INHIBITION OF TUMOR-CELL PROLIFERATION BY DEXAMETHASONE - P-31 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 culture d RIF-1 tumor cells following treatment with an antiproliferative ster oid, dexamethasone (DEX), After 48 h exposure to 4 mM DEX, acute cell viability was essentially unchanged: cells were 93+/-2% trypan blue ex cluding in both control and treated cultures (all values are mean+/-SD ). The fraction of actively proliferating cells in the S phase (as ind icated by incorporation of 5-bromodeoxyuridine) was only 4+/-3%, compa red 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, bu t 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 o f cell proliferation, DEX caused only a modest change in the P-31 NMR spectra of RIF-1 cells in vitro, The ratio bf phosphocreatine to nucle oside triphosphates (NTP) was 30% higher, on average, in treated than in control cells (n = 8, paired t-test, p<0.02), even when both treate d and control cell densities were low, The level of total phosphomonoe ster (relative to NTP) was lower at low cell density, but this was ind ependent of whether cells were growing rapidly (control low density) o r were growth inhibited by DEX, Neither the ratio of phosphocholine to NTP nor the intracellular pH was significantly different in DEX-treat ed cells.