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.