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  • 1
    ISSN: 1432-0843
    Keywords: Etoposide ; Topoisomerase II ; Apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A number of clinically important drugs such as the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26), the anthracyclines daunorubicin and doxorubicin (Adriamycin), and the aminoacridine amsacrine exert their cytotoxic action by stabilizing the cleavable complex formed between DNA and the nuclear enzyme topoisomerase II. We have previously demonstrated in several in vitro assays that the anthracycline aclarubicin (aclacinomycin A) inhibits cleavable-complex formation and thus antagonizes the action of drugs such as VP-16 and daunorubicin. The present study was performed to validate these in vitro data in an in vivo model. At nontoxic doses of 6 and 9 mg/kg, aclarubicin yielded a marked increase in the survival of non-tumor-bearing mice given high doses of VP-16 (80–90 mg/kg) in six separate experiments. In therapy experiments on mice inoculated with Ehrlich ascites tumor cells, aclarubicin given at 6 mg/kg roughly halved the increase in median life span induced by VP-16 at doses ranging from 22 to 33 mg/kg. An attempt to determine a more favorable combination of VP-16 and aclarubicin by increasing VP-16 doses failed, as the two drugs were always less effective than VP-16 alone. The way in which VP-16-induced DNA strand breaks lead to cell death remains unknown. However, VP-16 has been reported to cause apoptosis (programmed cell death) in several cell lines. To ascertain whether the protection given by aclarubicin could have a disruptive effect on the apoptotic process, we used the small intestine as an in vivo model. Whereas VP-16-induced apoptosis in crypt stem cells was detectable at a dose as low as 1.25 mg/kg, aclarubicin given at up to 20 mg/kg did not cause apoptosis. Indeed, aclarubicin caused a statistically significant reduction in the number of cells rendered apoptotic by VP-16. The present study thus confirms the previous in vitro experiments and indicates the value of including an in vivo model in a preclinical evaluation of drug combinations.
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  • 2
    ISSN: 0173-0835
    Keywords: Tumor suppressor protein p53 ; Apoptosis ; Lung cells ; Phosphorylation ; Expression ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: The expression of p53 tumor suppressor protein isoforms in H460a cells induced to undergo apoptosis by 2-methoxyestradiol was investigated by two-dimensional gel electrophoresis. Whole-cell proteins from control and apoptotic H460a cells were separated by two-dimensional electrophoresis and were transferred to nitrocellulose. The p53 isoforms were detected by immunoblotting using p53 monoclonal antibody Bp53-12. Four isoforms of p53 (2, 3, 5, and 6) differing in phosphorylation state were detected in control cells. Three additional isoforms (1, 4, and 7) were observed to be expressed at significant levels only in apoptotic cells. The differential expression of isoforms 1, 4, and 7 in apoptotic cells suggests that one or more specific phosphorylation events generating these forms of p53 could play a role in regulating the function of p53 in apoptosis.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-675X
    Keywords: Apoptosis ; endothelial ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Transfection of the wild-type p53 gene into an immortalized human endothelial cell line (ECV-304) by recombinant adenoviral delivery resulted in high level expression of the wild-type p53 protein and induction of apoptosis. Increases in the number of apoptotic cells were observed within 12 h after infection of ECV-304 cells with recombinant p53 adenovirus, as deter-mined by the appearance of internucleosomal DNA fragmentation ladders and by TUNEL and electron microscopic analyses. Control cells infected with a β-galactosidase recombinant adenovirus exhibited little or no increase in apoptosis over uninfected cells. The expression of Waf-1 and Bax gene products were in-creased substantially in apoptotic ECV-304 cells as determined by Northern blot, reverse transcription-PCR and immunoblotting analyses. Lesser increases in the expression of the PCNA gene were detected in ECV-304 cells undergoing apoptosis. Both control and apoptotic ECV-304 cells did not express detectable levels of Bcl-2 mRNA or protein in Northern blotting and immunoblotting analyses, respectively. The data suggest a role for the Bax gene product in p53-mediated apoptosis of endothelial cells.
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  • 4
    ISSN: 1573-675X
    Keywords: Apoptosis ; non-small cell lung carcinoma ; p53 ; phosphorylation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The natural metabolic byproduct of estradiol, 2-methoxyestradiol (2-MeOE2), induces apoptosis in human lung cancer cells by a p53-dependent mechanism. The expression of wild-type p53 isoforms was investigated in H1299 non-small cell lung carcinoma cells induced into apoptosis by 2-MeOE2. H1299 cells lack endogenous p53 and undergo predominantly a G1 arrest when infected with a recombinant wild-type p53 adenovirus. However, when H1299 cells transfected with p53 were treated with 2-MeOE2, they underwent rapid and extensive apoptosis. H1299 cells expressing mutant his273 p53 were unaffected by 2-MeOE2, indicating a dependence of 2-MeOE2-mediated apoptosis on the presence of a functional p53. Analysis of wild-type p53 phosphoisoforms in H1299 cells by two-dimensional gel electrophoresis revealed that 2-MeOE2 induced a unique group of acidic p53 isoforms. Although most of the wild-type p53 in untreated H1299 cells migrated as at least five diffuse species with isoelectric points from pH 5.5–6.3, as many as nine additional forms migrating toward the acidic region with pI values from 4.4–5.3 were detected in 2-MeOE2-treated apoptotic cells. Two other agents known to induce apoptosis, vinblastine and actinomycin D, induced a similar pattern of acidic p53 species as that observed for 2-MeOE2. The results indicated that the induction of apoptosis in H1299 cells by 2-MeOE2 is dependent on the upregulation of specific p53 isoforms. Identification of the specific p53 phosphoisoforms induced by MeOE2 will be an important step in understanding the regulation and function of p53 in apoptosis.
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