THE EFFECTS OF STRUCTURAL ANALOGS OF PUTRESCINE ON PROLIFERATION, MORPHOLOGY AND KARYOTYPE OF GLIOBLASTOMA CELLS IN CULTURE

In a previous study, we identified regions on the surface of tumor cel ls which act as acceptor sites for putrescine (Put) and studied the co mpetition between structural analogs of Put (N,N'-tetramethyl-alpha,om ega-diaminoalkanes) and Put bound to latex microspheres. A chain of fo ur to seven carbons was necessary for inhibition of Put-latex binding to the cell surface of human glioblastoma (U251) cells. We show here t hat under the experimental conditions, N,N'-tetramethyl-1,4-butanediam ine and N,N'-tetramethyl- 1,7-heptanediamine exhibit an antitumor effe ct. In a first step (I -48 h after treatment), cells exposed to these compounds show large intracellular vacuoles. We failed to detect any a cid phosphatase activity in these intracellular structures revealing t hat they were not lysosomes. Electron microscopy observations argue fo r the conclusion that these vacuoles are an hypertrophy of the endopla smic reticulum (ER) and/or of the Golgi vesicles. Our hypothesis is th at this typical effect of the analogs reveals that ER could be a physi ological target of endogenous polyamines. At a later stage (6 days aft er treatment), the cells undergo morphological and biochemical changes : thin and long expansions characterize the cells and the GFA protein is overexpressed. Correlated to both these effects, karyotypic modific ations are found in chromosomes 3 and 6. These changes evoke a differe ntiation of the treated cells. The work provides evidence that N-methy lated polyamine analogs taking the place of endogenous putrescine demo nstrate a hopeful antitumor effect.