RESUMO
The successful growth of tumors is dependent on the process of vascularization elicited by the tumor itself. As confirmed by many authors, there is a correlation between the presence of factors that stimulate tumor growth and angiogenesis. One of the approaches we have explored to control angiogenesis has been to synthesize compounds able to complex growth factors. A number of sulphonated derivatives of distamycin A were found active in inhibiting the binding of bFGF and PDGF beta on Swiss 3T3 cells with ID50 values ranging between 142-587 microM for bFGF and 28-79 microM for PDGF beta. The effect of these new derivatives in inhibiting angiogenesis was initially explored in the chorioallantoic membrane assay. It was observed that the selected compounds were active in this model system at the concentration of 350 nm/pellet. These new molecules present low or no cytotoxic activity on M5076 murine reticulosarcoma cells, the ID50 values being higher than 60 microM after 72 h continuous exposure in vitro.
Assuntos
Capilares/patologia , Distamicinas/farmacologia , Ácidos Sulfônicos/farmacologia , Células 3T3 , Animais , Capilares/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Distamicinas/síntese química , Doxorrubicina/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Linfoma Difuso de Grandes Células B , Camundongos , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos , Receptores do Fator de Crescimento Derivado de Plaquetas , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Células Tumorais CultivadasRESUMO
The effect of 5-methoxytryptoline (5-MeOT), 5-hydroxytryptoline (5-OHT) and tryptoline (Tp), putative endogenous derivatives of the tryptamines, on plasma prolactin (PRL) concentrations has been investigated in the adult male rat. The possible involvement of the hypothalamic serotonergic system has been considered in the mediation of the hormonal effect of the tryptolines. Therefore, plasma PRL levels have been evaluated in rats receiving tryptolines after different pharmacological manipulations of central serotonergic function. Although the three compounds increased the plasma titers of PRL in a dose-dependent manner and enhanced the hypothalamic content of serotonin (5HT), they appear to affect the serotonergic system through different mechanisms. In particular, 5-OHT might act at a presynaptic level, since its hyperprolactinemic effect was antagonized both by the depletion of central 5HT content after p-chlorophenylalanine and by the degeneration of serotonergic terminals after 5,7-dihydroxytryptamine. In contrast, 5-MeOT behaved as if it had a postsynaptic site of action, being counteracted by the serotonergic postsynaptic antagonists metergoline and cyproheptadine. The unsubstituted tetrahydro-beta-carboline, Tp, is probably active at both pre- and postsynaptic sites. The enhancing effect of Tp on PRL secretion was antagonized by chronic treatment with p-chlorophenylalanine, while it was also maintained in 5,7-dihydroxytryptamine-lesioned rats. These findings suggest that tryptolines may play a functional role in PRL secretion by interacting with central serotonergic systems through different biochemical mechanisms.