Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thorotrast is an alpha-particle-emitting radiological contrast medium that caused chronic exposure to internal alpha-particle radiation when it was administered systemically. Cancer incidence in 432 Swedish patients exposed to Thorotrast was evaluated by computerized linkage of the cohort with the Swedish Cancer Register. Standardized incidence ratios (SIRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. A total of 170 cancers occurring in 152 individuals were reported, whereas only 57 cases were expected. The SIR was significantly increased for cancer at all sites (3.0), with the largest excesses noted for primary liver and gallbladder cancer (SIR = 39.2). Other significantly elevated risks were observed for liver cancer not specified as primary, small intestine cancer, stomach cancer, leukemia, kidney cancer, CNS tumors, and pancreatic cancer. Among women, there was a significantly increased risk for lung cancer, based on a small number. Our results show that cumulative radiation exposure is directly related to carcinogenesis in the liver and gallbladder, which is consistent with earlier findings. In addition, there may be a relationship between radiation exposure and the development of other solid tumors.
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PMID:Cancer incidence among Swedish patients exposed to radioactive thorotrast: a forty-year follow-up survey. 1189 44

Using data from the 1960 and 1970 Swedish censuses and the Swedish Cancer Register for 1971 to 1989, this study investigated variations in cancer risk by gender associated with employment in painting trades and paint manufacturing. Among men, standardized incidence ratios were significantly increased for lung cancer among painters and lacquerers; bladder cancer among artists; and pancreas cancer, lung cancer, and nonlymphocytic leukemia among paint and varnish plant workers. Risks for women were elevated for cancers of the esophagus, larynx, and oral cavity among lacquerers and for oral cancer among glaziers. These findings are consistent with the report of the International Agency for Research on Cancer that classified painting as an occupationally related cause of cancer and provide further evidence that the risk of certain cancers is increased by exposures in the paint manufacturing process.
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PMID:Exposures in the painting trades and paint manufacturing industry and risk of cancer among men and women in Sweden. 1191 Oct 27

GIPC1/RGS19IP1/GIPC, GIPC2, and GIPC3 are a family of central PDZ-domain proteins with GH1 and GH2 domains. GIPC1 interacts with GTPase-activating protein RGS19/RGS-GAIP, TGFbeta type III receptor, receptor tyrosine kinase TrkA, and integrin alpha6A subunit. Xenopus homologue of human GIPCs interacts with Frizzled-3 class of WNT receptor. We investigated expression of human GIPC1 mRNA in normal tissues, cancer cell lines, and primary tumors. GIP1A probe (nucleotide position 1075-1483 of GIPC1 cDNA) hybridized to GIPC1 mRNA of 1.8 kb in size. GIPC1 mRNA was almost ubiquitously expressed in various normal tissues. Expression level of GIPC1 mRNA was relatively lower in bone marrow and peripheral blood leukocytes. GIPC1 mRNA was relatively highly expressed in gastric cancer cell lines OKAJIMA, TMK1, MKN28, MKN45, MKN74, KATO-III, pancreatic cancer cell line AsPC-1, colorectal cancer cell line SW480, and lung cancer cell line A549. On the other hand, GIPC1 mRNA was almost undetectable in leukemia/lymphoma cell lines HL-60, Raji, and Daudi. Expression of GIPC1 mRNA was down-regulated in 12 out of 14 cases of primary kidney tumors, 10 out of 18 cases of primary colorectal tumors, 3 out of 8 cases of primary gastric cancer, 3 out of 3 cases of primary prostate cancer. Because GIPC1 induces increased expression of TGFbeta type III receptor at the cell surface and enhanced responsiveness to TGFbeta, down-regulation of GIPC1 mRNA in tumors might promote cellular proliferation through interference of TGFbeta signaling.
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PMID:Expression of human GIPC1 in normal tissues, cancer cell lines, and primary tumors. 1195 58

Janssen is developing tipifarnib (formerly known as R-1 15777), an inhibitor of RAS farnesylation, for the potential treatment of neoplasia [287030], [289610]. Janssen commenced clinical trials in the US, in conjunction with the National Cancer Institute, in April 1997 [287030], [289610], and by May 1999, phase II trials in patients with advanced non-small cell lung cancer were being planned [325960]. By February 2001, phase III trials for the potential treatment of pancreatic cancer and leukemia had been initiated [399065], and by June 2001, it was in phase II trials for RAS-dependent solid tumors [412618]. In November 2001, Credit Lyonnais Securities predicted NDAfilings in 2002 and 2003 for pancreatic cancer and other cancers, respectively, and projected US introductions for these indications in 2004 and 2005, respectively [436939].
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PMID:Tipifarnib (Janssen Pharmaceutica). 1202 65

