Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 3,5-pyrazolidinediones proved to be potent cytotoxic agents against the growth of a number of murine and human tumor cell lines, e.g. human THP-I monocytic leukemia, Hut-78 lymphoma, MCF-7 breast effusion, A549 lung carcinoma, U87MG glioma, Hela uterine and A431 epidermoid skin cancer. In human Tmolt4 cell leukemia, the agents substantially suppressed DNA and RNA syntheses after 60 min at 100 microM. The de novo purine biosynthetic pathway appeared to be the major target of the agents with the inhibition of both PRPP-amido transferase and IMP dehydrogenase (IMPDH) activities. Suppression of IMPDH activity was due to the inhibition of both the Type I and II isoforms through an uncompetitive mechanism; however, the Type II isoform was preferentially inhibited at lower concentrations of compounds tested (>50-150 microM). Therefore IMPDH Type II activity, which predominates in cancer cells, was selectively inhibited over the Type I isoform (208-312 microM). The activities of other enzymes examined were inhibited which added to the overall suppression of DNA synthesis, i.e., ribonucleotide reductase, dihydrofolate reductase and nucleoside kinases. The agents caused Tmolt4 DNA strand scission but the DNA molecule itself did not appear to be a target of the compounds since there was no induced cross-linking of the DNA, intercalation between base pairs or alkylation of the DNA bases.
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PMID:Cytotoxicity and mode of action of 1-(1-cyclohexenyl) and 1-unsubstituted 3,5-pyrazolidinediones in human Molt4 T cell leukemia. 1149 69

3-Ethoxycarbonyl-5-phenyl-1, 3a, 4, 5, 6, 6a-hexahydropyrrolo[3,4-c]pyrazole-4, 6-dione, 2, 2, 6, 6-tetraethyl-1H, 5H-pyrazole[1, 2-a]pyrazole-1, 3, 5, 7-[2H, 6H]-tetraone and 6-ethoxycarbonyl-3-phenyl-3-azabicyclo[3.1.0] hexane-2, 4-dione demonstrated potent cytotoxic activity in the human Tmolt3, Tmolt4 and HL-60 leukemia screens, HuT-78 lymphoma and HeLa suspended uterine carcinoma cell lines. Most notable was the finding that these compounds were significantly more active than the standard cytotoxic agents examined in the MCF-7 breast (ED50 0.2-1.0 microg/ml) and U87MG glioma (ED50 1.3-2. 6 microg/ml) tumor screens. The agents inhibited Tmolt4 leukemia DNA and RVA syntheses after 60 min at 100 microM Multiple enzymes involved with nucleic acid metabolism appeared to be targeted including inhibition of RNA polymerases, ribonucleotide reductase and nucleoside kinase activities, however, inhibition of de novo purine synthesis at the key regulatory enzyme IMP dehydrogenase appeared to be the primary target. The predominant IMPDH isoform (Type II) detected in a number of human cancers, such as leukemias, ovarian and breast, was inhibited by the compounds yielding IC50 values in the microM range. Furthermore, inhibition of IMP dehydrogenase activity led to the selective depletion of dGTP pool levels by two of the compounds. The DNA molecule was not a target of the agents since no alkylation of the bases, cross-linking of the DNA strands or intercalation between base pairs occurred. Yet, the compounds did cause DNA fragmentation after incubating at 100 microuM for 24 h which was consistent with the observed decrease in ct-DNA viscosity.
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PMID:Analysis of the in vitro inhibition of murine and human tumor cell growth by pyrazole derivatives and a substituted azabicyclo [3.1.0] hexane-2,4-dione. 1172 88

Central diabetes insipidus (DI) can be the outcome of a number of diseases that affect the hypothalamic-neurohypophyseal axis. The causes of the condition can be classified as traumatic, inflammatory, or neoplastic. Traumatic causes include postoperative sella or transection of the pituitary stalk, while infectious or inflammatory causes include meningitis, lymphocytic hypophysitis, and granulomatous inflammations such as sarcoidosis and Wegener's granulomatosis. Various neoplastic conditions such as germinoma, Langerhans cell histiocytosis, metastasis, leukemic infiltration, lymphoma, teratoma, pituitary adenoma, craniopharyngioma, Rathke cleft cyst, hypothalamic glioma, and meningioma are also causes of central DI. In affected patients, careful analysis of these MR imaging features and correlation with the clinical manifestations can allow a more specific diagnosis, which is essential for treatment.
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PMID:MR imaging of central diabetes insipidus: a pictorial essay. 1175 30

Among methylating agents of clinical interest, temozolomide is a novel antitumor compound that has raised particular interest due to its acceptable safety profile and activity against tumors poorly responsive to conventional chemotherapy, such as malignant glioma and metastatic melanoma. Moreover, the drug has recently shown promising antitumor activity in a patient affected by primary brain lymphoma and is currently under phase II clinical trials for leptomeningeal metastases from leukemia and lymphoma or for brain metastases from lung and breast cancers. The antitumor activity of TMZ, that generates different types of methyl adducts (70% N7-methylguanine, 10% N3-methyladenine and 9% O6-methylguanine), has been mainly attributed to the formation of O6-methylguanine adducts. Indeed, tumor cell susceptibility to TMZ is strongly affected by the functional status of DNA repair systems, involved either in the removal of methyl adducts from O6G or in the apoptotic signaling triggered by O6-methylG:T mispairs. This review will focus on the different pharmacological strategies aimed at overcoming tumor resistance to TMZ such as new formulations of the drug or dosing schedules, and combined treatments with other chemotherapeutic agents, modulators of DNA repair systems, or gene therapy. The potential use of N3-methyladenine selective agents in the case of tumors tolerant to O6-methylguanine will be also discussed.
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PMID:Pharmacological strategies to increase the antitumor activity of methylating agents. 1205 67

The Neuropathology Study Group of the Korean Society of Pathologists conducted a nationwide collection of central nervous system (CNS) tumors to evaluate the relative frequency in Korea of CNS tumors belonging to the revised World Health Organization (WHO) classification categories. A total of 3221 histologically proven cases of CNS tumors were collected from 13 institutes between 1997 and 1998. All the cases were classified according to the revised WHO histological types and analyzed for the relative frequency, the distribution of age and sex, and location of tumors. The most frequent type of CNS tumors in Korea was meningiomas, followed by pituitary adenoma, glioblastoma, astrocytoma, and schwannoma. Among the pediatric CNS tumors, pilocytic astrocytoma, medulloblastoma, craniopharyngioma, germ cell tumors, and ependymomas were common types of tumors. Compared with a previous nationwide study, the rates for neuronal/glial tumors, glioblastoma, malignant lymphoma, and cystic lesion were increased, and the rate of embryonal tumors was decreased. The overall male to female ratio was 0.9: 1, which may be attributed to the greater number of female-predominate meningiomas and pituitary adenoma. Compared with Western countries, Koreans had higher rates of pituitary adenoma and meningiomas and lower rate of gliomas. The relative frequency of CNS tumors among Koreans is very similar to that reported in Taiwan. The occurrence rates for various subtypes of CNS tumors in Korea are distinct from those in the United States and Europe and similar in many ways to those in Asian and Mexican population.
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PMID:Tumors of the central nervous system in Korea: a multicenter study of 3221 cases. 1206 32

p53 interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function involving cell cycle control, gene regulation, cell differentiation, apoptosis and tumor suppression. To identify these proteins, we used the yeast two-hybrid system and screened a HeLa cDNA library. Six positive colonies were isolated from 1.5x10(6) transformants. The cDNA sequence of each positive colony was determined. Two novel cDNA fragments (p53BP1 and p53BP2) were cloned. These two cDNA fragments code for the same protein composed of 158 amino acids, which shows high similarity to the ubiquitin-conjugating enzyme (UBC9) of H. sapiens as well as to E2s from other organisms, such as UBC (76 %) of C. elegans, HUS5(66 %) of S. pombe, UBC(66 %) of A. thaliana and UBC9(56 %) of S. cerevisiae. A cDNA fragment from p53BP1 was used to probe a Northern blot containing poly(A)(+) RNA from various human tissues and various cell lines. At high stringency this probe hybridized to a single mRNA of approximately 1.2 kb that was expressed in heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, human cervical carcinoma cell (HeLa), human mammary carcinoma cell (MCF-7), human lymphoma cell (Jurkatt) and human teratocarcinoma cell (PA-I). It is not expressed in brain, lung, human lung carcinoma cell, human heptocellular carcinoma cell (HepG2) and human glioma cell(U251MG).
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PMID:A Novel cDNA Encoding Ubiquitin-conjugating Enzyme of Homo sapiens. 1217 72

