Enhancement of 1,3-bis(2-chloroethyl)-1-nitrosourea resistance by gamma-irradiation or drug pretreatment in rat hepatoma cells
- Institut Gustave Roussy, Villejuif (France)
Treatment of rat hepatoma cells (H4 cells) with various DNA-damaging agents increases the number of O6-methylguanine-DNA-methyltransferase (transferase) molecules per cell. Because the cellular resistance to chloroethylnitrosoureas depends on the number of transferase molecules, we studied the influence of pretreatment with gamma-irradiation, cis-dichlorodiammineplatinum(II), or 2-methyl-9-hydroxyellipticinium on the sensitivity of H4 cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The BCNU resistance depends on the gamma-ray dose and increases with time after irradiation: it is maximum when the drug is added 48 h after irradiation, which corresponds to the maximum enhancement of the transferase activity in the cells. Pretreatment with a single dose of cis-dichlorodiammineplatinum(II) or 2-methyl-9-hydroxyellipticinium also increases the cellular resistance to BCNU. This resistance is not due to a modification of the alkylation of the cellular DNA in the pretreated cells but is related to the increased transferase activity, as it is no longer observed when this activity is depleted by incubating the pretreated cells with the free base O6-methylguanine before BCNU treatment. These results suggest that tumor cells surviving after gamma-irradiation or drug treatment may become resistant to chemotherapy with chloroethylnitrosoureas.
- OSTI ID:
- 5836715
- Journal Information:
- Cancer Research; (USA), Vol. 51:4; ISSN 0008-5472
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTINEOPLASTIC DRUGS
BIOLOGICAL EFFECTS
NITROSOUREAS
TOXICITY
TUMOR CELLS
SENSITIVITY
BIOLOGICAL RADIATION EFFECTS
DNA
DOSE-RESPONSE RELATIONSHIPS
GAMMA RADIATION
METHYL TRANSFERASES
RATS
TIME DEPENDENCE
ANIMAL CELLS
ANIMALS
DRUGS
ELECTROMAGNETIC RADIATION
ENZYMES
IONIZING RADIATIONS
MAMMALS
NITROSO COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
RADIATION EFFECTS
RADIATIONS
RODENTS
TRANSFERASES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
560120 - Radiation Effects on Biochemicals
Cells
& Tissue Culture