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  • 1
    Electronic Resource
    Electronic Resource
    Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat (1991)
    Springer
    Cancer chemotherapy and pharmacology 29 (1991), S. 105-111 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P〈0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of ≈30% in function beginning at the 4th week after drug administration. The heart rate in these animals was ≈12% lower than that measured in age-matched control rats (P〈0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P〈0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P〈0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00687318
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin (1986)
    Springer
    Investigational new drugs 4 (1986), S. 17-23 
    Details
    ISSN: 1573-0646
    Keywords: Anthracyclines ; DNA intercalation ; antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172011
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    Paper (German National Licenses)
    Fulltext
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