Cell Cycle Control Processes Determine Cytostasis or Cytotoxicity in Thymineless Death of Colon Cancer Cells

Janet A. Houghton, Franklin G. Harwood, Peter J Houghton

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Thymidylate synthase (TS) is a target of critical importance to the survival of human colon cancer cells since, upon inhibition, cells subsequently undergo thymineless death induced by dTTP deficiency. Using genetically marked mutants deficient in TS (TS~) and a derived population (Thy4) that is resistant to commitment to thymineless death, resistance was conferred by the ability of cells to arrest at a point either in late G1 or at the onset of S induced by d Thd deprivation. Thus, Thy4 cells initially synchronized in G0 by leucine deprivation and released in the absence of d Thd remained viable at 5 days, demonstrated delayed onset of nucleosomal ladder formation, and retained clonogenic potential (cytostatic response). In contrast, TS~ and asynchronous Thy4 cells lost 50% clonogenic potential in 65 h and >90% in 5 days (cytotoxic response). [3H]DNA precursor studies indicated failure of synchronized Thy4 but not TS~ cells to progress through S, with arrest of Thy4 close to the G1/S boundary. Cell cycle control processes including: (a) the locus of dThd deprivation in G1; and (b) a potential checkpoint close to the G1/S border, may dictate whether consequences of dThd or dTTP restriction become cytostatic or cytotoxic.

Original languageEnglish (US)
Pages (from-to)4967-4973
Number of pages7
JournalCancer Research
Volume54
Issue number18
StatePublished - Jan 1 1994
Externally publishedYes

Fingerprint

Thymidylate Synthase
Cell Cycle Checkpoints
Colonic Neoplasms
Cytostatic Agents
Leucine
Survival
DNA
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cell Cycle Control Processes Determine Cytostasis or Cytotoxicity in Thymineless Death of Colon Cancer Cells. / Houghton, Janet A.; Harwood, Franklin G.; Houghton, Peter J.

In: Cancer Research, Vol. 54, No. 18, 01.01.1994, p. 4967-4973.

Research output: Contribution to journalArticle

@article{39bc98197ac24e889b9af47a375952fd,
title = "Cell Cycle Control Processes Determine Cytostasis or Cytotoxicity in Thymineless Death of Colon Cancer Cells",
abstract = "Thymidylate synthase (TS) is a target of critical importance to the survival of human colon cancer cells since, upon inhibition, cells subsequently undergo thymineless death induced by dTTP deficiency. Using genetically marked mutants deficient in TS (TS~) and a derived population (Thy4) that is resistant to commitment to thymineless death, resistance was conferred by the ability of cells to arrest at a point either in late G1 or at the onset of S induced by d Thd deprivation. Thus, Thy4 cells initially synchronized in G0 by leucine deprivation and released in the absence of d Thd remained viable at 5 days, demonstrated delayed onset of nucleosomal ladder formation, and retained clonogenic potential (cytostatic response). In contrast, TS~ and asynchronous Thy4 cells lost 50{\%} clonogenic potential in 65 h and >90{\%} in 5 days (cytotoxic response). [3H]DNA precursor studies indicated failure of synchronized Thy4 but not TS~ cells to progress through S, with arrest of Thy4 close to the G1/S boundary. Cell cycle control processes including: (a) the locus of dThd deprivation in G1; and (b) a potential checkpoint close to the G1/S border, may dictate whether consequences of dThd or dTTP restriction become cytostatic or cytotoxic.",
author = "Houghton, {Janet A.} and Harwood, {Franklin G.} and Houghton, {Peter J}",
year = "1994",
month = "1",
day = "1",
language = "English (US)",
volume = "54",
pages = "4967--4973",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Cell Cycle Control Processes Determine Cytostasis or Cytotoxicity in Thymineless Death of Colon Cancer Cells

AU - Houghton, Janet A.

AU - Harwood, Franklin G.

AU - Houghton, Peter J

PY - 1994/1/1

Y1 - 1994/1/1

N2 - Thymidylate synthase (TS) is a target of critical importance to the survival of human colon cancer cells since, upon inhibition, cells subsequently undergo thymineless death induced by dTTP deficiency. Using genetically marked mutants deficient in TS (TS~) and a derived population (Thy4) that is resistant to commitment to thymineless death, resistance was conferred by the ability of cells to arrest at a point either in late G1 or at the onset of S induced by d Thd deprivation. Thus, Thy4 cells initially synchronized in G0 by leucine deprivation and released in the absence of d Thd remained viable at 5 days, demonstrated delayed onset of nucleosomal ladder formation, and retained clonogenic potential (cytostatic response). In contrast, TS~ and asynchronous Thy4 cells lost 50% clonogenic potential in 65 h and >90% in 5 days (cytotoxic response). [3H]DNA precursor studies indicated failure of synchronized Thy4 but not TS~ cells to progress through S, with arrest of Thy4 close to the G1/S boundary. Cell cycle control processes including: (a) the locus of dThd deprivation in G1; and (b) a potential checkpoint close to the G1/S border, may dictate whether consequences of dThd or dTTP restriction become cytostatic or cytotoxic.

AB - Thymidylate synthase (TS) is a target of critical importance to the survival of human colon cancer cells since, upon inhibition, cells subsequently undergo thymineless death induced by dTTP deficiency. Using genetically marked mutants deficient in TS (TS~) and a derived population (Thy4) that is resistant to commitment to thymineless death, resistance was conferred by the ability of cells to arrest at a point either in late G1 or at the onset of S induced by d Thd deprivation. Thus, Thy4 cells initially synchronized in G0 by leucine deprivation and released in the absence of d Thd remained viable at 5 days, demonstrated delayed onset of nucleosomal ladder formation, and retained clonogenic potential (cytostatic response). In contrast, TS~ and asynchronous Thy4 cells lost 50% clonogenic potential in 65 h and >90% in 5 days (cytotoxic response). [3H]DNA precursor studies indicated failure of synchronized Thy4 but not TS~ cells to progress through S, with arrest of Thy4 close to the G1/S boundary. Cell cycle control processes including: (a) the locus of dThd deprivation in G1; and (b) a potential checkpoint close to the G1/S border, may dictate whether consequences of dThd or dTTP restriction become cytostatic or cytotoxic.

UR - http://www.scopus.com/inward/record.url?scp=0028001422&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028001422&partnerID=8YFLogxK

M3 - Article

VL - 54

SP - 4967

EP - 4973

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -