of added THGP on the enzymatic activity of adenosine deaminase (ADA) when using adenosine or 2'-deoxyadenosine as a substrate. In solution, THGP indeed formed complexes with nucleotides or nucleosides through their cis-diol group. Moreover, the ability of THGP to form complexes with nucleotides was influenced by the number of phosphate groups present on the ribose moiety. Notably, THGP also inhibited the catalysis of adenosine by ADA in a concentration-dependent manner. Thus, interactions between THGP and important biological nucleic acid constituents might be implicated in the physiological effects of Ge-132.

Topics: Adenosine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Biocatalysis; Germanium; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Nucleic Acids; Organometallic Compounds; Propionates; Spectrophotometry

Ge-132 is a synthetic organic germanium that is used as a dietary supplement. The antioxidant activity of Ge-132 on cultured mammalian cells was investigated in this study. First, Ge-132 cytotoxicity on mammalian cultured cells was determined by measuring lactate dehydrogenase (LDH) levels. Ge-132 had no cytotoxic effect on three different cell lines. Second, the cell proliferative effect of Ge-132 was determined by measuring ATP content of whole cells and counting them. Ge-132 treatment of Chinese hamster ovary (CHO-K1) and SH-SY5Y cells promoted cell proliferation in a dose-dependent manner. Finally, antioxidant activity of Ge-132 against hydrogen peroxide-induced oxidative stress was determined by measuring the levels of intracellular reactive oxygen species (ROS) and carbonylated proteins. Pre-incubation of CHO-K1 and SH-SY5Y cells with Ge-132 suppressed intracellular ROS production and carbonylated protein levels induced by hydrogen peroxide. Our results suggest that Ge-132 has antioxidant activity against hydrogen peroxide-induced oxidative stress.

Topics: Animals; Antioxidants; Cell Line, Tumor; Cell Proliferation; Cell Survival; CHO Cells; Cricetulus; Germanium; HeLa Cells; Humans; Hydrogen Peroxide; Organometallic Compounds; Oxidative Stress; Propionates; Reactive Oxygen Species

Compared with the in vivo environment, porcine in vitro embryo-culture systems are suboptimal, as they induce oxidative stress via the accumulation of reactive oxygen species (ROS). High ROS levels during early embryonic development cause negative effects, such as apoptosis. In this study, we examined the effects of the antioxidant carboxyethylgermanium sesquioxide (Ge-132) during in vitro culture (IVC) on embryonic development in porcine in vitro fertilization (IVF) embryos. Zygotes were treated with different concentrations of Ge-132 (0, 100, 200 and 400 μg/ml). All of the Ge-132 treatment groups displayed greater total cell numbers after IVC (98.1, 98.5 and 103.4, respectively) compared with the control group (73.9). The 200 μg/ml Ge-132 treatment group exhibited significantly increased intracellular GSH levels compared with the control group, whereas the ROS generation levels decreased in Ge-132 dose-dependent manner (P < 0.05). The mRNA expression levels of the KEAP1 gene and proapoptotic genes BAX and CASPASE3 were lower in the Ge-132 treated blastocysts compared with the control group (P < 0.05). The percentages of apoptotic and necrotic cells in the Ge-132 treated embryos on day 2 (48 h) were significantly lower than the untreated embryos (9.1 vs. 17.1% and 0 vs. 2.7%, respectively). In the day 7 blastocysts, the percentages of apoptotic cells in 200 µg/ml Ge-132 treated group were lower compared to controls (1.6 vs. 2.5%). More KEAP1 protein was found to be localized in cytoplasm of the 200 μg/ml Ge-132 treated blastocysts, whereas KEAP1 protein was predominantly nuclei in the control blastocysts. These results indicate that the developmental competence of embryos cultured under Ge-132 treatment may be associated with KEAP1 signaling cascades involved in oxidative stress and apoptosis during porcine preimplantation embryo development.

Topics: Animals; Apoptosis; Embryo Culture Techniques; Embryo, Mammalian; Germanium; Organometallic Compounds; Oxidative Stress; Propionates; Swine

To investigate the effects of β-carboxyethyl germanium sequioxide (Ge-132) and germanium dioxide (GeO

Topics: Catalase; Germanium; Germination; Malondialdehyde; Oenothera biennis; Organometallic Compounds; Peroxidase; Plant Roots; Plant Shoots; Propionates; Seeds; Sodium Chloride; Stress, Physiological; Superoxide Dismutase

Obese patients with chronic inflammation in white adipose tissue (WAT) have an increased risk of developing non-alcoholic steatohepatitis (NASH). The C-C chemokine receptor-2 (CCR2) has a crucial role in the recruitment of immune cells to WAT and liver, thereby promoting the inflammatory component of the disease. Herein, we examined whether intervention with propagermanium, an inhibitor of CCR2, would attenuate tissue inflammation and NASH development.. Male C57BL/6J mice received a high-fat diet (HFD) for 0, 6, 12 and 24 weeks to characterize the development of early disease symptoms of NASH, i.e. insulin resistance and WAT inflammation (by hyperinsulinemic-euglycemic clamp and histology, respectively) and to define the optimal time point for intervention. In a separate study, mice were pretreated with HFD followed by propagermanium treatment (0.05% w/w) after 6 weeks (early intervention) or 12 weeks (late intervention). NASH was analyzed after 24 weeks of diet feeding.. Insulin resistance in WAT developed after 6 weeks of HFD, which was paralleled by modest WAT inflammation. Insulin resistance and inflammation in WAT intensified after 12 weeks of HFD, and preceded NASH development. The subsequent CCR2 intervention experiment showed that early, but not late, propagermanium treatment attenuated insulin resistance. Only the early treatment significantly decreased Mcp-1 and CD11c gene expression in WAT, indicating reduced WAT inflammation. Histopathological analysis of liver demonstrated that propagermanium treatment decreased macrovesicular steatosis and tended to reduce lobular inflammation, with more pronounced effects in the early intervention group. Propagermanium improved the ratio between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, quantified by CD11c and Arginase-1 gene expression in both intervention groups.. Overall, early propagermanium administration was more effective to improve insulin resistance, WAT inflammation and NASH compared to late intervention. These data suggest that therapeutic interventions for NASH directed at the MCP-1/CCR2 pathway should be initiated early.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Arginase; CD11 Antigens; Chemokine CCL2; Diet, High-Fat; Germanium; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Organometallic Compounds; Propionates; Receptors, CCR2

Poly trans-[(2-carboxyethyl)germasesquioxane] (IUPAC name) is the most common water-soluble organic germanium compound. This compound is known as bis(carboxyethyl)germaniumsesquioxide and it is commonly called Ge-132; it is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGPA) in water. We have developed a method for the quantification of THGPA in rat plasma, using a novel extraction method based on a reversible chemical conversion. THGPA in plasma is converted to 3-(trichlorogermyl)propanoic acid (TCGPA) under acidic conditions using concentrated hydrochloride, which is followed by extraction with chloroform. TCGPA is then converted back to THGPA through hydrolysis. The extraction recovery of this method is approximately 100%. Moreover, we synthesized deuterated Ge-132, which was used as an internal standard in our experiments. This method covers a linearity range of 0.01-5 μg/mL for concentrations of THGPA in plasma. The intra-day and inter-day precisions of the analysis are about 4.1%, and the accuracy is within ±2.6% at THGPA concentrations of 0.025, 0.25, and 2.5 μg/mL. The total run time is 5 min. Our method was successfully applied to a pharmacokinetic investigation following oral administration of Ge-132.

Topics: Animals; Calibration; Chromatography, High Pressure Liquid; Germanium; Hydrolysis; Limit of Detection; Male; Organometallic Compounds; Propionates; Rats, Wistar; Reproducibility of Results; Tandem Mass Spectrometry

Poly-trans-[(2-carboxyethyl)germasesquioxane], Ge-132, is a water-soluble organic germanium compound with many reported physiological functions. The hydrolysate of Ge-132, 3-(trihydroxygermyl)propanoic acid, can interact with diol compounds; therefore, it can possibly interact with diol-containing sugar compounds, which have important physiological functions in sugar chains, glycoproteins, and glucolipids. In this study, we examined the interaction between sodium 3-(trihydroxygermyl)propanoate and monosaccharides using nuclear magnetic resonance. When 1,4-anhydroerythritol was mixed with sodium 3-(trihydroxygermyl)propanoate, a pattern of signals different from that obtained for each solute alone was observed. Some signals were broader, and novel signals with different chemical shifts appeared to originate from complex formation. Spectral observations for sodium 3-(trihydroxygermyl)propanoate and the sugar isomers of glucose and fructose indicated that sodium 3-(trihydroxygermyl)propanoate has a higher affinity for fructose (a ketose) than glucose (an aldose). Moreover, the β-furanosyl conformation of fructose was the structure that interacted most with sodium 3-(trihydroxygermyl)propanoate. These results demonstrate the ability of aqueous Ge-132 to form complexes with the cis-diol structures of saccharides. Thus, interactions among 3-(trihydroxygermyl)propanoic acid and the important biological sugar compounds might be implicated in the physiological function of Ge-132.

Topics: Germanium; Magnetic Resonance Spectroscopy; Monosaccharides; Organometallic Compounds; Propionates; Water

Carboxyethylgermanium sesquioxide (Ge-132) is an organogermanium compound known to exert biological activities, such as antioxidant and anticancer effects. In this study, we investigated the effect of Ge-132 on the IVM of porcine oocytes via analysis of nuclear maturation, intracellular glutathione (GSH) and reactive oxygen species (ROS) levels, and subsequent embryonic development after parthenogenetic activation (PA) and IVF. After 40 hours of IVM, no significant difference in nuclear maturation was observed in the 100, 200, and 400 μg/mL of Ge-132 treatment groups (89.9%, 91.3%, and 90.4%, respectively) compared with the control group (89.0%). However, intracellular GSH levels in oocytes treated with 200 μg/mL of Ge-132 increased significantly (P < 0.05), and the 200 and 400 μg/mL of Ge-132 treatment groups exhibited a significant (P < 0.05) decrease in intracellular ROS levels compared with the control group. Oocytes matured with 200 and 400 μg/mL of Ge-132 during IVM displayed significantly higher cleavage rates (78.7% and 82.7% vs. 67.5%, respectively), and the 200 μg/mL of Ge-132 treatment group displayed higher blastocyst formation rates and greater total cell numbers after PA (59.5% and 67.8 vs. 38.2% and 55.3, respectively) than the control group. Furthermore, oocytes matured with 200 μg/mL of Ge-132 during IVM failed to display significantly higher blastocyst formation rates (31.6% vs. 36.7%) but exhibited greater total cell numbers after IVF (71.5 vs. 101.3, respectively) than the control group. We also found that the Ge-132-treated oocytes showed significantly higher messenger RNA (mRNA) expression levels of the oxidative-related gene Nrf-2 and lower mRNA expression levels of the proapoptotic gene Bax than the control group (P < 0.05). In conclusion, our results suggest that treatment with Ge-132 during IVM improves the developmental potential of PA and IVF porcine embryos by increasing the intracellular GSH levels, thereby decreasing the intracellular ROS levels and reducing oxidative stress-induced apoptosis, thereby regulating the mRNA expression of oocytes during oocyte maturation.

Topics: Animals; Antioxidants; Apoptosis; Blastocyst; Cell Count; Cell Nucleus; Culture Media; Cumulus Cells; Cytoplasm; DNA Repair; Embryo Culture Techniques; Embryonic Development; Female; Fertilization in Vitro; Gene Expression; Germanium; Glutathione; In Vitro Oocyte Maturation Techniques; Oocytes; Organometallic Compounds; Parthenogenesis; Propionates; Reactive Oxygen Species; Sus scrofa

Of organogermanium compounds known to have an immunostimulatory action, propagermanium [PGe; 3-oxygermylpropionic acid polymer, (C3 H5 GeO3.5 )n] is the only one used as a pharmaceutical agent, to treat the hepatitis B virus in Japan. However, because of lack of information about its structure, PGe has been confused with a polymeric solid, repagermanium (RGe, Ge-132, poly-trans-[(2-carboxyethyl) germasesquioxane], (C18 H30 Ge6 O21 )n), which has the same essential formula as PGe. To clarify this issue, the structure of PGe was analyzed using X-ray diffraction (XRD). PGe has a polymeric ladder-shaped structure of a concatenated eight-membered ring composed of Ge-O bonds, which is clearly distinguished from the infinite sheet structure in RGe. Moreover, we observed temperature or moisture-dependent transformations among these compounds using powder XRD. For instance, PGe was easily dissolved in water, and transformed to RGe by exposure to water vapor, but transformed into another straight-chain structure when exposed to aqueous solution. As a result of these findings, PGe was indicated to have labile polymer packing against RGe. These characteristics of PGe may affect pharmaceutical properties such as respective stability and solubility, which indicate its unique impact on physiological activity.

