Characterization of a CHO cell line resistant to killing by the hypoxic cell cytotoxin SR 4233.
One approach to understanding the mechanism of selective hypoxic cell killing by the benzotriazine-di-N-oxide, SR 4233, is to characterize cell lines that exhibit increased resistance to killing by this drug. The Chinese Hamster Ovary cell line BL-10 was originally isolated on the basis of its hypersensitivity to killing by bleomycin. It is 2.7-fold more resistant to hypoxic cell killing by SR 4233 than wild-type CHO on comparison of D0's. However, both BL-10 and CHO possess the same sensitivity to killing by SR 4233 under aerobic conditions. We have excluded the explanation that differential metabolism of SR 4233 is responsible for its increased survival as both BL-10 and CHO produce the two-electron product SR 4317 at the same rate (3 nmoles/hr/10(6) cells). Analysis of free radical production, DNA double-strand break induction, and glutathione (GSH) levels suggested that the resistance of BL-10 to killing by SR 4233 might result from increased intracellular radical scavenger pathways. Using buthionine sulfoximine (BSO) to decrease cellular GSH levels, we found a marked increase in the sensitivity of BL-10 cells to SR 4233 killing under hypoxia, but a much smaller increase in the sensitivity of CHO cells. Taken together, these data imply that the high GSH levels in BL-10 cells is responsible for its resistance to SR 4233 cytotoxicity.
Giaccia
A J
AJ
Department of Radiation Oncology, Stanford University School of Medicine, CA 94305.
Biedermann
K A
KA
Tosto
L M
LM
Minchinton
A I
AI
Kovacs
M S
MS
Brown
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005609:Free Radicals; D005978:Glutathione / Q000502:physiology; D011355:Prodrugs / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005609:Free Radicals; D011355:Prodrugs; D014227:Triazines; D000077704:Tirapazamine; D004247:DNA; D005978:Glutathione