Reduced thiol content in L1210 cells treated with BSO increases DNA crosslinking by melphalan

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Abstract

Endogenous thiols such as glutathione (GSH) are known to mediate the activity of bifunctional alkylating agents such as melphalan (L-PAM). GSH levels can be reduced by cell growth in the presence of an analog of gamma glutamyl, α-aminobutyrate, L-buthionine (S/R) sulfoximine (L-BSO). L-1210 murine lymphocytic leukemia cells grown in vitro in the presence of 10 μM < 15% L-BSO possessed 1% of the normal GSH levels. This pretreatment regimen did not significantly alter cell viability but did enhance the cytotoxicity produced by a 15 μM-1hr L-PAM treatment. The increased cell killing correlated with enhanced DNA-DNA crosslinking immediately following L-PAM exposure. No effect of BSO pretreatments on the incomplete removal of crosslinks over 36 hr of observation was seen. These results suggest that GSH levels modulate the initial degree of L-PAM-induced DNA crosslinking, but not the long term repair of these lesions.

Original languageEnglish (US)
Pages (from-to)47-52
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume144
Issue number1
DOIs
StatePublished - Apr 14 1987

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Melphalan
Sulfhydryl Compounds
Crosslinking
DNA
Cells
Aminobutyrates
Lymphoid Leukemia
Alkylating Agents
Cell growth
Cytotoxicity
Glutathione
Cell Survival
Repair
Observation
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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title = "Reduced thiol content in L1210 cells treated with BSO increases DNA crosslinking by melphalan",
abstract = "Endogenous thiols such as glutathione (GSH) are known to mediate the activity of bifunctional alkylating agents such as melphalan (L-PAM). GSH levels can be reduced by cell growth in the presence of an analog of gamma glutamyl, α-aminobutyrate, L-buthionine (S/R) sulfoximine (L-BSO). L-1210 murine lymphocytic leukemia cells grown in vitro in the presence of 10 μM < 15{\%} L-BSO possessed 1{\%} of the normal GSH levels. This pretreatment regimen did not significantly alter cell viability but did enhance the cytotoxicity produced by a 15 μM-1hr L-PAM treatment. The increased cell killing correlated with enhanced DNA-DNA crosslinking immediately following L-PAM exposure. No effect of BSO pretreatments on the incomplete removal of crosslinks over 36 hr of observation was seen. These results suggest that GSH levels modulate the initial degree of L-PAM-induced DNA crosslinking, but not the long term repair of these lesions.",
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T1 - Reduced thiol content in L1210 cells treated with BSO increases DNA crosslinking by melphalan

AU - Dorr, Robert T

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N2 - Endogenous thiols such as glutathione (GSH) are known to mediate the activity of bifunctional alkylating agents such as melphalan (L-PAM). GSH levels can be reduced by cell growth in the presence of an analog of gamma glutamyl, α-aminobutyrate, L-buthionine (S/R) sulfoximine (L-BSO). L-1210 murine lymphocytic leukemia cells grown in vitro in the presence of 10 μM < 15% L-BSO possessed 1% of the normal GSH levels. This pretreatment regimen did not significantly alter cell viability but did enhance the cytotoxicity produced by a 15 μM-1hr L-PAM treatment. The increased cell killing correlated with enhanced DNA-DNA crosslinking immediately following L-PAM exposure. No effect of BSO pretreatments on the incomplete removal of crosslinks over 36 hr of observation was seen. These results suggest that GSH levels modulate the initial degree of L-PAM-induced DNA crosslinking, but not the long term repair of these lesions.

AB - Endogenous thiols such as glutathione (GSH) are known to mediate the activity of bifunctional alkylating agents such as melphalan (L-PAM). GSH levels can be reduced by cell growth in the presence of an analog of gamma glutamyl, α-aminobutyrate, L-buthionine (S/R) sulfoximine (L-BSO). L-1210 murine lymphocytic leukemia cells grown in vitro in the presence of 10 μM < 15% L-BSO possessed 1% of the normal GSH levels. This pretreatment regimen did not significantly alter cell viability but did enhance the cytotoxicity produced by a 15 μM-1hr L-PAM treatment. The increased cell killing correlated with enhanced DNA-DNA crosslinking immediately following L-PAM exposure. No effect of BSO pretreatments on the incomplete removal of crosslinks over 36 hr of observation was seen. These results suggest that GSH levels modulate the initial degree of L-PAM-induced DNA crosslinking, but not the long term repair of these lesions.

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