Topics: Antineoplastic Agents; Chemical Precipitation; Crystallography, X-Ray; Drug Stability; Germanium; Hot Temperature; Interferon Inducers; Isomerism; Models, Molecular; Molecular Conformation; Molecular Structure; Molecular Weight; Organometallic Compounds; Polymerization; Powder Diffraction; Propionates; Solubility; Water

In mammals, adrenaline and ATP are life-essential vicinal diol and cis-diol functional groups. Here, we show that interactions between a safe organogermanium compound and these cis-diol compounds have the potential to regulate physiological functions. In addition, we represent a possible new druggable target for controlling the action of cis-diol compounds.. We analyzed a single crystal structure of organogermanium 3-(trihydroxygermyl)propanoic acid (THGPA), a hydrolysate of safe Ge-132, in complex with catecholamine (adrenaline and noradrenaline), and evaluated the affinity between several cis-diol compounds and THGPA by NMR. An in vitro study using normal human epidermal keratinocytes was performed to investigate the inhibition of cis-diol compound-stimulated receptors by THGPA. At high concentration, THGPA inhibited the calcium influx caused by adrenaline and ATP.. This study demonstrates that THGPA can modify cis-diol-mediated cell-to-cell signaling.

Topics: Adenosine Triphosphate; Catecholamines; Cell Line; Crystallography, X-Ray; Epinephrine; Germanium; Humans; Hydrolysis; Magnetic Resonance Spectroscopy; Models, Molecular; Organometallic Compounds; Propionates

Chemokine receptor CCR2 mediates monocyte mobilization from the bone marrow (BM) and subsequent migration into target tissues. The degree to which CCR2 is differentially expressed in leukocyte subsets, and the contribution of CCR2 to these leukocyte mobilization from the BM are poorly understood. Using red fluorescence protein CCR2 reporter mice, we found heterogeneity in CCR2 expression among leukocyte subsets in varying tissues. CCR2 was highly expressed by inflammatory monocytes, dendritic cells, plasmacytoid dendritic cells and NK cells in all tissues. Unexpectedly, more than 60% of neutrophils expressed CCR2, albeit at low levels. CCR2 expression in T cells, B cells and NK T cells was greatest in the BM compared to other tissues. Genetic CCR2 deficiency markedly sequestered all leukocyte subsets in the BM, with reciprocal reduction noted in the peripheral blood and spleen. CCR2 inhibition via treatment with CCR2 signaling inhibitor propagermanium produced similar effects. Propagermanium also mitigated lipopolysaccharide-induced BM leukocyte egress. Consistent with its functional significance, CCR2 antibody staining revealed surface CCR2 expression within a subset of BM neutrophils. These results demonstrate the central role CCR2 plays in mediating leukocyte mobilization from the BM, and suggest a role for CCR2 inhibition in managing monocytes/macrophages-mediated chronic inflammatory conditions.

Topics: Animals; Bone Marrow Cells; Gene Expression Regulation; Germanium; Leukocytes; Mice; Mice, Transgenic; Organometallic Compounds; Propionates; Receptors, CCR2

Microbial fuel cells (MFCs) are bio-electrochemical system that can convert biomass spontaneously into electricity through the metabolic activity of microorganisms. We constructed MFCs of polypyrrole (PPy) coated carbon nanotube (CNT) composite as an electrode material and Shewanella oneidensis as the biocatalyst to increase power density. The PPy-coated CNT were synthesized by the in-situ chemical polymerization of pyrrole on CNT, and the electrochemical properties and performance of the modified electrode as an anode in MFC were then investigated. Treatment with 0.1 wt% Ge-132 on the acid-treated MWNTs helped to form better PPy-MWNT composite. The PPy-CNT/CF anode showed a noteworthy 38% power production improvement when compared to plain CF anode. The PPy-CNT composite could be a very efficient and promising electrode material for electricity generation of MFC.

Topics: Bioelectric Energy Sources; Electrodes; Germanium; Nanotubes, Carbon; Organometallic Compounds; Polymers; Propionates; Pyrroles

One-pot Si-Si/Si-O dehydrocoupling of hydrosilanes with alcohols (1:1.5 mole ratio), promoted by a mixture of AgNO3-H2PtCl6 (150/1 mole ratio) readily gave poly(alkoxysilane)s in good yield (62-91%). The addition of small amount of platinum complex to form nanoparticles facilitated the silicon polymer formation when compared to the reaction rate with AgNO3 alone. The primary/secondary hydrosilanes [p-X-C6H4SiH3 (X = H, CH3, OCH3, F), PhCH2SiH3, and (PhSiH2)2] and alcohols [MeOH, EtOH, (i)PrOH, PhOH, and CF3(CF2)2CH2OH] were used for the reaction. The weight average molecular weight and polydispersity of the poly(alkoxysilane)s were in the range of 1,690-7,100 Dalton and 1.44-3.49, respectively. The reaction of phenylsilane with ethanol (1:3 mole ratio) using the Ag-Pt complexes produced triethoxyphenylsilane only, as expected. The reaction of phenylsilane with Ge-132 produced an insoluble cross-linked gel.

Topics: Alcohols; Chemistry Techniques, Synthetic; Germanium; Molecular Weight; Nanoparticles; Organometallic Compounds; Platinum; Platinum Compounds; Polymers; Propionates; Silanes; Silver Nitrate

The organic germanium compound, Ge-132, has immune-modulating effects. We evaluated the symbiotic effects of Ge-132 with lactobacilli and oligosaccharide (LB/OS) on the immune responses of mice. The highest fecal IgA levels were observed in the mice receiving a low concentration of Ge-132 with LB/OS for 8 weeks. Our data suggest that LB/OS with a low concentration of Ge-132 stimulated the intestinal immunity.

Topics: Animals; Drug Synergism; Germanium; Immunity; Immunoglobulin A; Immunomodulation; Interferon Inducers; Intestines; Lactobacillus; Mice; Oligosaccharides; Organometallic Compounds; Propionates

Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion-associated inflammation.. We addressed the role of bone marrow-derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell-specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach.. Starting within 24 hours of stroke onset, immature Ly6c(hi) monocytes infiltrated into the infarct border zone and differentiated into mature Ly6c(lo) phagocytes within the lesion compartment. MO/MP infiltration was CCR2-dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow-derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin-walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)-β1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-β1 into the lesion border zone greatly reduced infarct bleeding in MO/MP-depleted mice.. Bone marrow-derived MOs/MPs recruited via CCR2 and acting via TGF-β1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2(+) MOs/MPs rather than blocking their hematogenous recruitment.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Ly; Brain Infarction; CD11b Antigen; Cell Differentiation; CX3C Chemokine Receptor 1; Diphtheria Toxin; Disease Models, Animal; Drug Administration Routes; Flow Cytometry; Gene Expression Regulation; Germanium; Heparin-binding EGF-like Growth Factor; Infarction, Middle Cerebral Artery; Intercellular Signaling Peptides and Proteins; Interferon Inducers; Intracranial Hemorrhages; Intracranial Thrombosis; Leukocyte Common Antigens; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Organometallic Compounds; Propionates; Receptors, CCR2; Receptors, Chemokine; Stroke; Time Factors; Transforming Growth Factor beta1

Poly-trans-[(2-carboxyethyl) germasesquioxane], Ge-132 is a water-soluble organic germanium compound. Oral intake of dietary Ge-132 changes fecal color and we attempted to identify the fecal red pigment, which increased by the intake of dietary Ge-132. Sprague Dawley rats were given diets containing Ge-132 from 0 to 0.5% concentration. Fecal red pigment was extracted and purified for optical and structural studies. We examined the fecal red pigment content by high performance liquid chromatography (HPLC), and hepatic gene expressions relating to heme synthesis by reverse transcription polymerase chain reaction (RT-PCR). The purified red pigment had particular optical characteristics on the ultraviolet (UV)-visible spectrum (Soret band absorbance at 400 nm) and fluorescence emission at 600 nm by 400 nm excitation, and was identified as protoporphyrin IX by LC-MS analysis. Protoporphyrin IX significantly (P<0.05) increased 2.4-fold in the feces by the intake of a 0.5% Ge-132 diet. Gene expression analysis of the liver explained the increase of protoporphyrin IX by dietary Ge-132 as it enhanced (P<0.05) aminolevulinic acid synthase 1 (Alas1), a rate-limiting enzyme of heme synthesis, expression 1.8-fold, but decreased ferrochelatase (Fech) expression 0.6-fold (P<0.05). The results show that the intake of dietary Ge-132 is related to heme metabolism. Because protoporphyrin IX is used to treat chronic hepatitis, Ge-132 may be a beneficial substance to increase protoporphyrin IX in the liver.

Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Feces; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Germanium; Heme; Male; Mass Spectrometry; Organometallic Compounds; Propionates; Protoporphyrins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are known to prevent the onset of stroke and to attenuate neural damage. Additional beneficial effects of ARBs, independent of AT(1) receptor blockade, have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2), due to its molecular structure. We examined the possible synergistic effects of co-administration of irbesartan with propagermanium, a CCR2 antagonist, on ischemic brain damage. Administration of propagermanium decreased ischemic brain area after middle cerebral artery occlusion (MCAO). To study the possible synergistic effects of propagermanium with ARBs, we employed non-effective lower doses of irbesartan and losartan. Administration of irbesartan with propagermanium decreased the ischemic brain area more markedly compared with propagermanium alone, but co-administration of losartan did not. MCP-1 mRNA level was significantly increased on the ipsilateral side after MCAO, and administration of irbesartan with propagermanium decreased the MCP-1 level, whereas co-administration of losartan did not. Similar results were obtained for MCP-1 protein level. CCR2 mRNA expression was significantly elevated on the ipsilateral side; however, no significant difference was observed between each group. mRNA levels of other inflammatory cytokines such as TNF-α and IL-1β also significantly increased on the ipsilateral side, but the expression levels were not changed by each drug treatment. Taking these findings together, irbesartan exerts more beneficial effects on ischemic brain damage with an MCP-1 receptor blocker, at least due to its inhibitory effects on MCP-1/CCR2 signaling beyond AT(1) receptor blockade.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Brain Ischemia; Germanium; Irbesartan; Losartan; Male; Mice; Mice, Inbred C57BL; Organometallic Compounds; Propionates; Receptors, CCR2; Signal Transduction; Tetrazoles

Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders.. C57BL/6 mice were fed a high fat and sucrose diet with or without propagermanium (CCR2 inhibitor, 5 or 50 mg/kg BW/day) for 12 weeks from 6 weeks of age. Then we analyzed lipid and glucose metabolism and tissue inflammation in the liver and adipose tissues along with serum markers in those mice.. Propagermanium treatment slightly decreased body weight gain and visceral fat accumulation in diet-induced obese (DIO) mice. Further, propagermanium suppressed macrophage accumulation and shifted adipose tissue macrophage polarization from the pro-inflammatory (M1) state to anti-inflammatory (M2) state in DIO mice. Expressions of TNF-alpha and MCP-1 mRNA in adipose tissue were reduced by propagermanium treatment, indicating that propagermanim suppressed inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance, insulin sensitivity, and decreased hepatic triglyceride in DIO mice. Thus, propagermanium improved diet-induced obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve diet-induced metabolic disorders, and that propagermanium may be a beneficial drug for the treatment of metabolic syndrome.

Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; Fatty Liver; Germanium; Inflammation; Insulin Resistance; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Organometallic Compounds; Propionates; Receptors, CCR2; Tumor Necrosis Factor-alpha

The aim of this work is to compare the radiosensitizing effect between organic and inorganic germanium compounds and to investigate whether nanometer-sized germanium particles can act as radiosensitizers.. Bis (2-carboxyethylgermanium) sesquioxide (Ge-132), germanium oxide (GeO(2)) and germanium nanoparticles were used in this study. Cell viability was determined by clonogenic survival assay. Cellular DNA damage was evaluated by alkaline comet assay, confocal microscopy and the cellular level of phospho-histone H2AX (gamma-H2AX).. Nanometer-sized germanium particles were fabricated. They have a similar radiosensitizing effect as that of GeO(2). Conversely, Ge-132 did not enhance the radiosensitivity of cells. Comet assay was employed to evaluate the level of DNA damage and confirmed that inorganic germanium compounds enhanced cellular radiosensitivity. Notably, the comet assay indicated that the nanoparticle itself caused a higher level of DNA damage. The possibility that germanium nanoparticles per se caused DNA damage was ruled out when the cellular level of gamma-H2AX was examined.. We demonstrated that inorganic but not organic germanium compounds exerted radiosensitizing effect in cells. Nanometer-sized germanium particles were fabricated and were able to enhance the radiosensitivity of cells. Confounding effect may occur when comet assay is used to estimate the level of DNA damage in the presence of germanium nanoparticles.

