Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenomatous polyps are neoplasms that may progress to colorectal cancer. The role of diet and other lifestyle habits in their etiology is now being elucidated. The aim of this study was to evaluate effects of nutritional habits, weight and weight gain, tobacco smoking, and physical activity in adenoma etiology. A quantified dietary history questionnaire was designed to evaluate long-term dietary habits in addition to more recent ones. The study population comprised 196 adenoma patients and matched asymptomatic, screened controls. Statistical analysis used multivariate conditional logistic models, adjusting for total energy intake and physical activity. Odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma associated with highest versus lowest tertiles of mean daily intake were as follows: for energy, OR 3.7 and CI 2.1-6.7; for animal fat, OR 2.4 and CI 1.2-4.7; for tobacco smoking, OR 3.1 and CI 1.1-2.8; and for weight gain, OR 2.2 and CI 1.2-4.1 (P for linear trend for all, < or = 0.01). Significant negative associations were found with intake of total carbohydrates (OR, 0.3; CI, 0.1-0.7) and fluids (OR, 0.4; CI, 0.2-0.8) (P for both < 0.01) as well as for physical activity (OR, 0.6; CI, 0.3-0.9; P = 0.03). Increased risk for adenoma was observed with decreased intake of carotene (OR, 0.6; CI, 0.3-1.0; P = 0.06), vitamin E (OR, 0.6; CI, 0.3-1.0; P = 0.07), and dietary fiber (OR, 0.6; CI, 0.3-1.3; not significant). The OR of interaction between water and dietary fiber was significant (OR, 0.7; CI, 0.6-0.9; P = 0.01), suggesting a synergistic protective effect. Specific dietary and lifestyle habits were identified as independent factors associated with colorectal adenomas; of special interest is the interaction between water and fiber intake. Avoiding these factors might delay or prevent neoplasia.
 ...
PMID:Nutritional and lifestyle habits and water-fiber interaction in colorectal adenoma etiology. 903 57

Understanding the relationship between chemical structure and biological properties of folate analogs, particularly their interactions with the target enzymes, transport proteins and folate-metabolizing enzyme, folylpolyglutamate synthetase (FPGS), has enabled the rational design and development of the selective thymidylate synthase (TS) inhibitors with folate-based structures for clinical uses. These compounds specifically inhibit TS devoid of concomitant effects at other loci, unlike 5-fluorouracil (5-FU). ZD1694 ('Tomudex') was designed as a non-nephrotoxic and highly active analog of N10-propargyl-5,8-dideazafolic acid (CB3717), which is a potent TS inhibitor but had unacceptable nephrotoxicity caused by its poor water solubility. The potent cytotoxic activity of ZD1694 is dependent upon active uptake into cells via the reduced folate carrier (RFC), and subsequent rapid and extensive metabolism to polyglutamate forms inside cells. Marked enhancement of the TS inhibitory activity has been noted as the glutamate chain is elongated. Polyglutamation is critical to the biological activity of ZD1694 against tumor and normal proliferating tissues. The retentive property of ZD1694 polyglutamates inside cells led to a single, infrequent administration schedule in clinical studies. ZD1694 has completed phase I and phase II evaluation with activity observed in several tumor types, particularly in colorectal cancer with a 26% objective response rate. A recent European phase III study of ZD1694, randomized against a 5-FU plus leucovorin regimen, demonstrated an equivalent response rate for advanced colorectal cancer (complete or partial responses; 20 versus 17%) and less toxicity than seen with the latter regimen. The newer selective TS inhibitors, which retain potency for TS inhibition but are not substrates for RFC and/or FPGS, are currently under clinical evaluation. These classes of compound may have benefits for circumvention of resistance by virtue of alterations in these protein functions and for the management of toxicity.
 ...
PMID:Folate-based thymidylate synthase inhibitors in cancer chemotherapy. 914 8

