TY - JOUR
T1 - Modulation of 6-Thioguanine Activity by Guanine in Human Promyelocytic Leukemia HL-60 Cells1
AU - Cheng, Hui Wen
AU - Armstrong, R. Douglas
AU - Sadae, Wolfgang
PY - 1988
Y1 - 1988
N2 - The effects of guanine coadministration on the metabolism and biological activity of 6-thioguanine (6-TG) were studied in human promyelocytic leukemia cells (HL-60). Cell growth, cytotoxicity (cloning assay), and cell differentiation were measured, along with nucleotide metabolism. Guanine was efficiently salvaged by HL-60 cells; at 200 μM,guanine suppressed the formation of 6-TG mononucleotides and abolished 6-TG incorporation into nucleic acids. Similarly, guanine antagonized 6-TG cytotoxicity in a dose dependent fashion. Furthermore, guanine (200 μM)fully suppressed the 6-TG (10 μm)induced HL-60 cell differentiation, which suggests that cell differentiation at pharmacological 6-TG concentrations is dependent on the anabolism of the drug to active nucleotides. 6-TG given alone reduced GTP levels and DNA synthesis rates in HL-60 cells, while a major intracellular 6-TG metabolite, 6-thioguanosine 5’-monophosphate, accumulated to high levels (~100 μm).It is suggested that accumulation of 6-thioguanosine 5’ -monophosphate and a resultant partial block of the de novo biosynthesis of guanine nucleotides is responsible for 6-TG induced cell differentiation in HL-60 cells.
AB - The effects of guanine coadministration on the metabolism and biological activity of 6-thioguanine (6-TG) were studied in human promyelocytic leukemia cells (HL-60). Cell growth, cytotoxicity (cloning assay), and cell differentiation were measured, along with nucleotide metabolism. Guanine was efficiently salvaged by HL-60 cells; at 200 μM,guanine suppressed the formation of 6-TG mononucleotides and abolished 6-TG incorporation into nucleic acids. Similarly, guanine antagonized 6-TG cytotoxicity in a dose dependent fashion. Furthermore, guanine (200 μM)fully suppressed the 6-TG (10 μm)induced HL-60 cell differentiation, which suggests that cell differentiation at pharmacological 6-TG concentrations is dependent on the anabolism of the drug to active nucleotides. 6-TG given alone reduced GTP levels and DNA synthesis rates in HL-60 cells, while a major intracellular 6-TG metabolite, 6-thioguanosine 5’-monophosphate, accumulated to high levels (~100 μm).It is suggested that accumulation of 6-thioguanosine 5’ -monophosphate and a resultant partial block of the de novo biosynthesis of guanine nucleotides is responsible for 6-TG induced cell differentiation in HL-60 cells.
UR - http://www.scopus.com/inward/record.url?scp=0023766006&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0023766006&partnerID=8YFLogxK
M3 - Article
C2 - 3163939
AN - SCOPUS:0023766006
SN - 0008-5472
VL - 48
SP - 3648
EP - 3651
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -
