This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Habraken, Y. Articles by Laval, F. Search for Related Content PubMed PubMed Citation Articles by Habraken, Y. Articles by Laval, F.

Enhancement of 1,3-Bis(2-chloroethyl)-1-nitrosourea Resistance by -Irradiation or Drug Pretreatment in Rat Hepatoma Cells¹

Groupe "Radiochimie de l'ADN," Unité 247 INSERM, Institut Gustave Roussy, 94805 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 -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 -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 -irradiation or drug treatment may become resistant to chemotherapy with chloroethylnitrosoureas.

¹ This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale and from the Association pour la Recherche sur le Cancer (Villejuif). Y. H. was the recipient of a fellowship from the European Science Foundation.

² To whom requests for reprints should be addressed.

Received 6/18/90. Accepted 11/30/90.