We conducted a population-based case-control study among different ethnic groups in Hawaii to evaluate the role of various types and components of fiber, as well as micronutrients and foods of plant origin, on the risk of colorectal cancer. We administered personal interviews to 698 male and 494 female Japanese, Caucasian, Filipino, Hawaiian, and Chinese cases diagnosed during 1987-1991 with adenocarcinoma of the colon or rectum and to 1,192 population controls matched to cases by age, sex, and ethnicity. We used conditional logistic regression to estimate odds ratios, adjusted for caloric intake and other covariates. We found a strong, dose-dependent, inverse association in both sexes with fiber intake measured as crude fiber, dietary fiber, or nonstarch polysaccharides. We found inverse associations of similar magnitude for the soluble and insoluble fiber fractions and for cellulose and noncellulosic polysaccharides. This protective effect of fiber was limited to fiber from vegetable sources, with an odds ratio of 0.6 (95% confidence interval = 0.4-0.9) and 0.5 (95% confidence interval = 0.3-0.7) for the highest compared with the lowest quartile of intake for men and women, respectively. We found associations of the same magnitude for soluble and insoluble vegetable fiber, but no clear association with fiber from fruits or cereals. This pattern was consistent between sexes, across segments of the large bowel (right colon, left colon, and rectum), and among most ethnic groups. The effect of vegetable fiber may be independent of the effects of other phytochemicals, since the effect estimates remained unchanged after further adjustment for other nutrients. Intakes of carotenoids, light green vegetables, yellow-orange vegetables, broccoli, corn, carrots, bananas, garlic, and legumes (including soy products) were inversely associated with risk, even after adjustment for vegetable fiber. The data support a protective role of fiber from vegetables against colorectal cancer, which appears independent of its water solubility property and of the effects of other phytochemicals. The data also indicate that certain vegetables and fruits may be protective against this disease through mechanisms other than their fiber content.
 ...
PMID:Dietary fiber and colorectal cancer risk. 934 66

Crystal structures of lithium, sodium, potassium, calcium and magnesium salts of adenosine 2'-monophosphate (2'-AMP) have been obtained at atomic resolution by X-ray crystallographic methods. 2'-AMP.Li belongs to the monoclinic space group P2(1) with a = 7.472(3)A, b = 26.853(6) A, c = 9.184(1)A, b = 113.36(1)A and Z= 4. 2'-AMP.Na and 2'-AMP.K crystallize in the trigonal space groups P3(1) and P3(1)21 with a = 8.762(1)A, c = 34.630(5)A, Z= 6 and a = 8.931(4), Ac = 34.852(9)A and Z= 6 respectively while 2'-AMP.Ca and 2'-AMP.Mg belong to space groups P6(5)22 and P2(1) with cell parameters a = 9.487(2), c = 74.622(13), Z = 12 and a = 4.973(1), b = 10.023(2), c = 16.506(2), beta = 91.1(0) and Z = 2 respectively. All the structures were solved by direct methods and refined by full matrix least-squares to final R factors of 0.033, 0.028, 0.075, 0.069 and 0.030 for 2'-AMP.Li, 2'-AMP.Na, 2'- AMP.K, 2'-AMP.Ca and 2'-AMP.Mg, respectively. The neutral adenine bases in all the structures are in syn conformation stabilized by the O5'-N3 intramolecular hydrogen bond as in free acid and ammonium complex reported earlier. In striking contrast, the adenine base is in the anti geometry (chiCN = -156.4(2)degrees) in 2'-AMP.Mg. Ribose moieties adopt C2'-endo puckering in 2'-AMP.Li and 2'-AMP.Ca, C2'-endo-C3'-exo twist puckering in 2'-AMP.Na and 2'-AMP.K and a C3'-endo-C2'-exo twist puckering in 2'-AMP.Mg structure. The conformation about the exocyclic C4'-C5' bond is the commonly observed gauche-gauche (g+) in all the structures except the gauche- trans (g-) conformation observed in 2'-AMP.Mg structure. Lithium ions coordinate with water, ribose and phosphate oxygens at distances 1.88 to 1.99A. Na+ ions and K+ ions interact with phosphate and ribose oxygens directly and with N7 indirectly through a water oxygen. A distinct feature of 2'-AMP.Na and 2'-AMP.K structures is the involvement of ribose 04' in metal coordination. The calcium ion situated on a two-fold axis coordinates directly with three oxygens OW1, OW2 and O2 and their symmetry mates at distances 2.18 to 2.42A forming an octahedron. A classic example of an exception to the existence of the O5'-N3 intramolecular hydorgen bond is the 2'-AMP.Mg strucure. Magnesium ion forms an octahedral coordination with three water and three phosphate oxygens at distances ranging from 2.02 to 2.11 A. A noteworthy feature of its coordination is the indirect link with N3 through OW3 oxygen resulting in macrochelation between the base and the phosphate group. Greater affnity of metal clays towards 5' compared to 2' and 3' nucleotides (J. Lawless, E. Edelson, and L. Manning, Am. Chem. Soc. Northwest Region Meeting, Seattle. 1978) due to macrochelation infered from solution studies (S. S. Massoud, H. Sigel, Eur J. Biochem. 179, 451-458 (1989)) and interligand hydrogen bonding induced by metals postulated from metal-nucleotide structures in solid state (V. Swaminathan and M. Sundaralingam, CRC. Crit. Rev. Biochem. 6, 245-336 (1979)) are borne out by our structures also. The stacking patterns of adenine bases of both 2'-AMP.Na and 2'-AMP.K structures resemble the 2'-AMP.NH4 structure reported in the previous article. 2'-AMP.Li, 2'-AMP.Ca and 2'-AMP.Mg structures display base-ribose 04' stacking. An overview of interaction of monovalent and divalent cations with 2' and 5'-nucleotides has been presented.
 ...
PMID:Metal-nucleotide interactions: crystal structures of alkali (Li+, Na+, K+) and alkaline earth (Ca2+, Mg2+) metal complexes of adenosine 2'-monophosphate. 951 55

Chlorination of drinking water results in the generation of low levels of numerous chlorinated hydrocarbons due to the reaction of chlorine with naturally occurring organic compounds in the water. Concern has been raised about the safety of these chlorinated contaminants as several of them, most notably chloroform (trichloromethane), have been shown to be carcinogenic in long-term rodent bioassays and weak correlations between trihalomethane levels in drinking water and an increased risk of bladder and colorectal cancer in humans have been found. Chloroform and carbon tetrachloride induce liver cancer in rats and mice only at doses where significant hepatotoxicity is observed and have been classed as non-genotoxic carcinogens. We have investigated the ability of chloroform, carbon tetrachloride and 1,1,1-trichloroethane to induce deletions via intrachromosomal recombination in the yeast Saccharomyces cerevisiae. Chloroform and carbon tetrachloride induced this genotoxic recombination event at similar doses, 1,1,1-Trichloroethane gave only a weak response in the DEL recombination assay and only at the highest dose. We further show that chloroform and carbon tetrachloride, but not trichloroethane, induced oxidative free radical species in our yeast strain. The free radical scavenger N-acetylcysteine reduced chloroform-induced toxicity and recombination, and both chloroform and carbon tetrachloride were able to oxidize the free radical-sensitive reporter compound dichlorofluorescein diacetate in vivo. The implications of these findings to the carcinogenic activities of the three compounds are discussed.
 ...
PMID:Chloroform and carbon tetrachloride induce intrachromosomal recombination and oxidative free radicals in Saccharomyces cerevisiae. 954 52

Irinotecan is a water-soluble camptothecin analogue. Its cytotoxicity effects are exerted through interaction with the topoisomerase I-DNA complex, eventually leading to cell death. In preclinical studies, irinotecan has demonstrated a broad spectrum of activity in vitro and in vivo, and synergistic effects have been observed when it is administered in combination with other antineoplastic agents. Phase I studies of irinotecan conducted in Europe, Japan and the US have provided useful information on optimal dosage and scheduling, as well as thorough evaluation of the toxicity profile of the drug. Phase II and III trials utilising either irinotecan alone or in innovative combinations with other drugs are currently in progress. Available data indicate that irinotecan alone or in combination with other cytotoxic agents has therapeutic potential in several types of malignancy, including colorectal, lung, ovarian, cervical and gastric cancers and non-Hodgkin's lymphoma. It is the first drug since fluorouracil to possess consistent antitumour activity against metastatic colorectal cancer. The principal toxicities associated with irinotecan are diarrhoea and leucopenia. Effective strategies have been developed to circumvent both the early- and delayed-onset diarrhoea induced by irinotecan, thus allowing safer delivery of this promising agent in the clinical setting.
 ...
PMID:A risk-benefit assessment of irinotecan in solid tumours. 963 86

