Selective cytotoxicity of L-glutamic acid gamma-monohydroxamate (GAH) for melanoma tumor cells.
We have previously shown that L-glutamic acid gamma-monohydroxamate (GAH) exhibits an antitumor activity, both in vitro and in vivo. In this report we explore the selective cytotoxicity of GAH in vitro by comparing the survival of tumor and normal cells. GAH exerts an irreversible delayed effect with tumoral cells and a reversible effect with normal cells: after a short incubation time of 6 hrs in the presence of 1.2 mM GAH and after removal of the drug, the survival of N Ter Dau and MRC5 cells was identical reaching about 85% after 24 hrs of culture. But, after another 48 hrs of culture, MRC5 cells recovered 100% cell survival while with N Ter Dau cells the survival decreased to 65%. A longer exposure time to GAH (18 hrs) and an additional 54 hrs of culture after removal of GAH led to 50 +/- 10% of cell survival with normal cells but only 25 +/- 10% with tumor cells. Using a long-term clonogenic assay, we showed that the 25% N Ter Dau cells surviving at 72 hrs after GAH treatment led mainly to abortive colonies (17% +/- 3%) with only 2.3 +/- 0.9% of surviving colonies. Such a difference does not exist for normal cells. Cell cycle analysis of tumor and normal cells treated with GAH (18 hrs, 1,2 mM) has shown that the drug prevents both cell type from cycling from G1 to S phase. However, the two cell types started to cycle again after removal of GAH but a delay of 24 hrs was observed for tumoral cells compared to normal cells.
Thomasset
N
N
INSERM U 218, Centre Léon Bérand, Lyon, France.
Chabanas
A
A
Tournaire
R
R
Malley
S
S
Navarro
C
C
Lawrence
J J
JJ
Doré
J F
JF
Vila
J
J
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D005971:Glutamates; D006877:Hydroxamic Acids; C050614:glutamate-gamma-hydroxamic acid