Inhibition of tumor cell proliferation by dexamethasone: 31P NMR studies of RIF-1 fibrosarcoma cells perfused in vitro.
The impact on tumor cell metabolism of a substantial reduction in cell proliferation rate without acute cytotoxicity was examined in cultured RIF-1 tumor cells following treatment with an antiproliferative steroid, dexamethasone (DEX). After 48 h exposure to 4 mM DEX, acute cell viability was essentially unchanged: cells were 93 +/- 2% trypan blue excluding in both control and treated cultures (all values are mean +/- SD). The fraction of actively proliferating cells in the S phase (as indicated by incorporation of 5-bromodeoxyuridine) was only 4 +/- 3%, compared with 13 +/- 3% in age-matched control cultures (n =4, paired t-test: p < 0.004) and 23 +/- 7% at the beginning of the treatment. Three days of DEX treatment resulted in a limited increase in the level of apoptosis (programmed cell death): cells did not become rounded or detached, but the fraction expressing apoptotic DNA fragmentation (susceptible to nick end labeling by terminal deoxy-nucleotidyl transferase) was 15 +/- 7%, vs 2 +/- 1% in control cultures (p < 0.02). Despite a 75% inhibition of cell proliferation, DEX caused only a modest change in the 31P NMR spectra of RIF-1 cells in vitro. The ratio of phosphocreatine to nucleoside triphosphates (NTP) was 30% higher, on average, in treated than in control cells (n = 8, paired t-test, p < 0.02), even when both treated and control cell densities were low. The level of total phosphomonoester (relative to NTP) was lower at low cell density, but this was independent of whether cells were growing rapidly (control low density) or were growth inhibited by DEX. Neither the ratio of phosphocholine to NTP nor the intracellular pH was significantly different in DEX-treated cells.
Abraha
A
A
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shim
H
H
Wehrle
J P
JP
Glickson
J D
JD
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D010758:Phosphorus; D014407:Tumor Cells, Cultured
D010758:Phosphorus; D003907:Dexamethasone; D001973:Bromodeoxyuridine