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  • cytotoxicity  (2)
  • neural cell adhesion molecule  (2)
  • 13C and 15N assignments  (1)
  • Apoptosis  (1)
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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.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Digestive diseases and sciences 34 (1989), S. 1894-1899 
    ISSN: 1573-2568
    Keywords: achalasia ; eosinophils ; eosinophil cationic protein ; cytotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Smooth-muscle specimens from the lower esophagus of nine patients operated on for esophageal achalasia were examined with routine hematoxylin-eosin staining. This procedure revealed only a few eosinophils in or between the external smooth-muscle layers. Using specific immunohistochemical methods for the detection of the eosinophil cationic protein (ECP), however, varying degrees of eosinophil infiltration and extracellular deposit of ECP were disclosed in the achalasia specimens. The ECP also reacted with the monoclonal antibody, EG2, indicating secretion of the cytotoxic ECP. Few or no eosinophils were seen in the muscularis externa in specimens from six control patients without esophageal disease. In two controls many eosinophils were observed in the muscularis externa. However, no extracellular ECP was detected and very few eosinophils reacted with the monoclonal antibody (EG2), suggesting that these eosinophils were not activated. Depletion or total absence of peptidergic innervation was seen in all achalasia specimens but not in controls. Since the eosinophil cationic protein (ECP), in its activated form, is cytotoxic, we propose a pathogenic role of the eosinophil infiltration in achalasia.
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  • 3
    ISSN: 1573-5001
    Keywords: 1H ; 13C and 15N assignments ; module-1 ; neural cell adhesion molecule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-5001
    Keywords: 1H and 15N assignments ; module-2 ; neural cell adhesion molecule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-0646
    Keywords: cytotoxicity ; DNA cleavage ; VP-16 ; aclarubicin ; antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with aclarubicin. The addition of aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with aclarubicin inhibited VP-16-induced DNA strand break formation. In anin vitro system with purified topo-II and naked DNA we likewise found, that postincubation with aclarubicin prevented VP-16 induced cleavage. In the samein vitro system, also baseline cleavage induced by topo-II was inhibited when aclarubicin was present. Importantly, aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity. In conclusion, our results support the notion that aclarubicin interferes with steps prior to the formation of the cleavable complex in the catalytic cycle of topo-II, and further that the antagonism of aclarubicin on the effect of topo-II targeting drugs may be due to a decrease in the initial noncovalent binding of topo-II to DNA.
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