Single amino acid (arginine) deprivation: rapid and selective death of cultured transformed and malignant cells.
The effects of arginine deprivation (-Arg) has been examined in 26 cell lines. Less than 10% of those with transformed or malignant phenotype survived for > 5 days, and many died more rapidly, notably leukaemic cells. Bivariate flow cytometry confirmed that vulnerable cell lines failed to move out of cell cycle into a quiescent state (G0), but reinitiated DNA synthesis. Many cells remained in S-phase, and/or had difficulty progressing through to G2 and M. Two tumour lines proved relatively 'resistant', A549 and MCF7. Although considerable cell loss occurred initially, both lines showed a 'cell cycle freeze', in which cells survived for > 10 days. These cells recovered their proliferative activity in +Arg medium, but behaved in the same manner to a second -Arg episode as they did to the first episode. In contrast, normal cells entered G0 and survived in -Arg medium for several weeks, with the majority of cells recovering with predictable kinetics in +Arg medium. In general, cells from a wide range of tumours and established lines die quickly in vitro following -Arg treatment, because of defective cell cycle checkpoint stringency, the efficacy of the treatment being most clearly demonstrated in co-cultures in which only the normal cells survived. The findings demonstrate a potentially simple, effective and non-genotoxic strategy for the treatment of a wide range of cancers.
Scott
L
L
Department of Cell Pathology, University of Aberdeen, MacRobert Building, 581 King Street, Aberdeen, AB24 5UA, UK.
Lamb
J
J
Smith
S
S
Wheatley
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D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000378:metabolism*; D002453:Cell Cycle; D002461:Cell Line, Transformed; D003470:Culture Media; D004173:Dipodomys; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008907:Mink; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D003470:Culture Media; D001120:Arginine