Development of resistance to antitumor chloroethylnitrosoureas in vitro in brain tumor cells.
Rat brain tumor cell lines (9L, C6-1, C6-2), human brain tumor cells (T98G), and HeLa S3 cells were studied to assess their acquired resistance to the chloroethylnitrosoureas (CENUs), 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyr anosid e (MCNU), after 10 repeated exposures of a panel of different drug concentrations. Assay end-point was colony-forming ability after 24-h drug exposure. Intrinsic resistance was tested at the 10% survival dose (SD10) and C6-1, T98G, and HeLa S3 cell lines were 3 to 16 times more resistant to ACNU than 9L and C6-2 cell lines. After repeated exposures to ACNU, 9L and C6-2 cells acquired 2- and 5-fold resistance to ACNU respectively, whereas C6-1 and T98G cells retained a resistance almost equivalent to the respective parent cells. HeLa S3 cells also acquired resistance to ACNU, as evidenced by a 3.5-fold increase. The SD10 of the cells to MCNU ranged from 4.3 microM (C6-2 cells) to 151.7 microM (T98G cells). After long-term exposure to MCNU, all five cell lines became significantly resistant compared to their respective parent cells. The easily obtained acquired resistance to CENUs suggests a clinical disadvantage of continual and repeated adjuvant monochemotherapy with these agents.
Mineura
K
K
Neurosurgical Service, Akita University Hospital, Japan.
Ishiyama
Y
Y
Kowada
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006367:HeLa Cells; D006801:Humans; D015376:Nimustine / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D015376:Nimustine; C020766:ranimustine