Radiosensitizing and cytotoxic effects of nitroimidazoles in CHO cells expressing elevated levels of glutathione-S-transferase.
A cell line, CHO-Chlr, which has elevated levels of glutathione-S-transferase (GST), is resistant to damage caused by bi-functional nitrogen mustards. This cell line has a similar radiation sensitivity to and value of oxygen enhancement ratio as the wild type cells, CHO-K1, from which the mutant line was derived. Hypoxic cell radiosensitizing efficiencies for misonidazole, etanidazole (SR2508), and pimonidazole (R0 03-8799) are similar in both cell lines with values for C1.6 of 0.5, 0.75, and 0.08 mmol dm-3 for each drug respectively. In contrast, for RSU 1069 the sensitizing efficiency is lower in the cell line showing elevated levels of GST. The hypoxic toxicity of RSU 1069 and misonidazole is similar in each cell line, whereas in air, toxicity is 2 fold less in the CHO-Chlr cells. These results suggest that reaction of the alkylating aziridine part of RSU 1069 contributes to the high sensitizing efficiency of this drug. This is likely to be a consequence of either binding of the sensitizing moiety at the target site (ie, increased local concentration or induction of sub-lethal damage that is only expressed on subsequent irradiation.
Stratford
I J
IJ
MRC Radiobiology Unit, Didcot, Oxon, U.K.
Hickson
I D
ID
Robson
C N
CN
Stephens
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D006224:Cricetinae; D017341:Etanidazole; D005982:Glutathione Transferase / Q000378:metabolism*; D008558:Melphalan / Q000494:pharmacology; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C033815:pimonidazole; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D005982:Glutathione Transferase; D008558:Melphalan; D010100:Oxygen