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  • Pharmacokinetics  (2)
  • Germline mutations  (1)
  • Key words Human gastric carcinoma cell line  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Suspected hereditary nonpolyposis colorectal cancer (1999)
    Springer
    Diseases of the colon & rectum 42 (1999), S. 710-715 
    Details
    ISSN: 1530-0358
    Keywords: Suspected hereditary nonpolyposis colorectal cancer ; Germline mutations ; Mismatch repair genes ; Genetic testing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The aim of this study was to determine the frequency of mutations in the mismatch repair genes in families suspected of having hereditary nonpolyposis colorectal cancer. METHODS: We devised two criteria for families suspected of having hereditary nonpolyposis colorectal cancer (Criteria I and II). Criteria I consist of at least two first-degree relatives affected with colorectal cancer with at least one of the following: development of multiple colorectal tumors including adenomatous polyp, at least one colorectal cancer case diagnosed before the age of 50, and occurrence of a hereditary nonpolyposis colorectal cancer extracolonic cancer (endometrium, urinary tract, small intestine, stomach, hepatobiliary system, or ovary) in family members. Criteria II consist of one colorectal cancer patient with at least one of the following: early age of onset (〈40 years); endometrial, urinary tract, or small intestine cancer in the index patient or a sibling (one aged 〈50 years); and two siblings with other integral hereditary nonpolyposis colorectal cancer extracolonic cancers (one aged 〈50 years). A questionnaire was mailed to members of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the families fulfilling these criteria. For comparison the mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria in each institution was also obtained. RESULTS: Data were obtained from eight different institutions (in 7 different countries). In a total of 123 patients from 123 families (67 families fulfilling Criteria I and 56 families fulfilling Criteria II), genetic testing for germline mismatch repair gene variants was performed. Germline mutations of the hMLH1 or hMSH2 genes were identified in 24 families (20 percent). Of these, the mutation detection rate for families fulfilling Criteria I was 28 percent (19/67). The mutation detection rate for families fulfilling Criteria II was 9 percent (5/56). In these eight institutions, the overall mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria was 50 percent (77/154). CONCLUSION: The Criteria I for suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear families and they can include extracolonic cancers. The results of this study suggest that families fulfilling Criteria I should be offered genetic testing. The relatively low mutation detection rate in those families fulfilling Criteria II suggests that, using current techniques, genetic testing in these families is not practical.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02236922
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Absence or decreased levels of the hMLH1 protein in human gastric carcinoma cell lines: implication of hMLH1 in alkylation tolerance (1998)
    Springer
    Journal of cancer research and clinical oncology 124 (1998), S. 421-426 
    Details
    ISSN: 1432-1335
    Keywords: Key words Human gastric carcinoma cell line ; hMLH1 ; MNNG tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Defective hMLH1 function has been increasingly associated with acquired cellular resistance to DNA alkylation damage in human colorectal and endometrial cancer cells. To investigate the relationship between the DNA alkylation tolerance and the hMLH1 status in human gastric carcinoma cells, we determined the cellular response to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), the mutational changes, and the expression of hMLH1 in 11 human gastric carcinoma cell lines. Of 11 cell lines, 4 (SNU-5, -16, -620, and -719) were sensitive, whereas 7 (SNU-1, -216, -484, -520, -601, -638, and -668) were resistant to the cytotoxic effect of MNNG. As determined by Western analysis, it was evident that all the MNNG-resistant cell lines except one (SNU-601) produced very low or undetectable levels of hMLH1 protein compared to the MNNG-sensitive cell lines. A homozygous non-sense mutation that resulted in truncated protein was found in one MNNG-resistant cell line (SNU-1). Therefore, to determine whether the sensitivity of cells to MNNG can be restored by exogenous expression of hMLH1 protein, wild-type hMLH1 cDNA was introduced into the MNNG-resistant cells (SNU-1). The cytotoxicity test showed that expression of exogenous wild-type hMLH1 protein caused an increase in sensitivity to the cytotoxic effect of MNNG. This restoration was confirmed by an increase in the cell population containing less than the G1 amount of DNA (cell death) in the wild-type hMLH1-transfected cells, as determined by flow cytometry analysis. Together our results suggest that (1) the absence or decreased level of wild-type hMLH1 protein may be a frequent event in the human gastric carcinoma cell lines, (2) such alterations in the hMLH1 protein are closely associated with the MNNG tolerance in the human gastric carcinoma cell lines, and (3) the hMLH1 protein participates not only in the repair of DNA mismatches but also in the mechanism of escape from the cytotoxic effects of DNA alkylation damage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004320050194
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and antitumor activity of a new platinum compound,cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl- 1, 3-dioxolane]platinum(II), as determined by ex vivo pharmacodynamics (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 1-6 
    Details
    ISSN: 1432-0843
    Keywords: SKI 2053R ; Pharmacokinetics ; Antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics and ex vivo pharmacodynamics studies oncis-malonato[(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0→∞) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72±2.74 μg h ml−1 (mean ± SD), with an initial half-life of 0.37±0.20 h, a terminal half-life of 2.19±0.93 h, a total clearance of 16.83±4.76 ml min−1 kg−1, and a steady-state volume of distribution of 1.57±0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R 〉 CBDCA 〉 CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P〈0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685622
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    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R,5R )-4,5-bis(aminomethyl)-2-isopropyl- 1, 3-dioxolane]platinum(II), as determined by ex vivo pharmacodynamics (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 1-6 
    Details
    ISSN: 1432-0843
    Keywords: Key words SKI 2053R ; Pharmacokinetics ; Antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The pharmacokinetics and ex vivo pharmaco- dynamics studies on cis-malonato[(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentrationtime curve (AUC0→∞) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72±2.74 μg h ml-1 (mean±SD), with an initial half-life of 0.37±0.20 h, a terminal half-life of 2.19±0.93 h, a total clearance of 16.83±4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57±0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R〉CBDCA 〉CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P〈0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050360
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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