[Perspectives of inhibition of multidrug resistance during cancer chemotherapy, in vitro and in vivo experiments].
The development of pharmacological agents able to counteract the mechanisms of multidrug resistance in oncology has remained a major goal for the past ten years. Our purpose was to find multidrug resistance reversal agents less toxic than verapamil among various synthetic compounds: cinnamylidene ketones; 1,4-dihydropyridines; phenothiazines; heat shock 90 inhibitor peptides; betti base derivative of tylosin and among some naturally occurring plant derived jatrophane and lathyrane-type diterpenes. The first part of this thesis presents the inhibition of multidrug resistance through inhibition of the P-glycoprotein efflux pump in various cell lines. In general, the newly identified multidrug resistance modifiers were able to enhance the antiproliferative activity of selected anticancer drugs in a synergistic or additive way in in vitro experiments. The in vitro activity of betti base derivative of tylosin was confirmed by further in vivo efficacy studies in DBA/2 mice. As an alternative way of antitumor effect, apoptosis inductions of resistance modifiers were studied. The substituted dihydropyridine 13 was the most promising apoptosis inducer on mouse lymphoma cells. Human cytomegalovirus was used in a modified in vitro model for characterizing lathyrane compounds with antipromotion effect on human lung cancer cells. All the six macrocyclic lathyrane-type diterpenoids reduced the promotion in vitro , except latilagascene D, decreased IE-antigen expression of cytomegalovirus to prevent progression of tumor malignancy.
Engi
Helga
H
Szegedi Tudományegyetem, Altalános Orvostudományi Kar Orvosi Mikrobiológiai és Immunobiológiai Intézet Szeged.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003587:Cytomegalovirus; D004095:Dihydropyridines / Q000494:pharmacology; D018450:Disease Progression; D004224:Diterpenes / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D010640:Phenothiazines / Q000494:pharmacology; D010641:Phenotype; D011437:Propylamines / Q000494:pharmacology; D015645:Tylosin / Q000494:pharmacology; D014700:Verapamil / Q000009:adverse effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004095:Dihydropyridines; D004224:Diterpenes; D018841:HSP90 Heat-Shock Proteins; D010640:Phenothiazines; D011437:Propylamines; C530345:jatrophane; C530347:lathyrane; C058556:cinnamylamine; C038806:1,4-dihydropyridine; D004317:Doxorubicin; D014700:Verapamil; D015645:Tylosin