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This work compares the biological properties of cis-diammine- dichloroplatinum (cisplatin) and its new analogue cis-[Pt(AF)2Cl2] (AF stands for 3-aminoflavone), which contains two aminoflavone substituents as non-leaving ligands. Both compounds were tested for their antiproliferative activity against cultured L1210 cells, and their DNA interstrand crosslinking activity in cells and in a cell-free system. Cisplatin was found to be an approximately 6 times more cytotoxic drug than its new analogue. Platinum complexes reacted with purified calf thymus DNA in a cell-free system producing DNA interstrand crosslinks. The kinetics of crosslink formation was very similar for both compounds but the maximal level of crosslinks was 20% higher for cisplatin. In cells, however, crosslinks were produced by cisplatin, whereas this type of DNA lesion was almost undetected in cells treated with the aminoflavone analogue as assayed by DNA alkaline elution. At higher drug concentrations, strong degradation of DNA was observed in L1210 cells treated with cis- [Pt(AF)2Cl2] but not in the cells incubated with cisplatin. This DNA degradation seems to reflect very efficient apoptosis induction by cis-[Pt(AF)2Cl2] as the electrophoretic patterns of DNA from cells incubated with this drug showed a ladder typical for apoptotic cells.
 This work was undertaken to compare cytotoxicity, DNA damaging properties and effect on DNA cleavage by topoisomerase II of the anthracycline drug doxorubicin (DOX) and its two derivatives with a formamidino group containing a cyclic amine moiety such as morpholine (DOXM) or hexamethyleneimine (DOXH). The tetrazolium dye colorimetric assay was used to determine the cytotoxic activity of anthracyclines toward L1210 leukemia cells. DNA damage was measured by alkaline elution technique. The effect of anthracyclines on DNA cleavage was studied in a cell-free system containing supercoiled pBR322 DNA and purified human topoisomerase II. The cytotoxicity data and the results of studies on the mechanism of DNA break formation by anthracyclines at the cellular level and in the cell-free system showed that the presence of the formamidino group in the doxorubicin molecule reduced its ability to stimulate DNA cleavage by DNA topoisomerase II. Conclusion: DNA topoisomerase II is not a primary cellular target for DOXM or DOXH. An advantageous feature of formamidinoanthracyclines is their mechanism of cytotoxic action which is not related to the inhibition of DNA topoisomerase II. Therefore this class of anthracyclines seems to be a good source for selection of an anticancer drug directed toward cancer cells with the developed multidrug resistance attributed to the presence of altered DNA topoisomerase II.
9-Aminoacridine carboxamide derivatives studied here form with DNA intercalative complexes which differ in the kinetics of dissociation. Inhibition of total RNA synthesis catalyzed by phage T7 and Escherichia coli DNA-dependent RNA polymerases correlates with the formation of slowly dissociating acridine-DNA complex of time constant of 0.4-2.3 s. Their effect on RNA synthesis is compared with other ligands which form with DNA stable complexes of different steric properties. T7 RNA polymerase is more sensitive to distamycin A and netropsin than the E. coli enzyme while less sensitive to actinomycin D. Actinomycin induces terminations in the transcript synthesized by T7 RNA polymerase. Despite low dissociation rates of DNA complexes with acridines and pyrrole antibiotics no drug dependent terminations are observed with these ligands.
The uptake of six 9-aminoacridinecarboxamide derivatives by L1210 cells in relation to their lipophilicity and cytotoxic activity was studied. The amount of acridines taken up by cells was estimated by fluorimetric measurements. It was found that the uptake efficiency of this class of compounds by cells depends on the size of carboxamide residue as well as on position of the substituent. The increase of size of carboxamide chain resulted in the loss of capability of acridines to penetrate cell membrane. Cytotoxic effects of acridines were well correlated with the level of drugs accumulated by cells, whereas no clear correlation between uptake and lipophilicity was observed. It is concluded that uptake of 9-aminoacridinecarboxamides is the most important factor determining their antiproliferative activity.
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