| Abstract: |
During treatment of HL-60 myeloid leukemia cells in culture with polar solvents or retinoic acid at a concentration inducing terminal maturation in 90-95% of the cells, there is a rapid decline (within 2 h) in the V(max) for influx of the folate analogue, [3H]methotrexate. Following 24 h of exposure to these agents, there is no effect on growth, but influx V(max) is reduced by 70%. After 7 days of exposure, influx V(max) is reduced 90-95%. A similar time course was seen for the reduction in intracellular levels of dihydrofolate reductase, a marker of cellular proliferation. Both the extent of terminal maturation (as determined by the extent of nitro blue tetrazolium reduction) and decrease in influx showed the same dependence on the concentration of inducer. In contrast to the effect seen on influx V(max), both influx K(m) and mediated efflux of [3H]methotrexate remained unchanged in HL-60 cells exposed to inducers of maturation. Finally, evidence is presented for the coupling of this alteration on [3H]methotrexate influx with commitment of HL-60 cells to terminal maturation. This evidence shows that the effect on folate analogue influx precedes commitment and documents the irreversible nature of the reduction in influx once the majority of the cells exposed to inducer were committed to the process of maturation. The possible relevance of these results to the process of neoplastic transformation is discussed. |
| Keywords: |
human cell; drug efficacy; methotrexate; cells, cultured; cell line; cell differentiation; in vitro study; carcinogenesis; lymphatic system; kinetics; leukemia cell; folic acid; radioisotope; dihydrofolate reductase; retinoic acid; aminopterin; pharmacokinetics; mathematics; dose time effect relation; tretinoin; biological transport, active; cell strain hl 60; leukemia, myelocytic, acute; hexamethylenebisacetamide; acetamides; human; priority journal; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; methotrexate h 3; aminopterin h 3; inulin c 14
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