Topics: Animals; Cell Survival; CHO Cells; Cricetinae; Cricetulus; DNA Damage; Germanium; Histones; Nanoparticles; Organometallic Compounds; Phosphorylation; Propionates; Radiation Tolerance; Radiation-Sensitizing Agents

Accumulating evidence indicates the crucial contribution of chronic inflammation to various types of carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2-specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation.

Topics: Animals; Azoxymethane; Chemokine CCL2; Colitis, Ulcerative; Colonic Neoplasms; Cyclooxygenase 2; Dextran Sulfate; Female; Germanium; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Organometallic Compounds; Propionates; Receptors, CCR2; RNA, Messenger

Recently, adipose tissue inflammation induced by macrophage infiltration through MCP-1/C-C chemokine receptor-2 (CCR2) pathway is considered to play a role in the development of visceral obesity and insulin resistance. In the present study, to further examine the role of CCR2 in the development of obesity and type 2 diabetes, we studied the effect of pharmacological inhibition of CCR2 from the early stage of obesity in db/db mice.. Db/+m (lean control) and db/db mice were fed with a standard diet with or without 0.005% propagermanium, as a CCR2 inhibitor for 12 weeks from 6 weeks of age. Propagermanium treatment decreased body weight gain, visceral fat accumulation, and the size of adipocytes only in db/db mice. Further, propagermanium suppressed macrophage accumulation and inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance and insulin sensitivity, and decreased hepatic triglyceride contents in db/db mice.. Propagermanium improved obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve obesity and type 2 diabetes by interfering adipose tissue inflammation, and that propagermanium may be a beneficial drug for the treatment of the metabolic syndrome.

Topics: Adipose Tissue; Adiposity; Animals; Cell Size; Fatty Liver; Germanium; Insulin Resistance; Liver; Macrophages; Male; Metabolic Syndrome; Mice; Mice, Mutant Strains; Mice, Obese; Obesity; Organometallic Compounds; Propionates; Receptors, CCR2; Triglycerides; Weight Gain

Monocyte chemoattractant protein (MCP-1) is an important mediator for macrophage recruitment in atherosclerosis and various glomerulonephritis. However, the role of MCP-1 and its receptor CCR2 in the progression of diabetic nephropathy remains unknown. Using a type 1 diabetic nephropathy model that shows noticeable glomerulosclerosis, we examined the role of MCP-1/CCR2 by propagermanium (Pro; CCR2 antagonist) treatment, and confirmed it by transfection of plasmids carrying the 7ND (a mutant of MCP-1) gene. We measured the mesangial matrix expansion, type IV collagen (Col4), transforming growth factor (TGF)-beta1 positive area, and macrophage infiltration in glomeruli after 12 weeks. Mesangial matrix expansion and macrophage infiltration were increased in diabetic mice and inhibited by Pro or 7ND-treatment. Increased glomerular expression of Col4 and TGF-beta1 in diabetic mice was also ameliorated. Thus blocking the MCP-1/CCR2 pathway ameliorated glomerulosclerosis, indicating that the MCP-1/CCR2 pathway plays a crucial role in the progression of diabetic nephropathy.

Topics: Animals; Chemokine CCL2; Diabetic Nephropathies; Germanium; Mice; Mice, Inbred ICR; Organometallic Compounds; Propionates; Receptors, CCR2; Receptors, Chemokine; Signal Transduction; Transforming Growth Factor beta1

A series of Ge132 derivatives have shown enhanced antitumor activity. Previous studies suggest that DNA can be their primary target. Here we show direct evidence that two newly synthesized Ge132 derivatives can intercalate into DNA. Unexpected methyl substitution effect of the novel derivatives on DNA sequence selectivity and cytotoxicity was observed.

Topics: Animals; Antineoplastic Agents; Cattle; Cell Cycle; Cell Proliferation; DNA; Drug Screening Assays, Antitumor; Germanium; Humans; Inhibitory Concentration 50; Intercalating Agents; Male; Organometallic Compounds; Propionates; Prostatic Neoplasms; Quinolines; Tumor Cells, Cultured

Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a major cause of sepsis in patients who are immunosuppressed by their burns. In this study, an immunological regulation of MRSA infection was attempted in a mouse model of thermal injury. SCIDbg mice were resistant to MRSA infection, while SCIDbgMN mice (SCIDbg mice depleted of neutrophils and macrophages (Mphi)) were susceptible to the same infection. Also, thermally injured SCIDbg mice were shown to be susceptible to MRSA infection. On the other hand, the resistance of SCIDbgMN mice to the infection was completely recovered after an inoculation with Mphi from normal mice. However, anti-MRSA resistance was not shown in SCIDbgMN mice inoculated with Mphi from thermally injured mice. Mphi from MRSA-infected thermally injured mice were identified as alternatively activated Mphi, and Mphi from MRSA-infected unburned mice were characterized as classically activated Mphi. Mphi from thermally injured SCIDbg mice previously treated with 2-carboxyethylgermanium sesquioxide (Ge-132) protected SCIDbgMN mice against MRSA infection. Ge-132 has been described as an inhibitor of alternatively activated Mphi generation. These results suggest that MRSA infection in thermally injured patients is controlled immunologically through the induction of anti-MRSA effector cells and elimination of burn-associated alternatively activated Mphi, which are cells that inhibit the generation of classically activated Mphi.

Topics: Animals; Burns; Cells, Cultured; Chemokines; Cytokines; Disease Models, Animal; Disease Susceptibility; Germanium; Immunity, Innate; Interferon Inducers; Macrophages; Methicillin Resistance; Mice; Mice, SCID; Neutrophils; Organometallic Compounds; Propionates; Staphylococcal Infections; Staphylococcus aureus; Wound Infection

Fibrosis is a hallmark of progressive organ diseases. Monocyte chemoattractant protein (MCP)-1, also termed as macrophage chemotactic and activating factor (MCAF/CCL2) and its receptor, CCR2 are presumed to contribute to progressive fibrosis. However, the therapeutic efficacy of MCP-1/CCR2 blockade in progressive fibrosis remains to be investigated. We hypothesized that blockade of CCR2 may lead to the improvement of fibrosis. To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors. Cell infiltrations, most of which were F4/80-positive, were reduced in CCR2 knockout mice. In addition, dual staining revealed that CCR2-positive cells were mainly F4/80-positive macrophages. Importantly, CCR2 blockade reduced renal interstitial fibrosis relative to wild-type mice. Concomitantly, renal transcripts and protein of MCP-1, transforming growth factor-beta, and type I collagen were decreased in CCR2-null mice. Further, this CCR2-dependent loop for renal fibrosis was confirmed by treatment with CCR2 antagonists in a unilateral ureteral obstruction model. These findings suggest that the therapeutic strategy of blocking CCR2 may prove beneficial for progressive fibrosis via the decrease in infiltration and activation of macrophages in the diseased kidneys.

Topics: Animals; Antigens, Differentiation; CD3 Complex; Cell Movement; Chemokine CCL2; Collagen Type I; Disease Models, Animal; Fibrosis; Germanium; Immunohistochemistry; Kidney; Macrophage Activation; Macrophages; Mice; Mice, Knockout; Organometallic Compounds; Propionates; Receptors, CCR2; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Transforming Growth Factor beta; Ureteral Obstruction

The effect of therapeutic agents on trabecular bone loss in the mandible was investigated in ovariectomized rats. Eighty-seven Wistar SPF female rats were ovariectomized (OVX) or given a sham operation (Sham), and maintained on a diet containing 0.1% calcium. Four weeks later, groups of OVX rats were treated with estriol (E3), calcitonin (CT), etidronate, or 2-carboxyethylgermanium sesquioxide (Ge-132). The Basal group was maintained on a diet containing 1.0% calcium, and the OVX and sham groups on a diet containing 0.1% calcium. The trabecular bone mineral density (BMD) and trabecular bone mineral content (BMC) in 11 mandibular slices from 0.5 mm at the mesial margin of the first molar to 0.5 mm at the distal margin of the third molar, were measured using peripheral Quantitative Computed Tomography (pQCT). The BMD in the OVX group was lower than that in the Sham group, and decreased BMC was observed only in the molar region. BMD and BMC were increased in the etidronate-treated group, but only BMC was increased in the CT group. E3 treatment increased BMD and BMC; significant increases were also observed beneath the molar. Ge-132 treatment increased both BMD and BMC, especially the latter.

Topics: Animals; Bone Density; Calcitonin; Calcium, Dietary; Estriol; Etidronic Acid; Female; Germanium; Mandibular Diseases; Minerals; Organometallic Compounds; Osteoporosis; Ovariectomy; Propionates; Rats; Rats, Wistar; Tomography, X-Ray Computed

Macrophages play an important role in the pathogenesis of atherosclerosis, for which monocyte chemoattractant protein (MCP)-1 and CCR2 chemokine receptors may be involved. The authors have recently demonstrated that propagermanium exerts inhibitory effect on the CCR2 receptors. In the current study, the authors examined whether the organic germanium suppresses the MCP-1-induced monocyte migration in vitro and the development of atherosclerosis in WHHL rabbits in vivo. In the in vitro experiment, propagermanium concentration-dependently suppressed the MCP-1-induced migration of THP-1 cells. In the in vivo experiment, 20 WHHL rabbits were randomly divided into two groups; one group was treated with oral administration with propagermanium (9 mg/kg/day) for 3 months, and another group served as a control (n = 10 each). After 3 months, the aorta was isolated and stained with oil red O staining, and neointimal formation was quantified. Macrophage accumulation in the aorta was also evaluated by immunostaining. Long-term treatment with propagermanium did not affect the serum lipid profiles. However, the treatment significantly suppressed the oil red O-positive area of the total aorta (p < 0.05). Similarly, propagermanium significantly suppressed the intimal lesions (maximal intimal thickness and intimal area) and macrophage staining-positive area (all p < 0.05). A significant positive correlation was noted between macrophage staining-positive area and intimal lesions (p < 0.0001). These results indicate that long-term treatment with propagermanium suppresses the development of atherosclerosis in WHHL rabbits, suggesting its usefulness for the treatment of atherosclerotic vascular disease in humans.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Arteriosclerosis; Cell Line; Germanium; Humans; Organometallic Compounds; Propionates; Rabbits; Receptors, CCR2; Receptors, Chemokine; Receptors, LDL

Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.

Topics: Animals; Coronary Artery Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Germanium; Macrophages; Male; Organometallic Compounds; Propionates; Swine

Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein 1 (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase-positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion.

Topics: Animals; Chemokine CCL2; Chemotaxis, Leukocyte; Gene Expression; Germanium; Granulocytes; Interferon Inducers; Kidney; Kidney Tubular Necrosis, Acute; Macrophages; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Organometallic Compounds; Propionates; Receptors, CCR2; Receptors, Chemokine; Reperfusion Injury; RNA, Messenger; Signal Transduction

Monocyte chemoattractant protein-1 (MCP-1), which binds to C-C chemokine receptor 2, has been implicated as the primary source of monocyte chemoattractant function in the early stages of atherosclerosis. Recently, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, has been shown to inhibit C-C chemokine receptor 2 function and suppress monocyte/macrophage infiltration in vitro and in vivo. Given the importance of monocyte infiltration in atherogenesis, the inhibition of it by propagermanium might prevent atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were fed an atherogenic high cholesterol diet with or without 0.005% propagermanium for 8 or 12 weeks. Although the plasma lipid levels were unchanged by the drug treatment, atherosclerotic lesion area in the aortic root was reduced by 50% in the drug-treated apoE-KO mice compared with the nontreated apoE-KO mice after 8 weeks of cholesterol feeding (0.62+/-0.12 versus 1.27+/-0.07 mm2, respectively; P<0.01). Moreover, the accumulation of macrophages in the lesions was markedly reduced in the drug-treated group (macrophage positive area, 0.23+/-0.06 mm2 [drug-treated group] versus 0.67+/-0.07 mm2 [control group]; P<0.01). After 12 weeks of cholesterol feeding, atherosclerotic lesion formation in the aortic root and in the descending thoracic aorta was significantly reduced in the drug-treated group. Inhibition of macrophage infiltration by propagermanium prevented the formation of atherosclerotic lesions in apoE-KO mice. This drug may serve as a therapeutic tool for the treatment of atherosclerosis.