A novel receptor, named 1C7 or NKp30 and involved in natural cytotoxicity, was recently identified. This receptor is encoded by the 1C7 gene, which is located within the class III region of the human MHC, HLA. It is a member of the immunoglobulin gene superfamily (IgSF) and, remarkably, is expressed at the mRNA level as six different splice variants in human. Recent investigations have indicated that the 1c7 gene of the mouse is silenced by in-frame stop codons. In this study, the molecular characterization of the rat 1c7 gene is described. cDNA derived from this gene encode a protein of 192 amino acid residues predicted to contain a single IgV-set domain in the extracellular region and a positively charged residue in the transmembrane region. Expression of the gene was detected in freshly isolated rat Natural Killer (NK) and T splenocytes. Transfection of rat 1C7 into the NK cell line RNK-16 induced cytolytic activity against glioma as well as lymphoma tumor cells. In addition, binding of a r1C7-Fc fusion protein by a panel of target cells correlated with susceptibility to killing by RNK-16-1C7 effector cells. These results indicate that the r1C7 molecule could function as an NK activating receptor as previously reported for the human NKp30 receptor molecule.
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PMID:Molecular characterization of the novel rat NK receptor 1C7. 1254 65

Diphenhydramine hydrochloride is a widely used antihistaminic drug in human and veterinary medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing USP-grade diphenhydramine hydrochloride (greater than 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, dietary concentrations ranged from 620 to 10,000 ppm for rats and from 310 to 5,000 ppm for mice. All rats that received diets containing 10,000 ppm and 9/10 rats that received diets containing 5,000 ppm died before the end of the studies. The final mean body weights of rats receiving 1,250 or 2,500 ppm were 12%-13% or 30%-34% lower than those of controls. Feed consumption by rats at the three highest concentrations was more than 30% less than that by controls. All mice receiving 5,000 ppm, 4/5 males and 4/5 females receiving 2,500 ppm, and 4/5 males receiving 1,250 ppm died before the end of the studies. The final mean body weights of mice that received 1,250 or 2,500 ppm were lower than the initial weights. All dosed rats and mice were hyperactive and sensitive to sound and/or touch. In the 13-week studies, dietary concentrations of diphenhydramine hydrochloride ranged from 156 to 2,500 ppm for rats and from 78 to 1,250 ppm for mice. All rats lived to the end of the studies. The final mean body weights of rats receiving 1,250 or 2,500 ppm were about 15% or 35% lower than those of controls. The final mean body weight of female rats receiving 625 ppm was 9% lower than that of controls. Increased activity was observed for all male and female rats receiving 1,250 and 2,500 ppm. Cytoplasmic vacuolization of the liver, characteristic of fat accumulation, was observed in male and female rats receiving 313-2,500 ppm. The severity of this change increased with increased dose. For mice, 1/10 males receiving 313 ppm, 2/10 males receiving 625 ppm, and 8/10 males receiving 1,250 ppm died before the end of the studies. The final mean body weights of mice that received 625 or 1,250 ppm were about 9% or 16% lower than those of controls. No compound-related histopathological effects were observed in mice. Based on the mortality and body weight effects of diphenhydramine hydrochloride in the short-term studies, dietary concentrations selected for the 2-year studies were 0,313, and 635 ppm diphenhydramine hydrochloride for male rats and 0, 156, and 313 ppm for female rats and male and female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and control rats were similar throughout the studies, and mean body weights of dosed mice were 3%-13% lower than those of controls throughout most of the studies. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: control, 29/50; low dose, 32/50; high dose, 24/50; female rats: 35/50; 32/50; 36/50; male mice: 29/50; 30/50; 24/48; female mice: 37/50; 39/50; 32/50). The estimated average daily feed consumption by dosed rats and dosed mice was similar to that by controls. The average amount of diphenhydramine hydrochloride consumed per day was approximately 13 or 27 mg/kg for low dose or high dose male rats, 7 or 15 mg/kg for low dose or high dose female rats, and 21 or 46-47 mg/kg for low dose or high dose male and female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: For three high dose male rats, astrocytomas were found in brain sections taken by routine sampling procedures. Gliomas, containing neoplastic astrocytes and oligodendrocytes, were found in one control and one additional high dose male rat. The incidence of glial cell tumors in high dose male rats (4/50) exceeded the highest incidence in historical controls in the Program (2/50). The historical incidence of glial cell tumors is less than 0.7% in approximately 2,000 untreated control male F344/N rats. Three addiless than 0.7% in approximately 2,000 untreated control male F344/N rats. Three additional sections of brain were prepared from the residual fixed tissues of each male and female rat. One additional astrocytoma in a high dose male rat and one astrocytoma in a high dose female rat were observed in these sections. Adenomas of the anterior pituitary gland in female rats occurred with a significant positive trend; the incidences in low dose male and high dose female rats were marginally greater than those in controls (male: control, 11/49; low dose, 21/50; high dose, 14/49; female: 23/50; 26/50; 35/50). The incidence of alveolar/bronchiolar adenomas in low dose male rats was slightly greater than that in controls (0/49; 5/50; 3/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in dosed male rats were not significantly different from that in controls (1/49; 6/50; 5/50) but exceeded the highest incidence in historicalcontrols (4/49). The historical incidence of alveolar/bronchiolar neoplasms in untreated control male F344/N rats is approximately 2.2%. Adenomatous hyperplasia of the lung was not increased in incidence in dosed male rats compared with controls. The incidences of granulomas of the liver were increased in dosed rats (male: 0/49; 3/50; 4/50; female: 8/50; 15/49; 18/50). At no site were the incidences of neoplastic lesions in dosed mice considered to be compound related. Cytoplasmic vacuolization (fatty metamorphosis) of the liver was observed at an increased incidence in high dose female mice (0/49; 1/49; 8/49). Genetic Toxicology: Diphenhydramine hydrochloride was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in either the presence or absence of exogenous metabolic activation. Exposure to this chemical did not induce trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with or without metabolic activation. In cytogenetic tests with cultured CHO cells, diphenhydramine hydrochloride induced chromosomal aberrations in the absence, but not the presence, of exogenous metabolic activation (S9); no induction of sister chromatid exchanges (SCEs) was observed in these cells with or without S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of diphenhydramine hydrochloride for male F344/N rats, based on marginally increased incidences of uncommon brain neoplasms (astrocytomas or gliomas) and of alveolar/bronchiolar neoplasms. There was equivocal evidence of carcinogenic activity for female F344/N rats, based on a marginal increase in the incidence of pituitary gland adenomas. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 156 or 313 ppm diphenhydramine hydrochloride. Synonyms: 2-diphenylmethoxy-N,N-dimethylethanamine hydrochloride; 2-(benzhydryloxy)-N,N-dimethylethylamine hydrochloride; b-dimethylaminoethyl benzhydryl ether hydrochloride; benzhydramine hydrochloride Trade Names: Alleran; Benadryl
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PMID:NTP Toxicology and Carcinogenesis Studies of Diphenhydramine Hydrochloride (CAS No. 147-24-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1270 39

This study was undertaken to assess the contribution of the combination of (201)Tl SPECT and (99m)TcO(4)(-)SPECT to the differential diagnosis of brain tumors and tumor-like lesions. In the 8 patients selected for this study, both (201)Tl SPECT and (99m)TcO(4)(-) SPECT were performed because of clinical or radiological suspicion of brain tumor, no therapy was initiated before either SPECTs, diagnosis was based on biopsy, and MRI findings were stable in the interval between SPECTs. Histological diagnoses consisted of low grade glioma (n=1), high grade glioma (n=2), lymphoma (n=1), metastasis (n=1), multiple sclerosis (n=2) and cavernous angioma (n=1). Two high grade astrocytomas, one malignant lymphoma and one metastatic tumor showed (201)Tl accumulation and were diagnosed as tumor. The combination of (201)Tl and (99m)TcO(4)(-) did not change the diagnosis. One cavernous angioma showed no (201)Tl accumulation and was diagnosed as non-tumor. The combination of (201)Tl and (99m)TcO(4)(-) did not change the diagnosis. One low grade astrocytoma showed faint (201)Tl accumulation and was diagnosed as non-tumor. As (201)Tl uptake was higher than (99m)TcO(4)(-) uptake, the combination of (201)Tl and (99m)TcO(4)(-) changed the diagnosis to tumor. Two multiple sclerosis showed (201)Tl accumulation and were diagnosed as tumor. As (99m)TcO(4)(-) uptake was higher than (201)Tl uptake, the combination of (201)Tl and (99m)TcO(4)(-) changed the diagnosis to non-tumor. In three of the eight patients (38%), the combination of (201)Tl SPECT and (99m)TcO(4)(-) SPECT altered the diagnosis made by (201)Tl SPECT alone. In all of these three cases, the diagnosis made by the combination of (201)Tl SPECT and (99m)TcO(4)(-) SPECT was correct.
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PMID:Contribution of the combination of (201)Tl SPECT and (99m)T(c)O(4)(-) SPECT to the differential diagnosis of brain tumors and tumor-like lesions. A preliminary report. 1271 94

Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative&percnt;; 2/50, 4&percnt;; 5/49, 10&percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6&percnt;; 3/50, 6&percnt;; 5/49, 10&percnt;). Negative trends (P&lt;0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG
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PMID:NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). 1275 Jul 52


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