Dimethylsilane polyamines: cytostatic compounds with potentials as anticancer drugs. II. Uptake and potential cytotoxic mechanisms.
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.
Le Roch
N
N
Synthèse et Electrosynthèse Organique, Institut de Chimie, Université de Rennes 1, Rennes, France.
Douaud
F
F
Havouis
R
R
Delcros
J G
JG
Vaultier
M
M
Moulinoux
J P
JP
Seiler
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000031:analogs & derivatives* / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004273:DNA, Neoplasm / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D007930:Leucine / Q000037:antagonists & inhibitors / Q000378:metabolism; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D008709:Methenamine / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011073:Polyamines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D012821:Silanes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013095:Spermidine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097667:Polyamine Oxidase
D000970:Antineoplastic Agents; D002147:Calmodulin; D004273:DNA, Neoplasm; D007930:Leucine; D008709:Methenamine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D012821:Silanes; D013095:Spermidine; D013936:Thymidine; D000097667:Polyamine Oxidase; C035684:5-dimethylaminonaphthalene-1-sulfonyl-calmodulin; C103070:bis(7-amino-4-azaheptyl)dimethylsilane