Perspectives in Cancer Chemotherapy, in vitro and in vivo Experiments

The development of pharmacological agents able to counteract the mechanisms of multidrug resistance (MDR) in oncology has remained a major goal for the past ten years. Several mechanisms are thought to be involved in drug resistance, including those associated with drug transport, detoxification and apoptosis. The first part of this thesis was focused on the inhibition of MDR through inhibition of the MDR P-glycoprotein (P-gp) in various cell lines. Six groups of compounds were involved in the P-gp efflux pump inhibitory studies: cinnamylidene ketones; 1,4-dihydropyridines derivatives; phenothiazines; HSP90 inhibitor peptide derivatives; Tylosin Betti base derivative and Euphorbia diterpenes. The majority of the tested compounds were able to increase the R123 accumulation in cancer cell lines. Generally, the newly identified MDR modifiers were able to enhance the antiproliferative activity of selected anticancer drugs in a synergistic or additive way in vitro on MDR cells. The in vitro activity of TBN was confirmed in further in vivo efficacy studies in DBA/2 mice. As an alternative way of antitumour effect, apoptosis inductions of resistance modifiers were studied. The substituted dihydropyridine 13 was the most promising apoptosis inducer on L 5178 Y cells. The human cytomegalovirus (CMV) 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, except latilagascene D, could reduce the promotion in vitro decreased IE-antigen expression of CMV to prevent progression of tumour malignancy.