Strabismus 1 (STB1/VANGL2) and Strabismus 2 (STB2/VANGL1), which have been cloned and characterized using bioinformatics and cDNA-PCR, are human homologues of Drosophila tissue polarity gene strabismus (stbm)/Van Gogh (Vang). STB1 and STB2 are tetra-membrane-spanning proteins with 73.1% total-amino-acid identity. Serine-rich domain and Strabismus-homology (STH1 and STH2) domains are conserved among human STB1, STB2, Xenopus Stbm, and Drosophila Stbm. STH2 domain with the C-terminal Ser/Thr-X-Val motif is implicated in binding with Dishevelled (DVL) proteins. STB1 gene is clustered with CASQ1 gene on human chromosome 1q21-q23, while STB2 gene is clustered with CASQ2 gene on human chromosome 1p13. STB1 and STB2 genes are located around cancer susceptibility loci or recombination hot spots in the human genome. STB1 is moderately expressed in K-562 (leukemia), G-361 (melanoma), and MKN7 (gastric cancer) cells. STB2 is highly expressed in MKN28, MKN74 (gastric cancer), BxPC-3, PSN-1, and Hs766T (pancreatic cancer) cells. On the other hand, STB1 and STB2 are significantly down-regulated in several cancer cell lines and primary tumors. Xenopus homologue of human STB1 and STB2 regulates negatively the WNT - beta-catenin signaling pathway. Loss-of-function mutations of genes encoding negative regulators of WNT - beta-catenin signaling pathway lead to carcinogenesis. Based on functional aspects and human chromosomal loci, STB1 gene and STB2 gene are predicted to be potent tumor suppressor gene candidates. STB1 and STB2 might be suitable targets for tissue engineering in the field of re-generative medicine and for chemoprevention and treatment in the field of clinical oncology.
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PMID:Strabismus (STB)/Vang-like (VANGL) gene family (Review). 1206 Aug 45

A novel cephalosporin derivative of monohydroguaiaretic acid (cephem-M(3)N, 7) was synthesized and found to possess anticancer activity against human leukemia (K562), breast carcinoma (MCF7), human lung cancer (A549), human colon cancer (Colo205) and pancreatic cancer cells (Capan2 and MiaPaCa2). A tumor targeting fusion protein (dsFv3-beta-lactamase) was also used in conjunction with cephem-based M(3)N 7 and its potency toward K562, MCF7, A549, Colo205, Capan2, and MiaPaCa2 was found to approach that of the free M(3)N (4). In the presence of dsFv3-beta-lactamase, tumor cells were found to be much more susceptible to conjugate 7 than normal human embryonic lung (HEL) cells and normal fibroblasts (Hef522). These notions provide a new approach to the use of nordihydroguaiaretic acid (NDGA) and its derivatives for antitumor therapy.
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PMID:Design, synthesis, and biological evaluation of a cephalosporin-monohydroguaiaretic acid prodrug activated by a monoclonal antibody-beta-lactamase conjugate. 1211 Mar 14

