Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ampicillin trihydrate is a broad-spectrum semi-synthetic penicillin that is effective in the treatment of gram-positive and gram-negative bacterial infections produced by Streptococcus, Bacillus anthracis, Haemophilus influenzae, Neisseria gonorrhoeae, and Escherichia coli. This antibiotic is used in the treatment of upper respiratory tract infections, genital and urinary tract infections, and otitis media in children. Toxicology and carcinogenesis studies of ampicillin trihydrate (97%-99% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Male and female rats received doses of 0, 750, or 1,500 mg/kg, and male and female mice received doses of 0, 1,500, or 3,000 mg/kg. Doses selected for the 2-year studies were based on the lack of body weight effects and histopathologic effects at 2,400 mg/kg in the 14-day studies and 3,000 mg/kg in the 13-week studies. Clinical signs in the 13-week studies included diarrhea at 3,000 mg/kg in male and female rats and male mice. Corn oil suspensions containing more than 300 mg ampicillin trihydrate/ml were too viscous to be administered by gavage; therefore, a high dose of 1,500 mg/kg was selected for rats and a high dose of 3,000 mg/kg was selected for mice. During the 2-year studies, mean body weights of male and female rats were similar to or slightly increased over those of the corresponding vehicle control groups. Mean body weights of low dose and high dose male mice were similar to those of the corresponding vehicle group during year 1 of the study but were slightly below those of the vehicle control group during the last half of the study. Mean body weights of low dose and high dose female mice were greater than those of the vehicle controls throughout most of the study. No significant differences in survival were observed in groups of rats or mice of either sex. Clinical signs observed in dosed rats included diarrhea, excessive urination, and chromodacryorrhea and in dosed mice included increased salivation and decreased activity. In male rats, administration of ampicillin trihydrate was associated with an increased incidence of mononuclear cell leukemia (vehicle control, 5/50; low dose, 14/50; high dose, 13/50). Malignant lymphomas were observed in one additional vehicle control male rat and two low dose male rats. Lymphocytic leukemia was seen in one high dose rat. High dose male rats showed increased incidences of pheochromocytomas of the adrenal gland medulla (13/50; 12/50; 23/49). Malignant pheochromocytomas were observed in 1/50 vehicle control, 5/50 low dose, and 1/49 high dose male rats. The incidence of adrenal gland medullary hyperplasia was not increased in male rats (14/50; 10/50; 8/49). There were increased incidences of C-cellhyperplasia of the thyroid gland in low dose male and high dose female rats. High dose male rats showed increased incidences of hyperkeratosis and acanthosis of the forestomach. In male and female mice, ampicillin trihydrate administration was associated with increased incidences of forestomach lesions, including ulcers, inflammation, hyperkeratosis, acanthosis, and evidence of fungal infection. Ampicillin trihydrate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Syrian hamster or male Sprague-Dawley rat liver S9 when tested according to preincubation protocol. Ampicillin trihydrate was not mutagenic in L5178Y mouse lymphoma cells with or without metabolic activation. Ampicillin trihydrate did not cause chromosomal aberrations or sister-chromatid exchanges in Chinese hamster ovary cells with or without metabolic activation. An audit was conducted for these 2-year studies. Animal/carcass identification discrepancies were observed in rats and mice. The most common findings were the failure to clip some toes in rats and opened ear holes in mice. A review of the inlife data (including body weights, clinical observations, and dosing records) indicrecords) indicated that animals had not been interchanged among groups. The data are considered adequate to support the conclusions. Under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenicity of ampicillin trihydrate for male F344/N rats as shown by increased incidences of pheochromocytomas of the adrenal medulla and by marginally increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for female F344/N rats receiving 750 or 1,500 mg/kg or for male and female B6C3F1 mice receiving 1,500 or 3,000 mg/kg per day. Nonneoplastic lesions of the forestomach were seen in male rats and male and female mice. Synonyms and trade names: Acillin; Amcap; Amcill; Aminobenzylpencillin trihydrate; a-Aminobenzylpencillin trihydrate; Amperil; Ampichel; Ampikel; Ampinova; Amplin; Cymbi; Divercillin; Liffampil; Morepen; Pen A; Pensyn; Polycillin; Princillin; Principen; Ro-ampen; Trafarbiot
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PMID:NTP Toxicology and Carcinogenesis Studies of Ampicillin Trihydrate (CAS No. 7177-48-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 35

Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radioresistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Solid evidence exists that administering standard chemotherapeutic agents during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites. These therapeutic improvements, however, have been achieved at the expense of considerable normal tissue toxicity. To improve chemoradiotherapy further, there have been extensive explorations of the potential of newer chemotherapeutic agents, including irinotecan (CPT-11, Camptosar) and other topoisomerase inhibitors. Preclinical studies have shown that these agents are potent radiosensitizers, providing a strong biologic rationale for using these drugs in combination with radiotherapy. These studies also generated information critical for designing effective treatment schedules in clinical settings. The therapeutic efficacy of topoisomerase inhibitor-radiation combinations is currently being tested clinically. Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, that promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, and hence may serve as potential targets for augmentation of radio (or chemo) response. COX-2 is often overexpressed in premalignant lesions and cancer, and is involved in carcinogenesis, tumor growth, and metastatic spread. Preclinical studies provided solid evidence that inhibition of this enzyme with selective COX-2 inhibitors prevents carcinogenesis, slows the growth of established tumors, and enhances tumor response to radiation without appreciably affecting normal tissue radioresponse. The mechanisms of enhancement of tumor radioresponse involve direct actions on tumor cells and indirect actions, primarily on tumor vasculature. COX-2 inhibitors also improve tumor response to chemotherapeutic agents, including irinotecan. Additional therapeutic benefit was observed for celecoxib (Celebrex), a selective COX-2 inhibitor, consisting of a strong reduction in irinotecan-induced diarrhea. Thus, selective targeting of COX-2 may potentially improve radiotherapy, chemotherapy, or chemoradiotherapy--a therapeutic strategy that is currently being tested in clinical trials.
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PMID:Improvement of radiotherapy or chemoradiotherapy by targeting COX-2 enzyme. 1280 Jun 1

Aberrations in cell cycle control occurs in the majority of human malignancies due to inactivation of tumor suppressor gene Rb by the phosphorylation induced by "hyperactive" cyclin-dependent kinases. Thus, it is quite reasonable to design cdk modulators for the prevention and treatment of human neoplasms. In order to target the cdk complexes, 2 main strategies were considered: to target the ATP binding site of cdks (direct cdk modulators) and to target upstream pathways required for cdk activation (indirect cdk modulators). Examples for the first group include flavopiridol, roscovitine, BMS-387032. Examples for the second group include perifosine, lovastatin, UCN-01. The first example of a direct small molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation and has antiangiogenic properties. Clinical trials with this agent were performed with at least 3 different schedules of administration: 1 hour infusion, 24 hour infusion and 72 hour infusion. Main toxicities for infusions >/=24 hours are secretory diarrhea and pro-inflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. Some clinical responses were observed in several patients with refractory malignancies. Based on these encouraging results, a Phase 3 trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxi-staurosporine). UCN-01 has interesting preclinical features: inhibits ca2+-dependent PKCs, promotes apoptosis, arrest cell cycle progression at G1/S and abrogates checkpoints upon DNA damage. The first Phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72 hour continuous infusion every 4 weeks (second and subsequent cycles UCN-01 is administered as a 36-hour infusion). Other shorter schedules (i.e., 3 hours) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, Phase I trials with two novel small molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. Phase 2 trials and Phase I trials in combination with standard chemotherapy is being planned with these agents. In summary, novel small molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Novel small molecule cyclin-dependent kinases modulators in human clinical trials. 1450 85

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions >/=24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca(2+)-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Small-molecule cyclin-dependent kinase modulators. 1452 86

The possibility of links between psychosocial factors and cancer incidence and progression has generated considerable scientific and public interest. Tachykinins, including substance P, neurokinin A and B, hemokinin-1 and endokinins, are a family of neuropeptides, acting through three types of transmembrane G-protein coupled receptors denoted NK1, NK2 and NK3. Besides their role as neurotransmitters in peripheral and central nervous system, tachykinins and their receptors are also expressed in several non neuronal cells contributing to the fine connections between nervous systems and peripheral organ system such as respiratory, cardiovascular, immune, endocrine, gastrointestinal and genitourinary. Being so much involved in regulating physiological functions, they, of course, can concur to pathological conditions including cancer. Tachykinins can act on different steps of carcinogenesis. Tumors expressing NK receptors, such as astrocytoma, glioma, neuroblastoma, pancreatic cancer and melanoma, can misuse tachykinin-induced signaling, operating in normal cells, to promote proliferation and survival of cancer cells and to release cytokines and soluble mediators favoring tumor growth. In neuroblastoma, breast and prostate carcinomas tachykinins facilitate tumor metastatic infiltration in the bone marrow. In neuroendocrine carcinoma, tachykinins are responsible of symptoms associated with these pathologies including flushing, diarrhea, wheezing and right heart disease. In addition, regardless tumor histology, tachykinins may favor cancer incidence and metastatic progression by influencing blood flux and neovascularization in tumor formation as well as inducing immunosuppression mediated by neurogenic inflammation due to stress or surgery. However, the precise involvement of tachykinins in cancer pathologies and the potentiality to become effective pharmacological drug targets remain to be fully defined.
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PMID:Tachykinins and their receptors in human malignancies. 1691 32

