RESUMO
A first approach is presented to explain the entropic structural transition observed in the persistence length of DNA complexes formed with intercalating drug molecules. The proposed model is based on calculating the effective persistence length of two entropic springs associated in series, one intercalated with drug molecules and the other without drugs. As the total drug concentration in the sample increases, the lengths of the two entropic springs vary, modifying the effective persistence length. The theoretical predictions of this model are then compared to experimental results, and a good accordance was obtained.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Bacteriófagos/genética , DNA Viral/química , DNA Viral/efeitos dos fármacos , Daunorrubicina/farmacologia , Etídio/farmacologia , Substâncias Intercalantes/farmacologia , Antibióticos Antineoplásicos/química , Simulação por Computador , Daunorrubicina/química , Elasticidade , Entropia , Etídio/química , Substâncias Intercalantes/química , Modelos Químicos , Conformação de Ácido Nucleico/efeitos dos fármacos , Desnaturação de Ácido Nucleico/efeitos dos fármacos , Pinças ÓpticasRESUMO
A lipidic nanoemulsion termed LDE concentrates in neoplastic cells after injection into the bloodstream and thus can be used as a drug carrier to tumour sites. The chemotherapeutic agent daunorubicin associates poorly with LDE; the aim of this study was to clarify whether the derivatization of daunorubicin by the attachment of an oleyl group increases the association with LDE, and to test the cytotoxicity and animal toxicity of the new preparation. The association of oleyl-daunorubicin (oDNR) to LDE showed high yield (93 +/- 2% and 84 +/- 4% at 1:10 and 1:5 drug:lipid mass, respectively) and was stable for at least 20 days. Association with oDNR increased the LDE particle diameter from 42 +/- 4 nm to 75 +/- 6 nm. Cytotoxicity of LDE-oDNR was reduced two-fold in HL-60 and K-562 cell lines, fourteen-fold in B16 cells and nine-fold in L1210 cells when compared with commercial daunorubicin. When tested in mice, LDE-oDNR showed remarkable reduced toxicity (maximum tolerated dose > 253 micromol kg(-1), compared with <3 micromol kg(-1) for commercial daunorubicin). At high doses, the cardiac tissue of LDE-oDNR-treated animals had much smaller structural lesions than with commercial daunorubicin. LDE-oDNR is therefore a promising new preparation that may offer superior tolerability compared with commercial daunorubicin.
Assuntos
Daunorrubicina/química , Lipídeos/química , Nanopartículas/química , Receptores de LDL/metabolismo , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Daunorrubicina/administração & dosagem , Daunorrubicina/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Emulsões/química , Emulsões/metabolismo , Células HL-60 , Coração/efeitos dos fármacos , Humanos , Células K562 , Estimativa de Kaplan-Meier , Camundongos , Microscopia Eletrônica , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Nanopartículas/administração & dosagem , Tamanho da Partícula , Tecnologia Farmacêutica/métodos , Testes de Toxicidade Aguda/métodosRESUMO
We use optical tweezers to perform stretching experiments on DNA molecules when interacting with the drugs daunomycin and ethidium bromide, which intercalate the DNA molecule. Our results show that the persistence length of the DNA-drug complexes increases strongly as the drug concentration increases up to some critical value. Above this critical value, the persistence length decreases abruptly and remains approximately constant for larger drug concentrations, at least in the concentration range used in our experiments. Measured intercalators critical concentrations for the persistence length transition coincide with the reported values for the helix-coil transition of DNA-drug complexes obtained from sedimentation experiments. The contour length of the molecules increases monotonically and saturates as the drug concentration increases. The neighbor exclusion model fits to our results for the total drug concentration as a function of the relative increase of the contour length.
Assuntos
Antibióticos Antineoplásicos/química , DNA/química , Substâncias Intercalantes/química , Daunorrubicina/química , Interações Medicamentosas , Elasticidade , Entropia , Etídio/química , Modelos Biológicos , Conformação de Ácido Nucleico , Ultracentrifugação/métodosRESUMO
Anthracyclines have been widely used as anticancer drugs against different types of human cancers. The present study evaluated the mutagenic and recombinagenic properties of two anthracycline topoisomerase II (topo II) poisons, daunorubicin (DNR) and idarubicin (IDA), as well as the related topo II catalytic inhibitor aclarubicin (ACLA), using the wing Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. The three anthracyclines were positive in this bioassay, producing mainly mitotic homologous recombination. The results for spot-size distribution and recombinagenic activity indicate that recombinational DNA damage accounts for approximately 91, 86, and 62% of DNR, IDA, and ACLA genotoxicity, respectively. Besides being a catalytic inhibitor of topo II, ACLA is also a topoisomerase I (topo I) poison. This dual topo I and II inhibitory effect, associated with its DNA-intercalating activity, could contribute to the activity of ACLA in the SMART assay.