RESUMO
Bis(7-amino-4-azaheptyl)dimethylsilane (AzhepSi) and its bis(ethyl) derivative [bis(7-ethylamino-4-azaheptyl)dimethylsilane] (EtAzhepSi) are the first examples of a new type of aliphatic tetramine with a dimethylsilane group incorporated into the central carbon chain. AzhepSi shares certain properties with the natural polyamines, but in contrast with spermidine and spermine it inhibits the growth of L1210 leukemia cells in culture at micromolar concentrations. The bis(ethyl) derivative of AzhepSi was made, in analogy to bis(ethyl) spermine, a polyamine derivative, which gained much attention during the last decade as a potential anticancer drug. Chinese hamster ovary (CHO) cells accumulate the dimethylsilyl tetramines considerably more and are more sensitive to these drugs than are CHO-MG cells, a polyamine uptake-deficient mutant. This and related observations demonstrate that AzhepSi and EtAzhepSi are preferentially taken up by a polyamine transport system. Both tetramines inhibit the growth of a variety of tumor cells at micromolar concentrations. AzhepSi turned out to be either equipotent or more potent, but in no case less potent than EtAzhepSi. When given alone at daily doses of 25 micromol/kg, the compounds did not prolong the survival time of L1210 leukemia mice. However, in combination with 2-(difluoromethyl)ornithine and neomycin, AzhepSi had a significant effect on the life span of the animals. The growth rate of 3LL Lewis lung carcinoma was reduced by both compounds at daily doses of 25 micromol/kg. The observations presented in this work suggest that the dimethylsilyl tetramines are antiproliferative agents in vitro and in vivo. Due to enhanced general toxicity, the introduction of N-ethyl substituents was of no advantage in the case of these polyamine analogues.
Assuntos
Antineoplásicos/farmacologia , Silanos/farmacologia , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Cricetinae , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Leucemia L1210/tratamento farmacológico , Camundongos , Camundongos Endogâmicos DBARESUMO
N1-Dansylspermine and related sulfonamides of the natural polyamines are very potent blockers of NMDA-type glutamate receptors. They exhibit pharmacological properties which were not predicted from the constituents of the conjugates. Cytotoxicity and calmodulin antagonism of N1-dansylspermine were especially impressive. Calmodulin antagonism implies that N1-dansylspermine prevents induction of ornithine decarboxylase and inhibits its own active uptake via the polyamine transport system. Structure-activity considerations demonstrated that an aromatic character of the substituent is not required; amide bond formation with an aliphatic sulfonic acid is sufficient to transform spermine into a highly toxic calmodulin antagonist. Cytotoxicity and calmodulin antagonism are properties which are intrinsic to spermine, but they are observed only at very high concentrations. Amide bond formation at N1 with a lipophilic residue appears to 'amplify' these normally latent properties. The use of polyamine conjugates structurally related to the amides described in this work for targeting tumours may be marred by their calmodulin antagonism.
Assuntos
Amina Oxidase (contendo Cobre) , Antineoplásicos/farmacologia , Calmodulina/antagonistas & inibidores , Compostos de Dansil/farmacologia , Poliaminas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espermina/análogos & derivados , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Calmodulina/metabolismo , Bovinos , Compostos de Dansil/química , Compostos de Dansil/metabolismo , Técnicas In Vitro , Leucemia L1210 , Camundongos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas/química , Poliaminas/metabolismo , Putrescina/metabolismo , Espermina/química , Espermina/metabolismo , Espermina/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologiaRESUMO
Several members of a new class of structural analogues of the natural polyamines which contain a S1(CH3)(2)- group in the central carbon chain have previously been found to be potent cytostatics to various tumor cell lines. These compounds have been tested with regard to their ability to inhibit the growth of Lewis lung carcinoma grafts in DBA/2 mice. All compounds exerted consistently antitumor effects, however,growth inhibition was only partial at one or two daily doses of 25 mu mol/kg of the drugs. Among the dimethylsilane tetramines only (6-amino-3-azahexyl),(7-amino-4-azaheptyl)-dimethylsilane (AzhexAzhepSi) reduced tumor growth to a significant degree. A major central nervous system pharmacologic effect of the compounds, hypothermia, limitates the administrable amount of the compounds. The dimethylsilane amines have polyamine antagonist properties, and are weak polyamine mimetics, as became obvious from their effect on tumor cells in culture and the present in vivo experiments.
RESUMO
Dimethylsilane tetramines are structural analogues of spermine with a (CH3)2 Si-group incorporated into the central carbon chain. They have potential as anticancer drugs. Their cytotoxic effect was considered to rely mainly on their polyamine antagonist property. In order to obtain new ideas about cellular mechanisms, which are potential targets of the dimethylsilane polyamines, the effects of these compounds on some basic cell functions, such as protein and DNA synthesis, and calmodulin antagonism were studied. In addition, their mode of accumulation in cells was investigated. It became evident that the intracellular accumulation of dimethylsilane polyamines is almost exclusively achieved via the polyamine transport system. However, the exchange of a part of the intracellular natural polyamines against dimethylsilane polyamines has only a small effect on polyamine uptake. Binding to the endoplasmic reticulum and inhibition of protein synthesis are presumably important for the cytotoxic action of bis(11-amino-4,8-diazaundecyl)dimethylsilane, a hexamine, but seem of no importance for the tetramines. Calmodulin antagonism, however, is likely to contribute to their cytotoxic effect.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Calmodulina/análogos & derivados , Poliaminas/farmacologia , Poliaminas/farmacocinética , Silanos/farmacologia , Silanos/farmacocinética , Animais , Células CHO/efeitos dos fármacos , Células CHO/metabolismo , Calmodulina/metabolismo , Agregação Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Cricetinae , DNA de Neoplasias/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Leucina/antagonistas & inibidores , Leucina/metabolismo , Leucemia L1210/tratamento farmacológico , Leucemia L1210/metabolismo , Metenamina/farmacocinética , Metenamina/farmacologia , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Ratos , Espermidina/antagonistas & inibidores , Espermidina/farmacocinética , Timidina/antagonistas & inibidores , Timidina/metabolismo , Poliamina OxidaseRESUMO
Several dimethylsilane tetramines [homologs of spermine with an Si(CH3)2 group in the central carbon chain], a carbon analog of the dimethylsilane tetramines [containing C(CH3)2 instead of Si(CH3)2] and a dimethylsilane hexamine were studied with regard to their cytotoxic activity and their ability to interact with double-stranded DNA. All polyamine analogs exerted cytostatic effects to several cell lines at micromolar concentrations. Their ability to condense DNA was comparable to and their ability to displace ethidium bromide from binding to DNA was superior to that of spermine. Their cytostatic effect was not correlated with the depletion of cellular spermidine concentrations. It is suggested that the new polyamine analogs act mainly by displacing spermidine from binding sites which are essential for the promotion of cell growth.