Ginger, the rhizome of Zingiber officinalis, one of the most widely used species of the ginger family, is a common condiment for various foods and beverages. Ginger has a long history of medicinal use dating back 2500 years. Ginger has been traditionally used from time immemorial for varied human ailments in different parts of the globe, to aid digestion and treat stomach upset, diarrhoea, and nausea. Some pungent constituents present in ginger and other zingiberaceous plants have potent antioxidant and anti-inflammatory activities, and some of them exhibit cancer preventive activity in experimental carcinogenesis. The anticancer properties of ginger are attributed to the presence of certain pungent vallinoids, viz. [6]-gingerol and [6]-paradol, as well as some other constituents like shogaols, zingerone etc. A number of mechanisms that may be involved in the chemopreventive effects of ginger and its components have been reported from the laboratory studies in a wide range of experimental models.
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PMID:Cancer preventive properties of ginger: a brief review. 1717 86

Aberrant activation of some members of human epidermal growth factor receptor (HER) family plays a key role in breast carcinogenesis. Lapatinib is an oral dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor receptor (EGFR/ErbB1) and HER2/ErbB2. Having more targets, probably its antitumor activity could be more efficient. Clinical data have shown that lapatinib is active in HER2-positive breast cancer as monotherapy, in combination with trastuzumab, and in trastuzumab-resistant patients. Phase I clinical trials have shown also that lapatinib is well tolerated, with mild diarrhea and skin rush as common toxic effects and low incidence of cardiotoxicity. Phase II and III clinical trials' data provide encouraging evidence of the clinical effectiveness of lapatinib in advanced or metastatic breast cancer and for its potential in patients with brain metastases. Interim results from the large, phase III trial in 392 patients showed that in combination with capecitabine lapatinib almost doubled time to progression when compared with capecitabine alone. Several clinical trials that explore the efficacy of lapatinib in combination with conventional chemotherapeutic agents [paclitaxel (Taxol), capecitabine and platinoids], hormonotherapy and other target therapies are ongoing in advanced breast cancer or in neo-adjuvant and adjuvant settings. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.
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PMID:Lapatinib in breast cancer. 1759 27

Kindlin-1 is an epithelium-specific phosphoprotein and focal adhesion adaptor component. Mutations in the corresponding gene (KIND1) cause Kindler syndrome (KS), which is manifested by skin blistering, poikiloderma, photosensitivity and carcinogenesis. Some patients also exhibit gastrointestinal symptoms, but it has remained unclear whether these represent a feature of Kindler syndrome or a coincidence. We examined kindlin-1 in human gastrointestinal epithelia and showed that it is involved in the aetiopathology of Kindler syndrome-associated colitis. Kindlin-1 expression was assessed by indirect immunofluorescence, western blot and RT-PCR. Kindlin-1 is expressed in oral mucosa, colon and rectum. Both the full-length 74 kDa kindlin-1 protein and a 43 kDa isoform were detected in CaCo2 cells, the latter resulting from alternative splicing. In the first months of life, patients (homozygous for null mutations) had severe intestinal involvement with haemorrhagic diarrhoea and showed morphological features of severe ulcerative colitis. Later in childhood, histopathology demonstrated focal detachment of the epithelium in all segments of the colon, chronic inflammation and mucosal atrophy. These findings define an intestinal phenotype for Kindler syndrome as a consequence of a primary epithelial barrier defect. The different clinical intestinal manifestations in Kindler syndrome patients may be explained by partial functional compensation of kindlin-1 deficiency by the intestinal isoform or by the presence of truncated mutant kindlin-1.
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PMID:Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms. 1795 55

60 patients with irritable colon syndrome (ICS) were examined. They were divided into 2 groups. Group 1 included 30 patients who had ICS with dominating constipation (ICSc). Group 2 consisted of 30 patients with ICS and dominating diarrhea (ICSd). 12 practically healthy persons composed control group. The patients were being observed in dynamics (in periods of aggravation and remission), under uniform program including clinical, endoscopic, morphologic and immunohistochemical methods. It was established that ICSc development related to hyperplasia and hyperfunction serotonin producing cells together with decrease of number and functional activity of VIP-producing cells and mast cells. It was detected significant increase of colonocytes proliferative activity, shown throw number of immunopositive to cycline Dl epithelial cells, and compensatory increase of apoptosis activity. In patients with ICSd it was registered increase of number and functional activity of general population of apudocytes, serotonin-, melatonin- and VIP-produsing cells and mast cells. It was detected decrease of number of colonocytes immunopositive to cycline D1 and proliferating cell nuclear antigen, and growth of colon epithelial cells apoptosis activity. More significant changes of diffuse endocrine system in patients with ICSd set conditions for progress of changes of cell renovation with frequent colon mucous tunic atrophy, acting as a background for carcinogenesis.
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PMID:[The role of diffuse endocrine system and colonocytes cellular renovation in formation of clinical variants of irritable colon syndrome in young persons]. 1844 1

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.
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PMID:Safety assessment of poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate as used in cosmetics. 1883 Aug 66


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