The types and levels of fats in the diet are known to affect the incidence of certain neoplasms in humans and rodents. In long-term toxicity and carcinogenicity studies in rodents, the level of dietary fat is altered by using oil as a vehicle to administer unpalatable or volatile chemicals. Control male rats receiving a corn oil vehicle have a higher incidence of pancreatic proliferative lesions and a lower incidence of mononuclear cell leukemia than untreated control males. Therefore, the National Toxicology Program (NTP) designed studies to evaluate the role of several oils in altering cancer rates in male rats. The NTP study reported here was part of a larger program that included cooperative agreements with Dartmouth Medical School, Northwestern Medical School, and the University of Missouri. The program was designed to study the mechanisms by which corn oil induces pancreatic cancer. To evaluate corn oil as well as two other gavage vehicles for potential toxicity, corn oil, safflower oil, and tricaprylin were administered by gavage to male F344/N rats for 2 years. The rats that received corn oil were also made available to the university investigators for study of the corn oil-induced pancreatic lesions. Each vehicle was administered by gavage at volumes of 2.5, 5, or 10 mL/kg body weight once daily for 5 days per week. In the corn oil study, a control of 10 mL saline/kg was also included. To evaluate the potential role of corn oil in promoting a pancreatic proliferative effect, 500 mg dichloromethane/kg body weight was administered in 2.5, 5, or 10 mL corn oil/kg body weight for 2 years to male F344/N rats. Dichloromethane was chosen because the chemical appeared to cause pancreatic proliferative lesions when administered by gavage in a corn oil vehicle but not when the exposure was by inhalation. In each of these studies, the term "dose" refers to the volume of gavage vehicle administered. 2-YEAR STUDIES OF CORN OIL, SAFFLOWER OIL, AND TRICAPRYLIN: Survival and Body Weights: Two-year survival was increased in male rats receiving corn oil (untreated control, 26/50; saline control, 32/50; 2.5 mL/kg, 33/50; 5 mL/kg, 38/50; 10 mL/kg, 40/50) primarily due to a dose-related decreased incidence of mononuclear cell leukemia. The mean body weights of all dosed groups were at least 5% higher than those of the untreated and saline controls by week 48, but the mean body weights of groups receiving 2.5 or 5 mL corn oil/kg decreased during the final weeks of the study (after week 89) and were similar to those of the controls at the end of the study. Two-year survival was slightly increased in male rats receiving safflower oil relative to that of the controls (untreated control, 30/50; 2.5 mL/kg, 33/50; 5 mL/kg, 40/50; 10 mL/kg, 36/50). The mean body weight of male rats receiving 10 mL safflower oil/kg was at least 5% greater than that of the controls after week 45 and was 16% greater by the end of the study. Two-year survival of high-dose tricaprylin males was lower than that of the controls (untreated control, 31/50; 2.5 mL/kg, 30/50; 5 mL/kg, 31/50; 10 mL/kg, 23/53) due to moribund kills and deaths that appeared to be related to toxicity. The mean body weight of the high-dose group was lower than that of the controls throughout the study, although the difference was less than 5% after week 61. Pathology Findings: In the corn oil study, there were significant dose-related increased incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/50, 28/47, 28/50, 35/50; adenoma: 1/50, 8/47, 10/50, 23/50; carcinoma: 0/50, 0/47, 1/50, 0/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). The incidence and severity of nephropathy decreased with dose (incidence [mean severity grade]: 47/50 [2.1], 43/48 [1.8], 45/50 [1.4], 40/49 [1.2]). The incidences of pheochromocytomas (benign, malignant, or complex) of the adrenal medulla were also decreased in dosed rats (23/49, 21/50, 5/50, 9/50). The incidence of mononuclear cell leukemia was significantly decreased in rats dosed with corn oil (27/50, 16/50, 11h corn oil (27/50, 16/50, 11/50, 7/50). In rats receiving safflower oil, the incidences of pancreatic exocrine hyperplasia and adenoma increased significantly with dose (hyperplasia: 8/50, 14/50, 29/49, 30/50; adenoma: 1/50, 7/50,15/49, 28/50; carcinoma: 0/50, 0/50, 0/49, 1/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). There was a decrease in the severity, but not in the incidence, of nephropathy, a common lesion in aging F344/N rats (incidence [mean severity grade]: 49/50 [2.0], 50/50 [1.8], 47/50 [1.1], 49/49 [1.1]). There were decreased incidences of mononuclear cell leukemia (33/50, 19/50, 18/50, 7/51). In the tricaprylin study, there were significant dose-related increased incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/49, 9/49, 18/49, 28/50; adenoma: 2/49, 6/49,13/49,18/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). The incidence of proliferative lesions of the forestomach increased significantly with dose (basal cell hyperplasia: 4/50, 7/50, 12/49, 21/52; squamous cell papilloma: 0/50, 0/50, 3/50, 10/53). The incidence of nephropathy was significantly decreased in high-dose rats, and the severity of nephropathy decreased with dose (incidence [mean severity grade]: 46/50 [2.0], 42/50 [1.5], 45/50 [1.7], 27/49 [0.9]). In high-dose rats, the incidence of mononuclear cell leukemia was decreased (23/50, 28/50, 22/50, 9/53). 2-YEAR STUDY OF DICHLOROMETHANE IN CORN OIL: Survival and Body Weights: Two-year survival increased slightly with dose in the three groups receiving 500 mg dichloromethane/kg in 2.5, 5, or 10 mL corn oil/kg (23/50, 28/50, 31/50) due to a dose-related decrease in the incidence of mononuclear cell leukemia. The rats receiving 500 mg dichloromethane/kg without corn oil were sacrificed within the first 3 weeks of the study due to the severe toxicity of dichloromethane. The final mean body weight of the high-dose rats was greater than the final mean body weights of groups receiving dichloromethane in 2.5 or 5 mL corn oil/kg. Pathology Findings: There was a dose-related increase in the incidence of pancreatic proliferative exocrine lesions in rats receiving dichloromethane in 2.5, 5, and 10 mL corn oil/kg (hyperplasia: 28/50, 38/50, 44/50; adenoma: 9/50,19/50, 41/50; carcinoma: 0/50,1/50, 3/50). The incidences of pancreatic exocrine hyperplasia and adenoma in rats receiving dichloromethane in 5 or 10 mL, but not 2.5 mL, corn oil were increased compared to the incidences in rats receiving comparable volumes of corn oil alone (hyperplasia: 2.5 mL, 28/47; 5 mL, 28/50;10 mL, 35/50; adenoma: 8/47,10/50, 23/50; carcinoma: 0/47,1/50, 0/50). There were significantly increased incidences of pituitary gland pars distalis adenoma in rats receiving dichloromethane in corn oil (20/50, 18/49, 16/49) when compared to those in rats receiving comparable volumes of corn oil alone (10/50, 6/49, 7/50). The incidence of mammary gland adenoma and fibroadenoma (combined) was significantly increased in rats receiving dichloromethane in 10 mL corn oil/kg (7/50) when compared to rats receiving dichloromethane in 2.5 mL corn oil/kg (1/50), but was not significantly increased when compared to the group receiving 10 mL of corn oil alone (3/50). The incidences of mammary gland adenoma and fibroadenoma (combined) were 7/50 for the untreated safflower oil controls and 6/50 for the untreated tricaprylin controls. The incidence of mononuclear cell leukemia decreased in the group receiving dichloromethane in 10 mL corn oil/kg (13/50,14/50, 5/50). GENETIC TOXICOLOGY: Neither safflower oil nor corn oil was mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, with or without S9. Tricaprylin, in contrast, was mutagenic in strain TA1535 with, but not without, S9. Tricaprylin did not induce mutations in strains TA97, TA98, or TA100, with or without S9. SUMMARY: These studies were designed to evaluate the effects of various concentrations of an oil very high in polyunsaturated fat (safflower oil), an oil containing high levels of polyunsaturated and monounsaturated fats (corn oil), and an oil containing saturated medium-chain fatty acids (tricaprylin) on the incidence and pattern of neoplasms in the F344/N rat. In addition, safflower oil and tricaprylin were evaluated as replacements for the corn oil vehicle. These studies demonstrate that safflower oil and tricaprylin do not offer significant advantages over corn oil as a gavage vehicle in long-term rodent studies. Corn oil, safflower oil, and tricaprylin each caused hyperplasia and adenoma of the exocrine pancreas, decreased incidences of mononuclear cell leukemia, and reduced incidences or severity of nephropathy in male F344/N rats. There was an increased incidence of squamous cell papillomas of the forestomach in F344/N rats receiving 10 mL tricaprylin/kg. Further, the use of corn oil as a gavage vehicle may have a confounding effect on the interpretation of chemical-induced proliferative lesions of the exocrine pancreas and mononuclear cell leukemia in male F344/N rats. Synonyms: Corn Oil - Maize oil, Maydol Tricaprylin - Trioctanoin; 1,2,3-trioctanoyl glycerol; Glycerol trioctanoate
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PMID:NTP Comparative Toxicology Studies of Corn Oil, Safflower Oil, and Tricaprylin (CAS Nos. 8001-30-7, 8001-23-8, and 538-23-8) in Male F344/N Rats as Vehicles for Gavage. 1261 5