Topics: Abdomen; Animals; Apolipoproteins E; Arteriosclerosis; Cell Adhesion; Cell Line; Cell Migration Inhibition; Cells, Cultured; Chemokine CCL2; Cholesterol, Dietary; Endothelium, Vascular; Female; Germanium; Lipids; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Organometallic Compounds; Propionates; Thioglycolates

Monocyte chemoattractant protein-1 (MCP-1) promotes the migration and activation of monocytes and plays a pivotal role in the development of chronic inflammation. Propagermanium (3-oxygermylpropionic acid polymer) has been used as a therapeutic agent against chronic hepatitis B in Japan. We report here that propagermanium specifically inhibits in vitro chemotactic migration of monocytes by MCP-1. Propagermanium did not inhibit binding of MCP-1 to a human monocytic cell line, THP-1 cells, or affect intracellular Ca(2+) mobilization or the cAMP concentration in MCP-1-treated THP-1 cells. The effect of propagermanium seems to require glycosylphosphatidylinositol (GPI)-anchored proteins, as cleavage of GPI anchors by phosphatidylinositol-phospholipase C (PI-PLC) eliminated the inhibitory activity of propagermanium. Anti-GPI-anchored protein antibodies, such as anti-CD55 and anti-CD59, reduced staining of C-C chemokine receptor 2 (CCR2) with an anti-CCR2 antibody against the N-terminus of CCR2 in a flow cytometric analysis, and these antibodies also selectively inhibited MCP-1-induced migration of THP-1 cells. Furthermore, under fluorescence microscopy, GPI-anchored proteins colocalized with CCR2 on THP-1 cells. These results suggest that propagermanium may target GPI-anchored proteins that are closely associated with CCR2 to selectively inhibit the MCP-1-induced chemotaxis, thus providing a mechanistic basis for the anti-inflammatory effects of the drug.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; CD55 Antigens; Cell Line; Chemotaxis, Leukocyte; Germanium; Glycoproteins; Glycosylphosphatidylinositols; Humans; In Vitro Techniques; Integrin alphaXbeta2; Organometallic Compounds; Propionates; Receptors, CCR2; Receptors, Chemokine

Germanium-132 (Ge-132) was given at 200 mg/kg of body weight to 8-week-old Kurosawa and Kusanagi hypercholesterolemic (KHC) rabbits. Thirty-six weeks later, the susceptibility of plasma low-density lipoprotein to oxidation and the morphology of atherosclerosis in the aorta and coronary artery were investigated. Treatment with Ge-132 resulted in decreases in the oxidation rate and in the formation rate of thiobarbituric acid-reactive substances following copper-induced oxidation of LDL. Ge-132 is suggested to possess antioxidative properties, but this did not lead to any attenuation of atherosclerotic progression in the KHC rabbits.

Topics: Aging; Animals; Anticholesteremic Agents; Aorta, Thoracic; Arteriosclerosis; Female; Germanium; Hypercholesterolemia; Kinetics; Lipoproteins, LDL; Organometallic Compounds; Oxidation-Reduction; Oxidative Stress; Propionates; Rabbits; Thiobarbituric Acid Reactive Substances

To detect the antiproliferation of carboxyethyl germanium sesquioxide (Ge-132) on fibroblasts of pterygium in vitro and try to find a potentially effective agent for treatment of primary pterygium and prevention of its postoperative recurrence.. Primary culture and subculture of pterygium fibroblasts were established in vitro. Different concentrations of Ge-132 (39 - 5,000 mg/L) or mitomycin-C (3.13 - 4.00 mg/L, the control) were added to the fibroblast culture of the third or forth passage respectively. The inhibitory effect was determined by MTT (tetrazolium bromide) method. The influence of addition of Ge-132 on the growth curve of fibroblasts was observed, and the changing expression of proliferating cell nuclear antigen (PCNA) in fibroblasts was studied by immunohistochemical method.. The addition of Ge-132 in the culture caused significant inhibition of the fibroblast proliferation in dose dependent manner (625 - 50,000 mg/L) without cytotoxicity (IC(50) = 3,000 mg/L), the marked descent of growth curve and suppression of the expression of PCNA in cultured cells (P < 0.01).. Ge-132 can inhibit the proliferation of pterygium fibroblast in vitro significantly.

Topics: Cell Division; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; Germanium; Humans; Organometallic Compounds; Proliferating Cell Nuclear Antigen; Propionates; Pterygium

The effects of the synthetic antioxidant germanium (Ge-132) were studied on liver oxidant damage induced by paraquat (PQ) in senescence-accelerated mice (SAM). PQ administered intravenously to SAM-P/8 (susceptible) or SAM-R/1 (resistant) mice increased liver DNA strand breakage and malondialdehyde (MDA) levels, indicators of oxidant damage. Ge-132 effectively blocked the PQ-induced effects on liver DNA strand breaks and MDA levels. In addition, Ge-132 significantly elevated the activities of hepatic superoxide dismutase (SOD) and catalase following PQ pretreatment. Histopathologically, Ge-132 inhibited PQ-induced hepatic mitochondrial injury in both strains, but more effectively in the susceptible strain. Data suggest that Ge-132 may be useful as an antioxidant in view of its ability to prevent PQ-induced hepatic oxidant injury.

Topics: Aging; Animals; Antioxidants; Catalase; DNA Damage; Free Radicals; Germanium; Herbicides; Lipid Peroxidation; Liver; Malondialdehyde; Mice; Mice, Inbred Strains; Microscopy, Electron; Organometallic Compounds; Oxidative Stress; Paraquat; Propionates; Superoxide Dismutase

Inorganic germanium and carboxyethyl germanium sesquioxide (germanium-132) in health drinks were respectively determined by hydride generation-atomic fluorescence spectrometry (HG-AFS). The conditions of respective determination of inorganic germanium and germanium-132 in natural foods were preliminarily discussed.

Topics: Beverages; Flour; Food Analysis; Germanium; Organometallic Compounds; Propionates; Triticum

Propagermanium is an organic germanium compound with immunopotentiating activity. We examined the hepatoprotective effect of propagermanium and its mechanism in an experimental animal model of acute liver injury induced with Corynebacterium parvum (C. parvum) and lipopolysaccharide (LPS) injection. Oral pretreatment with propagermanium decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in a dose-dependent manner. Significant attenuation of ALT and AST activity was obtained at a dose of 3 mg/kg. Administration of propagermanium also inhibited the infiltration of mononuclear cells into the liver of mice induced by C. parvum/LPS. Immunohistochemical examination revealed infiltration of the liver by CD4-, CD8-, CD11b- and Gr-1-positive cells. Propagermanium prevented CD4- and CD11b-positive cells from infiltrating the liver. In this animal model, blood cytokine levels increased rapidly after LPS injection, causing severe hepatitis. Notably, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are important mediators of the progress of liver injury. We demonstrated that propagermanium reduced IFN-gamma production by 53% at a dose of 3 mg/kg and also significantly inhibited the production of interleukin-12 (IL-12). These results indicate that propagermanium inhibits cell infiltration in the liver and cytokine production, and improves massive liver injury in C. parvum/LPS mice.

Topics: Alanine Transaminase; Animals; Antibodies, Bacterial; Aspartate Aminotransferases; CD11 Antigens; CD4-Positive T-Lymphocytes; Corynebacterium Infections; Female; Germanium; Interferon-gamma; Interleukin-12; Lipopolysaccharides; Liver; Liver Diseases; Lymphocyte Subsets; Mice; Mice, Inbred ICR; Monocytes; Organometallic Compounds; Propionates; Propionibacterium acnes

Propagermanium (3-oxygermylpropionic acid polymer) is an organic germanium compound that activates the immune system. In this study, we investigated the action of propagermanium on T-cell-mediated murine hepatic injury induced by concanavalin A (Con A). Oral administration of propagermanium inhibited the development of liver injury about 10 h after ConA injection. Histological analysis demonstrated that propagermanium attenuated the extent of liver damage compared with controls, reducing infiltration by leucocytes, especially CD11b-positive cells. Infiltration by CD4-positive cells was not affected. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma are crucial for the development of hepatitis in this model. Propagermanium treatment induced significant inhibition of subsequent TNF-alpha production about 10 h after Con A injection, without affecting IFN-gamma, interleukin (IL)-10, IL-4 and IL-12 production. This effect on TNF-production coincided with the inhibition of aminotransferase activity late in the progression of Con A-induced liver injury. These facts suggest that this compound affects the macrophages (Mphi) function in the liver sinusoid. Therefore, Mphi were cultured with liver sinusoidal endothelial cells (SEC) and the effect of propagermanium on TNF-alpha production in the presence of IFN-gamma was determined. TNF-alpha production was reduced significantly in the coculture of Mphi and SEC when Mphi was treated with propagermanium. These results might explain the mechanisms by which propagermanium inhibits Con-A-induced liver injury. That is, propagermanium improves hepatitis through mechanisms including the reduced production of TNF-alpha, without modification of Th1- and Th2-cell function.

Topics: Animals; Antibodies; Cells, Cultured; Chemical and Drug Induced Liver Injury; Coculture Techniques; Concanavalin A; Endothelium, Vascular; Female; Germanium; Interferon Inducers; Interferon-gamma; Liver; Macrophages; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates; Rats; Rats, Inbred F344; Tumor Necrosis Factor-alpha

Recently, we reported that topical administration of 2-carboxyethyl germanium sesquioxide (Ge-132) concurrently with 50% galactose feeding delayed the establishment of mature cataracts and reduced advance glycation product. This study was to determine the effect of pretreatment of Ge-132 on galactose associated morphological changes and Na(+)-K(+)-ATPase activity.. Young Sprague Dawley rats received topical eye drops four times a day of either saline or Ge-132 seven days prior to the 50% galactose diet and during galactose feeding. At desired intervals the lenses were extracted, photographed and processed for either light microscopy, scanning electron microscopy or the determination of Na(+)-K(+)-ATPase activity.. In Ge-132 pretreated lenses as compared to saline pretreated lenses the following results were observed: (a) the galactose-induced morphological alterations in the majority of lenses were delayed and (b) Na(+)-K(+)-ATPase activity was protected.. Our previous and current studies show that in addition to osmotic stress post-translational protein modification, such as glycation, including enzymes may play a role in initiating changes that lead to cataract development. The inhibition of protein glycation by antiglycating compounds, such as Ge-132, delays sugar cataract formation. Currently, we are investigating the status of protein glycation and advanced glycation end products following pretreatment with Ge-132 and the role of Ge-132 on the activities of enzymes such as aldose reductase and Na(+)-K(+)-ATPase.

Topics: Animals; Antineoplastic Agents; Cataract; Galactose; Germanium; Glycosylation; Lens, Crystalline; Microscopy, Electron, Scanning; Ophthalmic Solutions; Organometallic Compounds; Propionates; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase

2-Carboxyethylgermanium sesquioxide (Ge-132), a synthesized organogermanium compound with immunomodulating activities, was shown to be an inducer of anti-suppressor T cells in normal mice. The suppressor cell activity of T6S cells, a clone of burn-induced CD8+ IL-4-producing suppressor T cells, was clearly inhibited when a mixed lymphocyte-tumor cell reaction of the clone was conducted with splenic mononuclear cells from mice treated orally with a 100 mg/kg dose of Ge-132. The activity of anit-suppressor cells was demonstrated in spleens of mice 2 days after treatment with Ge-132 and reached its peak on day 3. The anti-suppressor cells induced by the compound were of a contrasuppressor T cell-linage, because they were characterized as CD4+ CD28+ TCRalpha/beta+ Vicia villosa lectin-adherent T cells. These cells produced IFN-gamma but did not produce IL-2, IL-4, IL-6 or IL-10 in their culture fluids. CD4+ anti-suppressor T cells induced by Ge-132 may be different from other subsets of CD4+ T cells because Th1 and Th2 cells generated in our laboratory did not adhere to Vicia villosa lectin-coated petri dishes, and each produced specific cytokines. Th1 cells produced IFN-gamma and IL-2 while Th2 cells produce IL-4 and IL-10 in vitro. These results suggest that Ge-132 may be useful as an inducer of contrasuppressor T cells in immunocompromised individuals bearing suppressor T cells. To eliminate suppressor T cells from immunocompromised hosts may result in improved resistance from various opportunistic infections.

Topics: Animals; Cell Line; Clone Cells; Cytotoxicity, Immunologic; Germanium; Interferon Inducers; Kinetics; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates; Reference Values; Spleen; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Time Factors

Rats were fed with grain produced in the area prevalent of Keshan disease for 12 weeks, by adding certain amount of sodium selenite (Na2SeO3) and carboxylethylgermanium (Ge-132) to study the combined effects of selenium and germanium on lipid peroxidation and metabolism of free radicals in their bodies. Results showed selenium and germanium added to the grain could reduce the content of free radicals in rats' liver and kidney tissues, and that of lipid peroxide in their heart, liver and kidney, and increase the activities of glutathione peroxidase (GSH-Px) in their blood, in a synergic way.

