Cell cycle events associated with the termination of proliferation by cytotoxic and differentiation-inducing actions of 6-thioguanine on HL-60 cells

Edward L. Schwartz, O. C. Blair, A. C. Sartorelli

Research output: Contribution to journalArticle

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Abstract

Delayed growth arrest was observed in HL-60 acute promyelocytic leukemia cells after exposure to 6-thioguanine (TG). This growth arrest occurred in both wild-type HL-60 cells exposed to 2 μM TG and an HL-60 clone lacking hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity at a 500-fold higher concentration of drug. Both cell lines continued replication during an initial 4-day period of exposure to TG; however, upon removal of the purine antimetabolite and reincubation in fresh medium in the absence of drug, no further increase in cell number was observed over the next 4 days. Extensive differentiation, as measured by the reduction of nitroblue tetrazolium, occurred in TG-treated, HL-60 HGPRT-negative cells, whereas no significant increase in the number of nitroblue tetrazolium-positive cells was observed in wild-type HL-60 cells exposed to the purinethiol. Thus, termination of proliferation in wild-type cells appeared to be an expression of cytotoxicity, while in the HGPRT-negative clone, cell replication was apparently terminated by conversion of cells to end-stage forms with a mature phenotype. In support of this conclusion, differences occurred in the stage of the cell cycle arrest, determined on Day 6 after exposure to TG. Approximately 85% of parental HL-60 cells treated with TG were present in the S and G2 + M phases of the cell cycle, with the greatest proportional change from untreated controls being in the G2-M phase (i.e., a 63% increase over untreated controls). In contrast, HL-60 HGPRT-negative cells treated with TG accumulated in G1, with 68% of the population located in this phase (i.e., an 80% increase compared to controls), as might be expected for a differentiated population. Dimethyl sulfoxide, which produced differentiation in both parental HL-60 and HL-60 HGPRT-negative cells, was used as a positive control. Both cell lines responded identically to dimethyl sulfoxide, with growth arrest being due at least in part to differentiation, which corresponded to an increase in G1 cells.

Original languageEnglish (US)
Pages (from-to)3907-3910
Number of pages4
JournalCancer Research
Volume44
Issue number9
StatePublished - 1984
Externally publishedYes

Fingerprint

Thioguanine
HL-60 Cells
Cell Cycle
Hypoxanthine Phosphoribosyltransferase
Nitroblue Tetrazolium
G2 Phase
Dimethyl Sulfoxide
Cell Division
Growth
Clone Cells
Antimetabolites
Cell Line
Acute Promyelocytic Leukemia
Cell Cycle Checkpoints
Pharmaceutical Preparations
Population
Cell Count
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cell cycle events associated with the termination of proliferation by cytotoxic and differentiation-inducing actions of 6-thioguanine on HL-60 cells. / Schwartz, Edward L.; Blair, O. C.; Sartorelli, A. C.

In: Cancer Research, Vol. 44, No. 9, 1984, p. 3907-3910.

Research output: Contribution to journalArticle

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title = "Cell cycle events associated with the termination of proliferation by cytotoxic and differentiation-inducing actions of 6-thioguanine on HL-60 cells",
abstract = "Delayed growth arrest was observed in HL-60 acute promyelocytic leukemia cells after exposure to 6-thioguanine (TG). This growth arrest occurred in both wild-type HL-60 cells exposed to 2 μM TG and an HL-60 clone lacking hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity at a 500-fold higher concentration of drug. Both cell lines continued replication during an initial 4-day period of exposure to TG; however, upon removal of the purine antimetabolite and reincubation in fresh medium in the absence of drug, no further increase in cell number was observed over the next 4 days. Extensive differentiation, as measured by the reduction of nitroblue tetrazolium, occurred in TG-treated, HL-60 HGPRT-negative cells, whereas no significant increase in the number of nitroblue tetrazolium-positive cells was observed in wild-type HL-60 cells exposed to the purinethiol. Thus, termination of proliferation in wild-type cells appeared to be an expression of cytotoxicity, while in the HGPRT-negative clone, cell replication was apparently terminated by conversion of cells to end-stage forms with a mature phenotype. In support of this conclusion, differences occurred in the stage of the cell cycle arrest, determined on Day 6 after exposure to TG. Approximately 85{\%} of parental HL-60 cells treated with TG were present in the S and G2 + M phases of the cell cycle, with the greatest proportional change from untreated controls being in the G2-M phase (i.e., a 63{\%} increase over untreated controls). In contrast, HL-60 HGPRT-negative cells treated with TG accumulated in G1, with 68{\%} of the population located in this phase (i.e., an 80{\%} increase compared to controls), as might be expected for a differentiated population. Dimethyl sulfoxide, which produced differentiation in both parental HL-60 and HL-60 HGPRT-negative cells, was used as a positive control. Both cell lines responded identically to dimethyl sulfoxide, with growth arrest being due at least in part to differentiation, which corresponded to an increase in G1 cells.",
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