We compared mortality of 1,999 outdoor staff working as part of an insecticide application program during 1935-1996 with that of 1,984 outdoor workers not occupationally exposed to insecticides, and with the Australian population. Surviving subjects also completed a morbidity questionnaire. Mortality was significantly higher in both exposed and control subjects compared with the Australian population. The major cause was mortality from smoking-related diseases. Mortality was also significantly increased in exposed subjects for a number of conditions that do not appear to be the result of smoking patterns. Compared with the general Australian population, mortality over the total study period was increased for asthma [standardized mortality ratio (SMR) = 3.45; 95% confidence interval (CI), 1.39-7.10] and for diabetes (SMR = 3.57; 95% CI, 1.16-8.32 for subjects working < 5 years). Mortality from pancreatic cancer was more frequent in subjects exposed to 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (SMR = 5.27; 95% CI, 1.09-15.40 for subjects working < 3 years). Compared with the control population, mortality from leukemia was increased in subjects working with more modern chemicals (standardized incidence ratio = 20.90; 95% CI, 1.54-284.41 for myeloid leukemia in the highest exposure group). There was also an increase in self-reported chronic illness and asthma, and lower neuropsychologic functioning scores among surviving exposed subjects when compared with controls. Diabetes was reported more commonly by subjects reporting occupational use of herbicides. These findings lend weight to other studies suggesting an association between adverse health effects and exposure to pesticides.
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PMID:Health impacts of pesticide exposure in a cohort of outdoor workers. 1272 1