Topics: Animals; Antioxidants; Female; Germanium; Lipid Peroxidation; Male; Organometallic Compounds; Propionates; Rats; Rats, Wistar; Sodium Selenite

Measures to alleviate pain are the most important issue in care of the cancer patient. In the present study, we investigated whether the use of narcotics could be reduced in the use of Ge-132 (Repargermanium) when used alone or together with a narcotic as a means to facilitate pain management in home care. The patients have died at home over the past 2 years with various types of cancer under our hospital supervision. Five were cases of bone metastasis, 6 of ascites. All cases had been given Ge-132, 750 approximately 2,500 mg/day (mean 1,000 mg) either orally or by IV. For pain control the first choice was MS Contin, and when the need arose the route used was intravenous or by suppository. We investigated the rate of narcotic usage and the dosage of same. Narcotics were used in 7 of the 16 patients (44%) who died at home, and the daily dose was 20 approximately 240 mg (mean 60 mg). By using Ge-132 as a pain killer the rate of narcotics use and the dosage were decreased, resulting in less side effects from the narcotics. Thus, Ge-132 proved effective in relieving the pain of the terminal cancer patient receiving home care, and since it has no side effects it assures smooth home treatment.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Bone Neoplasms; Drug Therapy, Combination; Female; Germanium; Humans; Male; Middle Aged; Organometallic Compounds; Pain, Intractable; Palliative Care; Propionates

N-Methyl-N'-nitrosoguanidine (MNNG) was administered (100 mg/L) in drinking water in 100 Wistar rats for 24 weeks to induce the precancerous lesion in glandular stomach. 77 rats with the precancerous lesion in glandular stomach were divided into 3 groups randomly at the 25 thweek. Yeast selenium (Yse, 4 mg/L) and carboxyethyl germanium sesquioxide (Ge-132, 600 mg/L) in drinking water were administered respectively in the corresponding treatment groups: 100 ml/MNNG in drinking water was administered in the treatment group, and 100 ml/MNN in drinking water was administered in the treatment group and control group for another 5 weeks. The experiment ended at the end of the 37th week. The results showed that the incidence of glandular stomach cancer in the Yse group was significantly lower than that in the control group; the infiltrating depth of glandular stomach cancer in the Yse group and the Ge-132 group was remarkably shallower than that in the control group. These findings suggest that Yse and Ge-132 have some preventive effect on the precancerous lesion in rat glandular stomach induced by MNNG.

Topics: Animals; Antidotes; Antineoplastic Agents; Germanium; Male; Methylnitronitrosoguanidine; Organometallic Compounds; Precancerous Conditions; Propionates; Rats; Rats, Wistar; Selenium; Stomach Neoplasms; Yeast, Dried

To compare the pharmacokinetics after po different doses of beta-carboxyethylgermanium sesquioxide (Ge-132).. An atomic absorption spectrophotometric system was used to measure germanium concentrations in plasma and urine samples after po Ge-132 1 (low dose, LD), 2.5 (medium dose, MD), and 4 (high dose, HD) g.m-2 in 24 healthy volunteers (one dose per 8 subjects).. T1/2 alpha (LD, 1.2 +/- 0.7 h; MD, 1.1 +/- 0.6 h; HD, 1.2 +/- 0.5 h), T1/2 beta (LD, 5.2 +/- 1.2 h; MD, 5.8 +/- 2.5 h; HD, 5.5 +/- 1.4 h) and Cl/F (LD, 33 +/- 12 L.h-1; MD, 35 +/- 10 L.h-1; HD, 33 +/- 11 L.h-1) were not dose-related. Tmax was between 0.75 h and 2 h. Cmax (LD, 5.3 +/- 2.2 mg.L-1; MD, 13 +/- 5 mg.L-1; HD 18 +/- 8 mg.L-1, HD) and AUC (LD, 31 +/- 13 mg.h.L-1; MD, 60 +/- 16 mg.h.L-1; HD, 79 +/- 42 mg.h.L-1) were positive correlation to the dose of Ge-132. Urine-eliminated germanium within 24 h accounted for 11 +/- 3% of LD, 9 +/- 3% of MD, and 6 +/- 5% of HD (calculated from Ge/F) and showed a negative correlation to the dose.. 1) Intracorporal process of Ge after po Ge-132 coincided with the first-order absorption and elimination with two-compartment kinetic model; 2) The amount of germanium eliminated in urine was below 11%.

Topics: Adult; Antineoplastic Agents; Area Under Curve; Female; Germanium; Humans; Interferon Inducers; Male; Organometallic Compounds; Propionates; Spectrophotometry, Atomic

We studied DMH induced colon cancer in 120 wistar rats, which were divided into 8 groups based on different diets. They were killed and autopsied on 4 weeks after the last injection of DMH. The tumors in various organs including its characteristics, number, site, histological types and ultrastructural changes were observed. The results showed that high fat diet has a significant effect on DMH induced colon cancer. Selenium and calcium can inhibit the effect of DMH and decrease the incidence of colon cancer. Selenium can also interfere the effect of high fat diet but germanium has no effect on colon carcinogenesis.

Topics: Animals; Antineoplastic Agents; Calcium; Carcinogens; Carcinoma, Papillary; Colonic Neoplasms; Dietary Fats; Dimethylhydrazines; Germanium; Male; Organometallic Compounds; Propionates; Rats; Rats, Wistar; Selenium

Germanium compounds have been shown to be effective in preventing the formation of advanced glycation end-products and for reversible solubilization of glycated proteins. As protein glycation has been proposed to play a role in lens opacification, we initiated studies to evaluate the effects of 2-carboxyethyl germanium sesquioxide (germanium compound 132 or Ge-132) on galactose-induced cataractogenesis. For this study young Sprague-Dawley rats were fed a 50% galactose diet. One group of rats received topical saline and another group was administered Ge-132 in saline four times a day. The lenses were periodically examined with an ophthalmoscope and at desired intervals processed for light and scanning electron microscopy. Our observations, beginning at 3 days and continuing to 21 days of galactose feeding, exhibited the characteristic galactose-induced morphological alterations, which include the formation of vacuoles, cysts, membrane disruption and swelling of fibers and epithelial cells as well as disorganization of the bow in lenses of rats in both groups. However, in the majority of rats administered Ge-132 these alterations were delayed as compared to the lenses of rats administered saline. Our findings show that, although the initiation, progression and pattern of lens opacification in rats receiving saline and Ge-132 were similar, in the majority of lenses the progression and establishment of mature cataracts in the Ge-132 group of rats were delayed. Analysis of the water-soluble and water-insoluble lens-protein fractions for glycated proteins showed increased levels of the Amadori products and advanced glycation related fluorescent products in galactosemic rats treated with saline eye drops. In rats receiving the topical Ge-132 treatment the levels of these glycation products were substantially reduced to levels lower than control values. Prevention of glycation seems to be a mechanism by which cataract progression is delayed.

Topics: Animals; Cataract; Galactose; Germanium; Glycosylation; Lens, Crystalline; Microscopy, Electron, Scanning; Organometallic Compounds; Propionates; Rats; Rats, Sprague-Dawley

A histopathological study was performed to examine the influence of propagermanium and germanium dioxide (GeO2) on chemically induced renal lesions in rats. Animals were treated with adriamycin or mercuric chloride to induce glomerular or proximal tubular damage, and then given drinking water containing propagermanium (480 or 2,400 ppm solution) or GeO2 (300 or 1,500 ppm solution: equivalent to propagermanium in terms of germanium contents). The distal tubular epithelium after 8 weeks dosage with the 1,500 ppm solution of GeO2 was characterized by vacuolization and deposits of PAS-positive material not only in adriamycin-treated rats, but also in normal rats. In contrast, propagermanium administration was not associated with any alternation in the changes induced by adriamycin or mercuric chloride. We previously clarified that propagermanium had no biochemical influence on the renal function of these renal injured rats. The histological demonstration that this compound does not exert renal toxicity, even when given at a high dosage to renal injured rats, further indicates that it would not exacerbate renal dysfunction already present. This confirms that propagermanium may be a safe compound for use in individuals with compromised kidneys.

Topics: Animals; Doxorubicin; Epithelium; Germanium; Kidney Diseases; Kidney Tubules, Distal; Male; Mercuric Chloride; Organometallic Compounds; Propionates; Rats; Rats, Wistar

The effects of propagermanium (3-oxygermylpropionic acid polymer) on various virus-infected mice were investigated. Propagermanium did not inhibit the multiplication of various DNA or RNA viruses in vitro. Oral administration of propagermanium in mice infected with herpes simplex virus type I (HSV-1) significantly prolonged the mean survival days. The efficacy of propagermanium at doses of 1 and 10 mg/kg daily was 13.4 +/- 2.3 and 14.2 +/- 2.3 mean survival days in comparison with 7.7 +/- 0.5 mean survival days at control group. In vaccinia virus-infected mice, oral doses of propagermanium ranging from 0.2 to 10 mg/kg suppressed the number of pocks on the tail which induced by the virus. Propagermanium (0.5-10 mg/kg) orally given to HSV-1-infected mice induced cytotoxic T lymphocytes (CTL) against HSV-1 antigen. In addition, propagermanium (1-10 mg/kg) enhanced interferon-gamma (IFN-gamma) induction in mice treated with Mycobacterium bovis (BCG). In mice spleen cells cultured with Concanavalin A, 0.1 to 10 micrograms/ml of propagermanium stimulated interleukin 2 (IL-2) production. It seems likely that the antiviral activity of propagermanium was exerted via enhancement of host immune resistance against viral infection.

Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Behavior, Animal; Female; Germanium; Herpes Simplex; Herpesvirus 1, Human; In Vitro Techniques; Interferon-gamma; Interleukin-2; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mycobacterium bovis; Organometallic Compounds; Propionates; Spleen; T-Lymphocytes, Cytotoxic; Vaccinia; Vaccinia virus

1. The therapeutic effect of organic germanium compound, 2-carboxyethylgermaniumsesquioxide (Ge-132), for experimental osteoporosis was studied using ovariectomized rats maintained on a low calcium containing diet. 2. Serum calcitonin (sCT) level was decreased and serum parathyroid hormone (sPTH) level was increased by ovariectomy and the decrement and increment rates, respectively, were reduced by administration of Ge-132. Thus, the sCT/sPTH ratio was greater in the groups given Ge-132, indicating that the resorption was somehow inhibited by Ge-132. 3. The transverse strength of femur bone was significantly enhanced by Ge-132. 4. A trend was found in the group given Ge-132 for a larger femur cortical bone index. 5. The relative femur bone wet weight was greater in the group given Ge-132. 6. These results indicate that Ge-132 prevents decreased bone strength, and affects the femur cortical bone index, and bone mineral mass caused by osteoporosis.

Topics: Animals; Bone Density; Calcitonin; Calcium; Calcium, Dietary; Female; Femur; Germanium; Organ Size; Organometallic Compounds; Osteoporosis; Ovariectomy; Parathyroid Hormone; Phosphorus; Propionates; Rats; Rats, Wistar

To compare the effect of cancer prevention of China medical stone (CMS) and Ge-132, rats were subcutaneously injected with dimethylhydrazine for 15 weeks and orally administered with 10% china medical stone soak and Ge-132 for 27 weeks. Colorectal cancer incidence in CMS was found significantly lower than in Ge-132 and controls (P < 0.05-0.01). In Ge-132 only the mean cancer foci and the mean cancer volumes/rat were found significantly less than controls (P < 0.01). It was shown by endoscopy that a precancerous lesion of the bowel resulted from carcinogen was more mild in CMS and Ge-132 than in controls. Serum gamma-interferon titer and NK activity of spleen cells were significantly elevated in CMS and Ge-132. Researches explained that the effect of cancer prevention of CMS was better than that of Ge-132.

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Dimethylhydrazines; Female; Germanium; Materia Medica; Organometallic Compounds; Propionates; Rats; Rats, Wistar

The effect of 2-carboxythylgerumanium sesquioxide (Ge-132) as an interferon-gamma (IFN-gamma) inducer on post-surgical immunosuppression was evaluated from the immunological response augmented in canine neutrophils, macrophages and peripheral blood lymphocytes (PBL) using the chemiluminescence technique. Experimental gastrotomy was performed on dogs in two groups; one group was subjected to sham-surgery without any medication, and the other was treated by Ge-132 administration at 24 hr before operation. Although the phagocytic activities of neutrophils, macrophages and PBL in the sham-operated group were depressed transiently after surgery, those in the Ge-132-administered group (Ge-132 group) were enhanced for a long time after surgery. It appeared that the generated free radical, which blocked the phagocytosis of macrophages and PBL, was activated by IFN-gamma. These results suggest that Ge-132 pre-treatment may be efficacious and useful in preventing the multifaceted clinical symptoms induced by post-operative immunosuppression in dogs.

