Mecanismo de ação e atividade antitumoral de flavonóides, diterpenos e derivados mesoiônicos em tumores experimentais

Abstract

The antitumor activity in mice bearing Sarcoma 180 and Ehrlich carcinoma ascitic tumours, of four mesoionic derivatives [4-phenyl-5-(4-X-cinnamoyl)-1,3,4-thiadiazolium- 2-phenylamine chlorides, where X = H, OCH3, NO2 and OH], two biflavones amentoflavone and 7"-O-methylagathisflavone, the flavonol quercetin and two diterpenes, trans-crotonin (CTN) and trans-dehydrocrotonin (DCTN). The cytotoxic activity from these drugs on Ehrlich cells, the action on DNA topoisomerase I and the tumor necrosis factor (TNF-a) were determined. DNA profiles of Ehrlich cells treated with drugs were done by gel electrophoresis. The mesoionic derivatives OH and NO2 substituted, in ip treatment at total dosis of 10 and 30 mg/kg, respectively, showed significant antitumoral activity against Ehlich carcinoma and S180. The natural products 7"-Omethylagathysflavone e DCTN showed significant in vivo antitumour activity, against the Ehrlich carcinoma and S180 at total dosis of 140 and 80-120mg/kg, respectively. The antimetabolite, 5-fluorouracil, was used as a positive control had antitumour activity against S180 and Ehrlich tumours at dose of 38 mg/Kg and 84 mg/Kg, respectively. The cytotoxic studies of Ehrlich cells for 48 h showed that the natural products, the amentoflavone (23,9 mM), 7"-O-metilagathysflavone (10 mM), quercetin (44 mM), DCTN and CTN (44 mM) inhibited cellular proliferation. The biflavone 7"-Omethylagathysflavone, the flavonol quercetin and the mesoionic derivatives inhibited DNA and protein synthesis in S180 cells. The Ehrlich cells treated for 24 and 48 h with amentoflavone, 7"-O-methylagathysflavone and quercetin showed DNA "ladder" that were XX markedly inhibited in the presence of Zn2+. Amplification of a DNA fragment were obtained by PCR of DNA treated Ehrlich cells with flavonoids in the presence of oligonucleotides primers for the exons 5 and 8 of p53 gene. Mice treated with mesoionic NO2-substituted and DCTN at dosis of 25 and 80 mg/Kg respectively, showed a significant TNF-a augmented values, suggesting that an imunologic response were obtained in treated mice. The mesoionic derivatives inhibits topoisomerase I by stabilizing the DNAtopoisomerase complex. It was observed the binding of mesoionic derivatives and amentoflavone with DNA from spectrophotometric and spectrofluorimetric measurements. The antitumour activity shown in vivo and the other effects studied for the synthetic derivatives and natural products suggest that these substances may be useful in cancer chemotherapy.