Hypoxia occurs to a variable extent in a vast majority of rodent and human solid tumors. It results from an inadequate and disorganized tumor vasculature, and hence an impaired oxygen delivery. A probe for the non-invasive detection of tumor hypoxia could find important utility in the selection of patients for therapy with bioreductive agents, anti-angiogenic/anti-vascular therapies and hypoxia-targeted gene therapy. In addition, tumor hypoxia has been shown to predict for treatment outcome following radio- or chemotherapy in human cancers, the underlying mechanism for which may involve hypoxia driving genetic instability and resulting tumor progression. Beyond oncology, utility can also be envisaged in stroke, ischemic heart disease, peripheral vascular disease, arthritis and other disorders. Design, validation, preclinical development and current status of a fluorinated 2-nitroimidazole, N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-l-imidazolyl) acetamide (SR 4554, CRC 94/17), which has been rationally designed for the measurement of tumor hypoxia by magnetic resonance spectroscopy (MRS) and imaging (MRI), are reviewed. Application in positron emission tomography (PET) detection is also proposed. Design goals were: (i) a nitro group with appropriate redox potential for selective reduction and binding in hypoxic tumor cells; (ii) hydrophilic/hydrogen bonding character in the side chain to limit nervous tissue penetration and prevent neurotoxicity; and (iii) three equivalent fluorine atoms to enhance MRS/MRI detection, located in a metabolically stable position. Reduction of SR 4554 by mouse liver microsomes was dependent on oxygen content, with a half-maximal inhibition at 0.48 +/- 0.06%. SR 4554 underwent nitroreduction by hypoxic but not oxic tumor cells in vitro and electron energy loss spectroscopic analysis showed selective retention in the hypoxic regions of multicellular tumor spheroids. Pharmacokinetic design goals were met. In particular, low brain tissue concentrations were seen in contrast to excellent tumor levels, as measured by high performance liquid chromatography. The extent of this restricted entry to brain tumor was surprising given the overall octanol/water partition coefficient and was attributed to the hydrophilic/hydrogen bonding character of the side chain. Quantitative MRS was used to assess the retention of 19F signal in murine tumors and human tumor xenografts. The 19F retention index (FRI; ratio of 19F signal levels at 6 h relative to that at 45 min) ranged from 0.5 to 1.0 and 0.2 to 0.9 for murine tumors and human xenografts respectively. The correlation between SR 4554 retention and pO2 was not a linear one, but when FRI was > 0.5, the % pO2 < or = 5 mmHg was always > 60%, indicating that high FRI was associated with low levels of oxygenation. Finally, whole body 19F-MRI in mice demonstrated that SR 4554 and related metabolites localized mainly in tumor, liver and bladder regions. A selective MRS signal was readily detectable in tumors at doses at least 7-fold lower than those likely to cause toxicity in mice. We conclude that proof of principle is established for the use of SR 4554 as a non-invasive MRS/MRI probe for the detection of tumor hypoxia. Based on these promising studies, SR 4554 has been selected for clinical development.
 ...
PMID:Preclinical development and current status of the fluorinated 2-nitroimidazole hypoxia probe N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR 4554, CRC 94/17): a non-invasive diagnostic probe for the measurement of tumor hypoxia by magnetic resonance spectroscopy and imaging, and by positron emission tomography. 975 26