Topics: Animals; Cell Line; Dogs; Female; Germanium; Immunosuppression Therapy; Interferon Inducers; Interferon-gamma; Leukocyte Count; Luminescent Measurements; Lymphocytes; Lymphoma, Non-Hodgkin; Macrophages; Male; Organometallic Compounds; Phagocytosis; Propionates; Stomach; Time Factors; Tumor Cells, Cultured

Induction of tumor necrosis factor in sera (TNS) as a multidisciplinary cancer therapy by the administration of a combination of 2-carboxyethylgermanium sesquioxide (Ge-132) and lipopolysaccharide (LPS) on Meth-A sarcoma-bearing mice was attempted. In addition to the above TNS induction therapy (TNS therapy) per se, the potential on the above parameters by employing a multidisciplinary cancer therapy (immunothermotherapy), in which TNS therapy was coupled with regional hyperthermia treatment, was investigated. This immunothermotherapy enhanced the antitumor effects produced by the above TNS therapy.

Topics: Animals; Antineoplastic Agents; Combined Modality Therapy; Germanium; Hyperthermia, Induced; Immunotherapy; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates; Sarcoma, Experimental; Tumor Necrosis Factor-alpha

The effect of carboxyethylgermanium sesquioxide (Ge-132) on cultured neonatal rat myocytes and isoproterenol injured myocytes was studied. The results showed that Ge-132 (0.01 mmol.L-1 and 1 mmol.L-1) increased the incorporation of both [3H]-TdR and [14C]-UR, reduced the membrane lipid fluidity and inhibited the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Exposure of the myocytes to isoproterenol 0.5 mmol.L-1 for 6 hours resulted in 5-fold release of LDH compared with the control. All myocytes ceased beating. Ultrastructurally, severe sarcolemmal and mitochondrial damage was evident. When the cells were pretreated with Ge-132 before the addition of isoproterenol, the increased LDH release was inhibited significantly, and preservation of beat and ultrastructure of myocytes was observed. In addition, the activity of superoxide dismutase (SOD) was elevated by Ge-132. All the effects of Ge-132 were dose-related. The results indicate that Ge-132 may improve the metabolism of cultured neonatal rat myocytes and protect myocytes from isoproterenol-induced injury.

Topics: Animals; Cells, Cultured; DNA; Free Radical Scavengers; Germanium; Heart; Isoproterenol; L-Lactate Dehydrogenase; Mitochondria, Heart; Myocardium; Organometallic Compounds; Propionates; Rats; Rats, Inbred Strains; RNA; Superoxide Dismutase

The effect of 2-carboxyethylgermanium sesquioxide (Ge-132) on the generation of splenic suppressor macrophages (S-M phi) in C3H/He mice (H-2k) immunized with allogeneic spleen cells from C57Bl/6 mice (H-2b) was investigated. We have previously demonstrated that S-M phi expressing I-J antigen, which appeared during alloimmunization, inhibited cytotoxic T lymphocyte (CTL) generation in the MLR and the elimination of these S-M phi before subjection to the MLR resulted in more effective generation of CTL. The CTL activity, which was determined in vivo by the Winn's test, was markedly enhanced when immunized mice received a 100 mg/kg dose of Ge-132. The compound was found to be the most efficacious when injected simultaneously with the immunization. The activity of allospecific CTL co-cultured with M phi fractions obtained from immunized mice in a 4-h 51Cr-release assay was shown to be 31% lysis of the target cells as compared with 90% lysis of the target cells in effector cells co-cultured with normal M phi fractions. In contrast, effector cells co-cultured with M phi fractions from Ge-132-treated immunized mice lysed 95% of the target cells. Analysis of the level of I-J antigen expression on macrophages (M phi) obtained from mice 7 days after immunization revealed a > 2.5-fold increase, whereas I-A antigen expression remained constant when compared with splenic M phi from naive mice. In contrast, the opposite effect on I-J and I-A antigen expression was observed in splenic M phi from alloimmunized mice treated with Ge-132. These results suggest that Ge-132 could regulate CTL generation in alloimmunized mice by preventing the generation of I-J+ S-M phi.

Topics: Adjuvants, Immunologic; Animals; Antigens, Surface; Female; Germanium; Histocompatibility Antigens Class II; Immunization; Lymphocytes; Macrophage Activation; Macrophages; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Organometallic Compounds; Propionates; T-Lymphocytes, Cytotoxic

We investigated so-called superoxide scavenging activity (SSA) of plasma in patients with several immunological disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), polymyo-dermatomyositis (PM), progressive systemic sclerosis (PSS), myasthenia gravis (MG) and autoimmune thyroid disease (AT), using the electron paramagnetic resonance/spin trapping technique. Since carboxyethylgermanium sesquioxide, Ge-132, has been reported to modulate both the immune response and leukocyte functions, we have studied in vivo effect of Ge-132 on plasma SSA and other laboratory parameters in these disorders. The plasma SSA was significantly lower in RA, SLE, PM and PSS, but not in MG and AT, as compared with that in healthy controls. An inverse correlation was observed between plasma SSA and parameters such as erythrocytes sedimentation rates, absolute number of leukocytes, C-reactive protein and serum globulin levels. Furthermore, plasma SSA was significantly decreased in rheumatoid factor-positive patients as compared to negative patients. No correlation was observed between plasma SSA and factors such as ages, sex of patients or the other laboratory parameters, such as serum albumin, triglyceride, cholesterol, hemoglobin and serum iron levels. Patients treated with prednisolone, especially ones with RA, showed an increase of plasma SSA. It appears that Ge-132 promotes prednisolone effects. Our results indicate that a decrease in plasma SSA is not disease specific, but inversely correlates with the severity and activity of inflammation. The methodology to measure plasma SSA presented in this work provides a helpful tool for determining the actual activity of the diseases as well as in vivo studies of antiinflammatory agents.

Topics: Adolescent; Adult; Aged; Female; Free Radical Scavengers; Germanium; Humans; Immune System Diseases; Inflammation; Male; Middle Aged; Organometallic Compounds; Prednisolone; Propionates; Superoxides

The carboxyethylgermanium sesquioxide, Ge-132, is an organogermanium compound which has been shown to modulate leukocyte functions. In this study, we examined the effect of Ge-132 on the generation of superoxide radicals (O2-) either from leukocytes or in cell-free system, employing the highly sensitive 2-methyl-6-[p-methoxy-phenyl]-3,7-dihydroimidazo[1,2-alpha]pyra zin-3-one (MCLA)-dependent chemiluminescence method and the specific electron spin resonance/spin trapping method, respectively. In addition, the in vitro protective effect of Ge-132 on the leukocytes irradiated with 60Co was studied. The incubation with Ge-132 resulted in an increase in basal O2- release of intact leukocytes, but had no effect on O2- generation from leukocytes stimulated with phorbol myristate acetate (PMA). Irradiation with 60Co decreased the O2- generation from leukocytes in a dose-dependent manner. Ge-132 had no effect on basal O2- release from 60Co-irradiated leukocytes, but it prevented the decrease in PMA-stimulated O2- generation by irradiated leukocytes. Ge-132 itself had no superoxide scavenging activity in cell-free system. On the other hand, higher concentrations of Ge-132 had decreasing effects on both basal O2- release and PMA-stimulated O2- generation from leukocytes, but they did not affect leukocyte viability. Above results indicate that 1) Ge-132 can stimulate the basal O2- release from leukocytes, 2) Ge-132 can prevent the decrease of O2- generation by 60Co-irradiated leukocytes, 3) in higher concentrations, Ge-132 may have a membrane stabilizing effect.

Topics: Antineoplastic Agents; Cobalt Radioisotopes; Gamma Rays; Germanium; Humans; In Vitro Techniques; Leukocytes; Male; Organometallic Compounds; Oxygen Consumption; Propionates; Superoxides; Tetradecanoylphorbol Acetate

Chronic nephrotoxicity was investigated in rats orally administered germanium dioxide (GeO2) and carboxyethylgermanium sesquioxide (Ge-132) for 24 weeks. Increased BUN and serum phosphate as well as decreased creatinine clearance, weight loss, anemia and liver dysfunction were apparent at week 24 only in the GeO2 treated group. Vacuolar degeneration and granular depositions were observed by light microscope in the degenerated renal distal tubules in the rats of this group, with the semiquantitative scores of tubular degeneration being 95 +/- 9% in the GeO2 group, 3 +/- 1% in the Ge-132 group and 1 +/- 1% in the control group, respectively. Electron microscopy revealed electron-dense inclusions in the swollen mitochondrial matrix of the distal tubular epithelium in the GeO2 group. Although systemic toxicities were reduced after GeO2 was discontinued at week 24, renal tubulointerstitial fibrosis became prominent even at week 40 (16 weeks after discontinuation). A Ge.K alpha X-ray spectrum was clearly demonstrated in the mitochondrial matrix of the distal tubular epithelium in the GeO2 group with the help of electron probe X-ray microanalysis. On the other hand, neither toxic effects nor renal histological abnormalities were manifested in either the Ge-132 or the control group. The renal tissue content of germanium was high at weeks 24 and 40 in the GeO2 group. From these results, it is concluded that GeO2 causes characteristic nephropathy while Ge-132 does not. In addition, it appears that residual GeO2 remains for a considerably long time even after the cessation of GeO2 intake.

Topics: Animals; Electron Probe Microanalysis; Female; Germanium; Kidney Diseases; Kidney Tubules; Microscopy, Electron; Organometallic Compounds; Propionates; Rats; Rats, Inbred Strains; Tissue Distribution

After a brief recall of toxicological data about germanium compounds, the authors relate subacute and subchronic oral toxicities of beta bis carboxyethyl-germanium sesquioxide in rats. During 28 days and six months, male and female animals have received 1 mg/kg/day. No particular toxic symptoms, no behaviour trouble except a small decrease of body weight, in male rats, at the end of the 6-month experimentation, were observed. A light decrease of erythropoiesis and a general stimulation of cellular metabolism has been noticed after 28 days. The only marked effect was a moderate renal deficiency characterized by a tubular disease with presence of cylinders, swelling of tubulus cells and floculus amounts after 6 months. Germanium urinary excretion was constant and linked to the received dose. Six months later, no preferential accumulation in organs was observed.

Topics: Administration, Oral; Animals; Female; Germanium; Male; Organometallic Compounds; Propionates; Rabbits; Rats; Rats, Wistar; Time Factors

Proxigermanium (SK-818) is a synthesized organic germanium compound having various biological activities. The effects of proxigermanium on interferon (IFN) production in mice infected with influenza virus and virus-infected human peripheral blood mononuclear cells (hPBMC) were investigated. Proxigermanium alone did not induce IFN production in normal mice or in hPBMC without viral infection. On the other hand, proxigermanium enhanced alpha/beta IFN production in viral-infected mice and hPBMC. Since proxigermanium is known to have antiviral activity in vivo but not in vitro, it is likely that the IFN production augumenting activity of proxigermanium is involved in its antiviral activities.

Topics: 2',5'-Oligoadenylate Synthetase; Adjuvants, Immunologic; Animals; Cells, Cultured; Germanium; Humans; Indicators and Reagents; Influenza A virus; Influenza, Human; Interferons; Lung; Mice; Mice, Inbred BALB C; Neutrophils; Organometallic Compounds; Propionates

In rats anesthetized with urethane, intraperitoneal administration of a water-soluble organogermanium compound 2-carboxyethyl germanium sesquioxide (Ge-132) produced a dose-related reduction in either the mean arterial pressure or the heart rate. Both hypotension and bradycardia responses induced by Ge-132 injection were significantly inhibited by pretreatment of the animals with either spinal transection or bilateral vagotomy. The data indicate that Ge-132 induces both hypotension and bradycardia by promoting an activation of the parasympathetic efferent mechanisms and an inhibition of the sympathetic efferent mechanisms. On the other hand, following intraperitoneal injection of Ge-132, increased grooming and head swaying (as shown by an enhancement in fine movements monitored by an electronic activity counter) were provoked. Furthermore, the amphet-amine-induced enhancement in fine movements was potentiated by pretreatment of the animals with Ge-132. Thus, it appears that Ge-132 acts through the catecholaminergic mechanisms in the brain to induce locomotor stimulation in rats.

