RESUMO
The marked activity of [meso-1, 2-bis(2, 6-difluoro-3-hydroxyphenyl)ethylenediamine]platinum(II) (meso-3-PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) on the hormone-sensitive MXT-M-3, 2 breast cancer implanted in mice is most probably due to a mechanism based on the reduction of the endogenous estrogen level. Cytotoxic effects which are poorly pronounced in experiments on several breast cancer cell lines (e.g. MCF-7), do not significantly contribute to the anti-breast cancer activity of this compound. In contrast to this, the standard cisplatin and the structurally related comparison compound [meso-1, 2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (meso-4-PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) are strongly active in vivo as well as in vitro. Both effects entail programmed cell death, which is responsible for the inhibition of the tumor growth. The minor cytotoxicity of meso-3-PtLL' in breast cancer cell cultures is caused neither by an inappropriate rate of reaction with bionucleophiles (e.g. by a too fast inactivation by plasma proteins) nor solely by the observed poor absorption by the tumor cells resulting in an insufficient drug concentration at the DNA. Additionally, an impeded reaction with biologically important, guanine-rich sequences of DNA (owing to the 2, 6-standing F atoms which hinder the drug-target inter action) must be assumed as cause of its marginal cytotoxicity.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Absorção , Animais , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Morte Celular , Linhagem Celular Tumoral , DNA de Neoplasias/metabolismo , Feminino , Camundongos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Aqua[meso-1, 2-bis(2, 6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-3-PtSO(4)) and its racemate (rac-3-PtSO(4)) are highly active on the hormone-sensitive MXT-M-3, 2 breast cancer of the mouse. In vitro, on the MXT(+) cell culture derived from this tumor, however, they are inactive (meso-3-PtSO(4)) or moderately active (rac-3-PtSO(4)) in concentrations corresponding to levels of these drugs in animal experiments. The in vivo effect is mainly caused by a reduction of the endogenous estrogen level in the host animals due to an interference with the ovarian steroid biosynthesis as demonstrated for meso-3-PtSO(4). Therefore, a reversal of the breast cancer inhibiting effect of meso-3-PtSO(4) can be achieved by simultaneous estrone administration. Histological results on ovaries, uterus, and tumor of meso-3-PtSO(4)-treated mice also favor such a mode of action. However, especially for rac-3-PtSO(4) cytotoxic effects contributing to the anti-breast cancer activity cannot be excluded. Considerations on the mode of action of Pt-complexes which inhibit breast cancer by interference with estrogen receptor mediated processes of growth control and with DNA replication are presented.