Bis(7-amino-4-azaheptyl)dimethlysilane and bis(7-ethylamino-4-azaheptyl)dimethylsilane: inhibition of tumor cell growth in vitro and in vivo.
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.
Seiler
N
N
URA CNRS 1529, Institut de Recherche Contre le Cancer, Faculte de Medecine, Universite de Rennes, France.
Delcros
J G
JG
Vaultier
M
M
Le Roch
N
N
Havouis
R
R
Douaud
F
F
Moulinoux
J P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D012821:Silanes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D012821:Silanes; C103070:bis(7-amino-4-azaheptyl)dimethylsilane; C103071:bis(7-ethylamino-4-azaheptyl)dimethylsilane