Topics: Amphetamine; Animals; Antineoplastic Agents; Behavior, Animal; Blood Pressure; Decerebrate State; Dose-Response Relationship, Drug; Drug Synergism; Germanium; Heart Rate; Hemodynamics; Injections, Intraperitoneal; Male; Motor Activity; Organometallic Compounds; Propionates; Rats; Rats, Inbred Strains

The protective effect of carboxyethylgermanium sesquioxide (Ge-132) in mice infected with a mouse-adapted strain of influenza virus (H2N2) was investigated. When mice were exposed to a 10 LD50 dose of influenza virus via aerosol and were treated orally with 20 or 100 mg/kg of Ge-132 daily for 6 consecutive days, a significant protective effect was demonstrated. The antiviral effect of Ge-132 was indicated by an increase of survivors, a prolongation of mean survival days, an inhibition of the development of lung consolidation, and a decrease of virus titer in lung tissues, as compared to infected control mice treated with phosphate-buffered saline. Natural killer (NK) cell activity in the spleens and lungs of the infected mice was also significantly augmented after the oral administration of Ge-132. In addition, NK cells stimulated with Ge-132 in vivo showed killing activity against NK-insensitive Meth-A cells infected with influenza virus. Because no virucidal or virustatic activities of Ge-132 on the virus were found in vitro, this protective effect in mice against influenza virus infection may be displayed through immunomodulating activities of this compound such as the augmentation of NK cell activity.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Germanium; Influenza A virus; Interferons; Killer Cells, Natural; Lung; Mice; Mice, Inbred Strains; Organometallic Compounds; Orthomyxoviridae Infections; Propionates

Topics: Animals; Germanium; Graft Survival; Kidney; Kidney Transplantation; Male; Organometallic Compounds; Propionates; Rats; Rats, Inbred Strains; Reperfusion Injury; Tissue Preservation

The effects of dicarboxyethenylgermanium sesquioxide (DCG) on electrical and mechanical activity in isolated guinea pig papillary muscles and rabbit sinus node were studied by intracellular capillary glass electrode. The effects of DCG on slow action potential and contractile force (Fc) of preparations in which the fast Na+ channels were inactive by partial depolarization by increasing the concentration of K+ 25.4 mmol/L were observed. DCG (0.5 mol/L) increased Vmax and APA of fast action potential of guinea pig papillary muscles, but its Fc decreased from 105 +/- 12% of control to 80 +/- 16%. DCG prolonged the spontaneous cycle length (SCL) and APD90 of rabbit sinus node, but the slope of phase 4(SP4) was lowered. The functional refractory period (FRP) of rabbit left atria was determined by the paired stimulus method. In experiments involving one drug, the drug was added until equilibrium had been reached. It has been demonstrated by experiments that the administration of DCG resulted in an increase of atrial FRP. These findings suggest that the Ca2+ inward currents and the K+ outward current may be inhibited by DCG.

Topics: Action Potentials; Animals; Female; Germanium; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardial Contraction; Organometallic Compounds; Papillary Muscles; Propionates; Rabbits; Sinoatrial Node

Interferon (IFN)-inducing activity of the organogermanium compound Ge132 in human peripheral mononuclear cells was investigated. By using Percoll discontinuous density gradient centrifugation, peripheral blood nonphagocytic and nonadherent mononuclear cells were divided into the low-and high-density fractions. Natural killer (NK)-enriched low-density fractions, but not the T-cell-enriched high-density fractions, showed IFN production by the stimulation of Ge132. The maximal titer of IFN by NK-enriched fractions (F1 + F2) was observed after a 74-h cultivation in the presence of 200 micrograms/ml Ge132. IFN production by the NK-enriched fractions was abrogated by treatment of the cells with monoclonal antibody against human NK cells in the presence of complement. The treatment with antiserum-neutralizing human IFN-gamma resulted in a marked reduction, indicating that a major part of IFN was IFN-gamma. These results suggested that Ge132 might possess affinity to NK cells, inducing IFN production by NK cells.

Topics: Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Germanium; Humans; In Vitro Techniques; Interferon Inducers; Interferon-gamma; Killer Cells, Natural; Organometallic Compounds; Propionates

The administration of IFN-containing sera (Ge-sera) obtained from Ge-132-treated mice (Ge-mice) or the passive transfer of macrophages (M phi) to mice bearing ascites tumors resulted in the inhibition of tumor growth. The cooperative role of Ge-sera and Ge-M phi in the display of Ge-132-antitumor activity was studied. When mice were pretreated with antimouse IFN gamma antiserum, no IFN-inducing or antitumor activities of the compound were detected. Cytotoxic activities were detected in peritoneal M phi of mice treated with Ge-sera, and passive transfer of these M phi to tumor-bearing mice resulted in the inhibition of tumor growth. When tumor-bearing mice were pretreated with substances toxic to M phi, no antitumor activity of Ge-sera was observed. However, Ge-132 antitumor activity was observed in mice depleted of T-cells, even though the antitumor effects of the compound itself were not demonstrable in T-cell-depleted mice. Therefore, a part of the antitumor activity of Ge-132 appears to be expressed as follows: Ge-132 stimulates T-cells to produce circulating lymphokine(s) which are inactivated by anti-IFN gamma treatment; activated M phi are generated from resting M phi by these lymphokine(s); the transplanted tumors are inhibited by these M phi.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cytotoxicity, Immunologic; Female; Germanium; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organometallic Compounds; Propionates

The antitumor effect of combination immunochemotherapy with Ge-132 and antitumor agent was studied using C57BL/6 mice bearing Lewis lung carcinoma (3LL). Ge-132 was administered orally at a daily dose of 100 mg/kg. Antitumor agents were administered intraperitoneally once a week. Initially, the effect of combination immunochemotherapy with Ge-132 and 5-fluorouracil (5-FU) was studied on 3LL local tumor growth, pulmonary metastases, survival, delayed type hypersensitivity (DTH) and body weight in tumor-bearing mice, and the following results were obtained: Inhibition of tumor growth in the combined group; Enhanced anti-metastatic effect; Prolonged survival time, and; Recovery of loss of both DTH and body weight as a result of combination therapy. These antitumor effects were also obtained by adoptive transfer of Ge-132-stimulated splenocytes in 5-FU-treated mice bearing 3LL. These results therefore suggest that the effects of Ge-132 were expressed through modification of immunocytes. Furthermore, Ge-132 enhanced the antitumor activity of bleomycin as well as that of 5-FU. These facts suggested that Ge-132 is useful for antitumor combination immunochemotherapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Fluorouracil; Germanium; Hypersensitivity, Delayed; Lung Neoplasms; Mice; Mice, Inbred C57BL; Organometallic Compounds; Propionates

Twenty-eight species of carboxyethyl germanium sesquioxide (Ge-132) derivatives were examined for their inhibitory effects on enkephalin-degrading enzymes that were purified from monkey brain, the longitudinal muscle layer of bovine small intestine, and human cerebrospinal fluid (CSF). A series of the sulfurized Ge-132 derivatives showed strong inhibition of these purified enzymes. The most effective ones were Ge-014 and Ge-107, which showed IC50 values of 60 and 100 micrograms/ml, respectively, for dipeptidylcarboxypeptidase from the longitudinal muscle layer. They also exhibited inhibitory activity against aminopeptidase from human CSF, the IC50 values being 450 and 440 micrograms/ml, respectively. Furthermore, these compounds showed inhibition of dipeptidylaminopeptidase from monkey brain and the longitudinal muscle layer of bovine small intestine. These compounds are expected to have analgesic effects due to their inhibition of the degradation of endogenous opioid peptides.

Topics: Aminopeptidases; Analgesics; Animals; Brain; Carboxypeptidases; Cattle; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Endopeptidases; Enkephalins; Germanium; Guanidines; Haplorhini; Humans; Intestine, Small; Organometallic Compounds; Propionates; Protease Inhibitors

After oral administration of an organic germanium compound, Ge-132 (300 mg/kg), a significant level of interferon (IFN) activity was detected in the sera of mice at 20 hr and it reached a maximum of 320 U/ml at 24 hr. This IFN activity was lost after heat- or acid-treatment, suggesting that the induced IFN is of gamma-nature. The molecular weight of this IFN was estimated to be 50,000 daltons by gel filtration. The NK activity of spleen cells was increased 24 hr after the oral administration of Ge-132, and cytotoxic macrophages were induced in the peritoneal cavity by 48 hr. In the mice receiving an intraperitoneal (ip) injection of trypan blue or carrageenan 2 days before oral administration of Ge-132, neither induction of IFN nor augmentation of NK activity occurred, and X-ray irradiation of mice also rendered the mice incapable of producing IFN, all indicating that both macrophages and lymphocytes are required for this IFN induction. Both NK and cytotoxic macrophages appeared 18 hr after ip administration of the induced IFN with a titer as low as 20 U/ml. These facts suggest that both the augmentation of NK activity and activation of macrophages in mice after oral administration of Ge-132 are mediated by the induced IFN.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Germanium; Hot Temperature; Hydrogen-Ion Concentration; Immunosuppressive Agents; Interferons; Killer Cells, Natural; Macrophage Activation; Mice; Mice, Inbred Strains; Organometallic Compounds; Propionates; Whole-Body Irradiation

The antitumor activity of Ge-132 against a variety of allogeneic and syngeneic murine ascites tumors was first evaluated. The antitumor effects of Ge-132 were observed when mice inoculated with Ehrlich carcinoma (allogeneic) or RL male 1 leukemia (syngeneic) cells were treated orally. However, Ge-132 had no activity on a T-cell lymphoma (EL 4, syngeneic) or a methylcholanthrene-induced fibrosarcoma (Meth-A, syngeneic). The antitumor effect of Ge-132 in mice was related to the dose administered as well as the administration schedule. The antitumor activity of Ge-132 was next studied in mice pretreated with some blockers against immunocompetent cells. The antitumor efficacy of Ge-132 was not observed when tumor-bearing mice were treated with trypan blue and carrageenan or monoclonal anti-Thy 1.2 antibody. However, when natural killer cells were eliminated from mice bearing RL male 1 or Ehrlich ascites tumors by treatment with anti-asialo GM 1 antiserum, the antitumor efficacy of the compound was unchanged. These results suggest that Ge-132 is effective against certain ascites tumors regardless of whether the tumor is syngeneic or allogeneic. Further, its effect might be expressed through host defense mechanisms, including macrophages and/or T lymphocytes.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Germanium; Leukemia; Liver Neoplasms, Experimental; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organometallic Compounds; Propionates; T-Lymphocytes

Sera from C57Bl/6 mice treated orally with Ge-132 exhibited antitumour activity against Ehrlich (allogeneic) and RL male 1 (syngeneic) ascites tumours in BALB/c mice. Sera obtained from mice 24 h after Ge-132 administration displayed the greatest antitumour effect and this was dose dependent. Sera prepared from mice 12, 36, or 48 h after Ge-132 treatment had no protective effect. Circulating interferon (IFN) was induced at 24 h after administration of Ge-132 but was not detected in the sera at 12, 36, or 48 h after administration. The antiviral activity of sera from Ge-132-treated mice was inactivated by treatments with trypsin, low pH, and anti-IFN gamma antiserum. The inactivated preparations of serum IFN induced by Ge-132 did not exhibit antitumour activity when administered to tumour-bearing mice. These results suggest that antitumour activity in the sera of Ge-132-treated mice may be expressed through activities of Ge-132-induced lymphokine(s), such as IFN gamma.

Topics: Animals; Carcinoma, Ehrlich Tumor; Dose-Response Relationship, Immunologic; Female; Germanium; Interferon-gamma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms, Experimental; Organometallic Compounds; Propionates; Time Factors

Serum specimens from mice treated orally with Ge-132 (100 mg/kg) exhibited antitumor activity against Ehrlich (allogeneic) and RL 1 (syngeneic) ascites tumors in BALB/c mice. Sera obtained from mice 24 hours after Ge-132 administration displayed the highest antitumor effect and the antitumor activity was dose-dependent. Sera prepared from mice 12, 36 or 48 hours after Ge-132 treatment had no protective effect. Circulating interferon (IFN) was induced at 24 hours after administration. The antiviral activity of serum from Ge-132-treated mice was inactivated by treatment with trypsin, low pH, and anti-IFN-gamma antiserum. The inactivated preparations of serum IFN induced by Ge-132 did not show antitumor activity when administered to mice bearing Ehrlich ascites tumors. These results suggest that the antitumor activity in the sera of Ge-132-treated mice may have been expressed through IFN-gamma which was induced by Ge-132.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Germanium; Immunization, Passive; Interferon-gamma; Leukemia, Experimental; Macrophage Activation; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates

The effects of two novel organic germanium compounds, 1-phenyl-2-carbamoylethylgermanium sesquisulfide (PCAGeS) and 1-phenyl-2-carbamoylethylgermanium sequioxide (PCAGeO), on transplantable murine tumors and immune responses were studied. Both drugs showed low toxicity for mice. In culture, neither substance displayed significant cytotoxicity against murine tumor cells L1210 leukemia, L5178Y lymphoma, or IMC carcinoma. Growth of subcutaneously transplanted IMC carcinoma or Meth-A fibrosarcoma was markedly reduced by oral administration of PCAGeS. PCAGeO exhibited a similar but smaller effect on the tumor growth. Pulmonary metastasis of Lewis lung carcinoma was inhibited by oral or intraperitoneal treatment with PCAGeS. The activity of cyclophosphamide or Adriamycin against L1210 leukemia was significantly potentiated by oral administration of PCAGeS. PCAGeS enhanced the delayed-type hypersensitivity response to sheep red blood cells (SRBC) of mice or restored the response suppressed by ascitic IMC carcinoma, but did not significantly affect the formation of antibody to SRBC. PCAGeO similarly stimulated the DTH reaction. Phagocytic activity of peritoneal macrophages was enhanced by oral treatment of mice with PCAGeS. The results suggest that PCAGeS and PCAGeO display tumor-inhibitory activity by modification of the immune mechanism.

