Enhancement of 1,3-bis(2-chloroethyl)-1-nitrosourea resistance by γ-irradiation of drug pretreatment in rat hepatoma cells

• Published in: Cancer research (Chicago, Ill.) Vol. 51; no. 4; pp. 1217 - 1220
• Main Authors: HABRAKEN, Y, LAVAL, F
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.1991
• Subjects: 560120 - Radiation Effects on Biochemicals, Cells, & Tissue Culture; 560300 - Chemicals Metabolism & Toxicology; ANIMAL CELLS; ANIMALS; Antineoplastic agents; Antineoplastic Agents - pharmacology; ANTINEOPLASTIC DRUGS; Biological and medical sciences; BIOLOGICAL EFFECTS; BIOLOGICAL RADIATION EFFECTS; Carcinoma, Hepatocellular - therapy; Carmustine - pharmacology; Cisplatin - pharmacology; Combined Modality Therapy; DNA; Dose-Response Relationship, Radiation; DOSE-RESPONSE RELATIONSHIPS; Drug Resistance - radiation effects; Drug Synergism; DRUGS; ELECTROMAGNETIC RADIATION; Ellipticines - pharmacology; ENZYMES; GAMMA RADIATION; Gamma Rays; General aspects; IONIZING RADIATIONS; Liver Neoplasms - therapy; MAMMALS; Medical sciences; METHYL TRANSFERASES; Methyltransferases - biosynthesis; NITROSO COMPOUNDS; NITROSOUREAS; NUCLEIC ACIDS; O-Methylguanine-DNA Methyltransferase; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; Pharmacology. Drug treatments; RADIATION EFFECTS; RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT; RADIATIONS; RATS; RODENTS; SENSITIVITY; TIME DEPENDENCE; Time Factors; TOXICITY; TRANSFERASES; TUMOR CELLS; Tumor Cells, Cultured; VERTEBRATES; Antineoplastic agent; Cell culture; Rat; Enzyme; Nitrosoureas; Methylated-DNA-protein-cysteine methyltransferase; Rodentia; In vitro; Resistance; Vertebrata; Alkylating agent; Gamma irradiation; Ionizing irradiation; Mammalia; Enzymatic activity; Liver cell carcinoma; Tumor; Tumor cell
• ISSN: 0008-5472; 1538-7445

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.