A sensitive and specific RP-HPLC assay was developed to measure the levels of polymorphonuclear elastase (PMN-E) activity in growing cell cultures. By combining a pre-incubation of the cells with a relatively non-toxic, PMN-E-specific inhibitor, MeOSuc-Ala-Ala-Pro-Val-chloromethylketone (MAAPVCK), the p-nitroaniline formed by the hydrolysis of the substrate MeOSuc-Ala-Ala-Pro-Val-p-NA by PMN-E is quantified. Elastase-like activity was measured in 14 human cells lines: 13 cancer cell lines (HL-60, U-937, A-427, LCLC-103H, YAPC, DAN-G, PA-TU-8902, KYSE-70, -510, -520, 5637, SISO and MCF-7) and one immortalized epithelial cell line (hTert-RPE1). Activity was detected in all lines; the lowest was found in hTert-RPE1 cells while the highest was detected in a pancreas adenocarcinoma line (PA-TU-8902). When the results were normalized according to cell volume instead of cell number, the leukemia line HL-60 had the highest activity and PA-TU-8902 ranked second. A 1 h pre-incubation with 9.0 microM of the irreversible PMN-E inhibitor MAAPVCK led to varying degrees of enzyme inhibition depending on the cell line; the strongest inhibition was observed with the PA-TU-8902 pancreatic cancer cell line (90% inhibition) while the weakest was seen with the A-427 lung cancer cell line (52%). These results indicate that PA-TU-8902 is a suitable in vitro model for testing the efficacy of PMN-E-activated prodrugs of antitumor agents.
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PMID:Quantification of elastase-like activity in 13 human cancer cell lines and in an immortalized human epithelial cell line by RP-HPLC. 1281 79

Troxacitabine [BCH 4556; SPD 758; Troxatyl] is a DNA synthesis inhibitor. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is a member of a novel class of nucleoside analogues discovered by BioChem Pharma and is the first example of a synthetic L-nucleoside analogue to have shown anticancer activity in animal models. On 11 May 2001, BioChem Pharma was acquired by, and integrated into, Shire Pharmaceuticals Group. In February 2002 Shire announced that it intended to pursue development of troxacitabine as a treatment for solid tumours. In addition, Shire indicated that it would pursue the drug's development for acute myeloid leukaemia. In March 1999, phase II trials were initiated to investigate the efficacy and tolerability of troxacitabine in a variety of solid tumours including pancreas, prostate, colorectal, renal and non-small cell lung cancers and melanoma. The trials were conducted throughout North America and were closed to patient accrual in 2000. Two phase I combination chemotherapy trials in solid tumours (one with cisplatin and another with paclitaxel) have been initiated. One of these trials is in patients with pancreatic cancer. A phase III trial in patients with pancreatic cancer is expected to begin during the second or third quarter of 2003. In addition, further clinical development was initiated in May 2000, in the form of a combination chemotherapy trial in patients with acute leukaemia. A phase II trial in patients with acute myeloid leukaemia (AML) and chronic myeloid leukaemia-blast phase (CML-BP) has reported that troxacitabine demonstrated significant activity in these cancers. However, Shire indicated that no further development for CML-BP will be conducted. The company indicated that it would focus future development in the haematological malignancy area on AML and has initiated an exploratory phase III trial of troxacitabine in previously untreated patients with poor prognosis AML. The study will compare troxacitabine in combination with either cytarabine or idarubicin, with a control drug regimen. The aim is to identify the most promising treatment regimens in a relatively small number of patients before commencing the larger pivotal trial. A pivotal phase III trial is expected to begin in the first half of 2003. In September 2002, Shire Pharmaceuticals forecast Troxatyl to reach peak sales of $US100-200 million, for the indications of pancreatic cancer and myeloid leukaemia.
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PMID:Troxacitabine: BCH 4556, SPD 758, Troxatyl. 1284 94


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