Topics: Animals; Antibody Formation; Antineoplastic Agents; Cyclophosphamide; Doxorubicin; Drug Synergism; Female; Fibrosarcoma; Germanium; Hypersensitivity, Delayed; Leukemia L1210; Lung Neoplasms; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Neoplasms, Experimental; Organometallic Compounds; Phagocytosis; Propionates

Effects of the organogermanium compound Ge-132 (i.p.) were examined on the 3LL local tumor (1 X 10(5)/mouse, s.c.) and its pulmonary metastases in B6 mice. A characteristic feature of its action was the preferential antimetastatic effect under strictly defined conditions. Either inhibition or facilitation was observed depending on the treatment schedules; 7 daily doses of 100 mg/kg yielded the inhibition ratio 49% when started from day 1, whereas the treatment from day 8 resulted in the ratio -99%. The maximum inhibition was obtained at 100 mg/kg. The postsurgical-adjuvant treatment with Ge-132 was of no beneficial effect. The local tumor growth was affected only marginally and temporarily. When inoculum size was minimized (1 X 10(4)), a single dose of 300 mg/kg on day 1, but not on day 8, was effective in prolonging the latency before tumor take. The antitumor action of Ge-132 was discussed with reference to its interferon (IFN)-inducing activity.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Germanium; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Organometallic Compounds; Propionates

In a murine model it has been shown that the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132) can be depleted by administration of macrophage (M phi) blockers. In the present study, the role that M phi play in the antitumor activity of the compound was investigated. Oral administration of Ge-132 in mice was demonstrated to be effective in activating M phi (Ge-132-cytotoxic M phi), and the cytotoxic activity of these M phi appeared in the peritoneal cavity of mice 48 hours after the oral administration of the compound. Co-cultivation of RL male-1 leukemia or Ehrlich carcinoma cells with Ge-132-cytotoxic M phi in vitro resulted in marked suppression of the growth of tumor cells. The transfer of peritoneal exudate cells (PEC), or purified M phi fractions of PEC from Ge-132-treated mice to mice bearing Ehrlich or RL male-1 ascites tumors resulted in significant protection. However, when the cytotoxic M phi were depleted by carbonyl-iron treatment in vitro, no antitumor effect was demonstrated in mice bearing Ehrlich or RL male-1 ascites tumors. Macrophage fractions obtained from PEC of Ge-132-treated mice exhibited an inhibitory effect against certain tumors both in vivo and in vitro suggesting that the antitumor effect of Ge-132 observed in vivo resulted from the activation of M phi.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cytotoxicity, Immunologic; Germanium; Leukemia, Experimental; Liver Neoplasms, Experimental; Macrophage Activation; Macrophages; Mice; Organometallic Compounds; Peritoneal Cavity; Propionates

The antitumor effect of an organic germanium compound, carboxyethylgermanium sesquioxide (Ge-132), was examined in mice using two systems: one, the ascitic form of Ehrlich carcinoma in DDI mice, and the other, the solid form of Meth-A fibrosarcoma in BALB/c mice. In the mice with Ehrlich ascitic tumors, a remarkable prolongation in life span was observed after intraperitoneal (i.p.) or per oral (p.o.) administration of Ge-132 (300 mg/kg), but not after intravenous (i.v.) injection of the same compound. Following i.p. or p.o. administration, cytotoxic macrophages (Mø) were induced in the peritoneal cavity after 48 h. although this was not the case after i.v. injections. When the in vivo effect of these in vitro active Mø was examined after adoptive transfer to mice bearing Ehrlich ascitic tumor cells, a significant antitumor effect was noted. In the mice bearing solid Meth-A tumors, i.v. injections of Ge-132 (100 mg/kg) were found to inhibit tumor growth remarkably, although i.p. and p.o. administrations did not have the same result. This inhibitory effect of Ge-132 by i.v. administration was explained by the continued augmentation of NK activity in peripheral blood, which was followed by the induction of specific killer cells appearing in the spleen. When the mice which had recovered from Meth-A tumor growth, following i.v. injections of Ge-132, were challenged with the same tumor on day 30, all mice were able to tolerate the challenge, but not a challenge of RL male 1 tumor cells. These observations may indicate that the differing antitumor effects of Ge-132 produced when different administration methods are used can be explained by the variation in effector cells induced by such different administration routes.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Drug Administration Schedule; Germanium; Infusions, Parenteral; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates

As reported previously, gamma interferon (IFN-gamma) production was selectively decreased in thermally injured mice (TI-Mice) and spleen cell cultures from the mice following stimulation with various IFN inducers. The decrease in IFN production was associated with splenic suppressor macrophages. The present study demonstrated that TI-Mice treated with Ge-132 (TGe-Mice) produced IFN following stimulation with IFN-gamma inducers. The level of IFN activity detected in the sera of TGe-Mice approximated that of controls. Similar results were obtained when spleen cells prepared from TGe-Mice were stimulated with IFN-gamma inducers in vitro. While transfer of spleen cells from TI-Mice resulted in the suppression of IFN production in normal mice (N-Mice) stimulated with IFN-gamma inducers, the transfer of spleen cells derived from TGe-Mice did not induce suppression of IFN production in N-Mice. Mononuclear cells (MNC) prepared from N-Mice produced IFN following concanavalin A (Con A) stimulation when they were co-cultured with macrophage-enriched populations (PAC) obtained from the spleens of TGe-Mice. In contrast, MNC stimulated with Con A did not produce IFN activity when they were co-cultured with PAC of TI-Mice. These results suggest that the generation of suppressor macrophages in TI-Mice may be altered by the administration of Ge-132.

Topics: Animals; Antineoplastic Agents; Burns; Concanavalin A; Enterotoxins; Female; Germanium; Interferon Inducers; Interferon-gamma; Kinetics; Macrophages; Mice; Mice, Inbred BALB C; Newcastle disease virus; Organometallic Compounds; Poly I-C; Propionates

In order to evaluate effects of interferon (IFN) and its inducers on neutrophil functions, neutrophil chemiluminescence (ChL) was assayed in 12 patients treated with IFN (human lymphoblastoid interferon, 3.0 X 10(6) units/day i.m. daily) or Ge-132 (2,250 mg/day p.o. daily). The peak levels of neutrophil ChL, assayed one week after the initiation of treatment, were increased in comparison to those before treatment, but one month after treatment they were decreased to pretreatment levels in spite of the daily administration of the agent. On the basis of these results, it was concluded that IFN and Ge-132 enhanced the host defence mechanism including the activation of neutrophils, which appeared at the early phase of the host reaction.

Topics: Adenocarcinoma; Adult; Aged; Female; Germanium; Humans; Interferon Inducers; Interferon Type I; Kidney Neoplasms; Leukemia, Myeloid; Luminescent Measurements; Lymphoma; Male; Middle Aged; Multiple Myeloma; Neutrophils; Organometallic Compounds; Oxygen Consumption; Phagocytosis; Propionates

The natural killer (NK) activity of peripheral blood lymphocytes from 18 cancer patients was studied prior to and after multiple administration of organo-germanium compound (Ge-132). In successive oral administration of Ge-132 at a dose of 1000 mg/day for 10 days, NK-activity of patients was augmented at 3 days, but by 10 days, depression of NK activity was observed in all cases. In intermittent oral administration of Ge-132, however, more than half of the patients with augmented NK activity at day 3 maintained the high activity level at day 10. This result suggests the superiority of intermittent administration of Ge-132 for clinical use.

Topics: Colonic Neoplasms; Cytotoxicity, Immunologic; Germanium; Humans; Killer Cells, Natural; Lung Neoplasms; Organometallic Compounds; Propionates; Stomach Neoplasms

A novel organogermanium compound, Ge-132, carboxyethylgermanium sesquioxide, showed enhancement of 0.5 mg/kg morphine analgesia in both administration routes of oral administration (p.o.) and intraperitoneal injection (i.p.) in the Tail-Flick test, and the effect was completely abolished by 0.5 mg/kg Naloxone, stereospecific opiate antagonist. Ge-132 alone, 250 mg/kg i.p., did not show any antinociceptive action by assessing the Tail-Flick test and the Hot-Plate test. By the intracerebral injection of Ge-132, 100-1000 micrograms, prolongation of Tail-Flick latency was observed and the action was abolished by 50 micrograms CaCl2 injection. Although bestatin which is reported to enhance the morphine analgesia inhibits enkephalinase and enkephalin aminopeptidase, Ge-132 did not show any inhibition on both enkephalin degrading enzymes. The possibility for the mode of action of Ge-132 was discussed.

Topics: Analgesics; Animals; Endopeptidases; Germanium; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Morphine; Neprilysin; Organometallic Compounds; Propionates; Rats; Rats, Inbred Strains; Reaction Time

After oral administration of an organic germanium compound, Ge-132 (300 mg/kg), a significant level of interferon (IFN) activity was detected in the sera of mice at 20 hr and it reached a maximum of 320 U/ml at 24 hr. This IFN activity was lost after heat- or acid-treatment, suggesting that the induced IFN is of gamma nature. The molecular weight of this IFN was estimated to be 19,000 daltons by gel filtration. After the oral administration of Ge-132, NK activity of spleen cells had increased at 24 hr and cytotoxic macrophages were induced in the peritoneal cavity at 48 hr. In mice, receiving intraperitoneal (i.p.) injections of trypan blue or carrageenan 2 days before oral administration of Ge-132, neither induction of IFN nor augmentation of NK activity followed. X ray irradiation of mice also rendered the mice incapable of producing IFN, all suggesting that both macrophages and lymphocytes are required for this IFN induction. After i.p. administration of induced IFN, both NK and cytotoxic macrophage activities appeared at 48 hr with as little as 20 U/ml titered IFN. These facts may indicate that the augmentation of NK and activation of macrophages in mice after oral administration of Ge-132 is mediated by induced IFN.

Topics: Administration, Oral; Animals; Cytotoxicity, Immunologic; Germanium; Interferon Inducers; Interferons; Killer Cells, Natural; Macrophage Activation; Male; Mice; Organometallic Compounds; Propionates

Topics: Cesium Radioisotopes; Escherichia coli; Gamma Rays; Germanium; Mutation; Organometallic Compounds; Propionates; Radiation Genetics

The effect of NK-421(Bestatin) and Ge-132 (an organic germanium compound) on the ADCC and natural killing (NK) activities of the spleen cells of MH-134 tumor-bearing mice were studied. In the tumor-bearing mice, the ADCC activity was enhanced, and NK activity was reduced in accordance with the progress of the tumor. By oral administration of Bestatin at doses of 5, 10 and 50 mg/kg, ADCC activity was potentiated, and at a dose of 10 mg/kg, NK activity was significantly increased. Intraperitoneal administration of Ge-132 at 50 mg/kg potentiated the ADCC activity of tumor-bearing mice. A higher activity was observed in the plastic dish adherent fraction. Ge-132 also potentiated the reduced NK activity of tumor-bearing mice to higher level than normal mice. The elevated activities of ADCC and NK following Bestatin and Ge-132 administration were decreased with anti-Thy-1 antibody and complement; however, the percent reduction was lower compared to that of the control cancer animals. This result indicates that Bestatin and Ge-132 may act on non-T cells and augment ADCC and NK activities.

Topics: Adjuvants, Immunologic; Animals; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Germanium; Leucine; Liver Neoplasms, Experimental; Mice; Mice, Inbred C3H; Organometallic Compounds; Propionates; Spleen

Topics: Administration, Oral; Animals; Antineoplastic Agents; Germanium; Male; Methylcholanthrene; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Organometallic Compounds; Propionates