Monitoring of personal exposure of population from environmental pollution is a very complicated process. There are many different pollutants in environment in very low concentrations and their distribution is non-homogenous. To measure these pollutants is not often feasible or possible due to technical problems. On the other side these can influence the health status of inhabitants by the way of a long time exposition by low doses. In our work we studied an incidence of the cancer of colon and rectum in rural area of Trnava district during the years 1986-1995. These are the most frequent types of cancer in our district-13.4%, incidence rate is 27.5 per 100,000 inhabitants. The standardised incidence ratio (observed/expected cases) were calculated for all villages, including statistical parameters. The population in this small area (1390 km2) is relatively stabile from point of view of migration and nutritional habits. The urban area consisting from five towns was excluded from analysis because the life style and nutritional habits of people living in towns and villages are different. These suppositions enabled to concentrate our attention to the study of environmental factors which can influence development of the colorectal cancer. The SIR's were correlated with time of public drinking water supply, surface water quality, location of waste dumps, and time of gas heating using as kind of house heating. Positive and statistically significant correlation's were found between SIR of the colorectal cancer and waste dump location for females and weaker for surface water and SIR for males. Statistically significant elevation of SIR both for males and females were found in one village. Ecological design of study did not allow to study confounders, yet served enough information for preparation of analytical studies and public health decision-making process on local level.
 ...
PMID:Colorectal cancer and environmental pollution. 978 18

Folate analogues that inhibit thymidylate synthase (TS) selectively were developed based on TS and folate molecular structures and properties. The structure-activity relationship, preclinical and clinical development, and issues of potential importance in the future success of these TS inhibitors are reviewed herein. Properties of these new compounds depend mainly on the use of the reduced folate carrier (RFC) proteins for cellular entry and on intracellular polyglutamation, which augments TS inhibitory function and cellular retention. CB3717 [Zeneca (formerly ICI Pharmaceuticals), Macclesfield, United Kingdom], the first selective TS inhibitor developed, demonstrated antineoplastic activity in Phase I trials, but its development was abandoned due to nephrotoxicity. ZD1694 (Tomudex; Zeneca), a water-soluble, nonnephrotoxic quinazoline, demonstrated activity in colorectal, breast, and pancreatic cancer. Phase III trials of Tomudex in advanced colorectal cancer were completed recently. LY231514 (Eli Lilly Research Labs, Indianapolis, IN) uses the RFC and polyglutamation to exert its selective TS inhibitory action. Phase I trials of this compound have been completed. ZD9331 (Zeneca), currently in preclinical studies, was designed to obviate the use of the RFC for cellular entry. 1843U89 (Glaxo-Wellcome, Research Triangle Park, NC), currently in Phase I trial, does not require the RFC; polyglutamation of this potent TS inhibitor leads to its higher cellular retention without augmenting its TS inhibitory activity. Currently in clinical trials, AG337 (p.o. and i.v. forms) and AG331 (both by Agouron, La Jolla, CA) are lipophilic potent TS inhibitors with action independent of the RFC and polyglutamation. Multiple mechanisms through which cells may overcome TS inhibition have been described. Combining TS inhibitors with other agents that affect TS, interfere with TS gene and mRNA regulation, or inhibit salvage mechanisms of thymidylate depletion may potentially enable greater clinical utility of this class of compounds.
 ...
PMID:Thymidylate synthase inhibitors. 981 65

Since 1990, 230 operations for focal pathologies in the liver have been carried out at the Center's clinics using such advanced procedures and equipment as radio-isotope examination of hepatic function, ultrasonography of the liver during surgery, ultrasound aspirator, water-flow scalpel, argon coagulator and adhesive dressing materials. The study included 75 resections for primary hepatic tumor (lethality-14.6%), 114 resections-disseminated tumor (lethality-5.2%) and 41 resections for benign tumors and non-tumor pathologies (no lethality). Preoperative chemotherapy was found to significantly increase the risk of postoperative complications in cases of liver resection. Five-year survival in such patients with primary tumor was 33.3%. The seven most significant prognostic factors in primary hepatic carcinoma were: portal invasion by tumor cells, number of tumor nodes in the liver, alpha-fetoprotein concentration, tumor node size, concomitant cirrhosis, age and extent of surgery. In patients with hepatic resection for solitary metastasis of the large bowel, 5-year survival was 28.6%. A regimen of adjuvant chemotherapy for solitary metastasis of colorectal cancer into liver is suggested. The data on 37 surgical patients with hepatic metastasis of non-colorectal cancer are presented. It was demonstrated that the liver should be resected in cases of solitary metastasis of renal carcinoma, adrenal gland, ovary, tests, breast, gallbladder and carcinoid.
 ...
PMID:[Current approaches to surgical treatment of liver tumors]. 988 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>