Cross-resistance pattern in brain tumour cells resistant to antitumour chloroethylnitrosoureas

We tested acquired resistance and cross-resistance of brain tumour cells after repeated treatments of antitumour agents including chloroethylnitrosoureas (CENUs) in clinical use for brain tumour chemotherapy. Within ten repeated 2-day incubation periods with either 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) or methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyr anoside (MCNU), brain tumour cells (9L) developed high degrees of resistance to these drugs, as evidenced by about 3- and 6-fold increases, respectively, at the 10% survival dose (SD10). The resistance has unchanged with time after termination of challenging treatments. Repeated challenges with bleomycin (BLM), cis-diaminedichloroplatinum (II) (CDDP), and methotrexate (MTX) did not develop a significant resistance. ACNU-resistant (9L/ACNU) cells showed complete cross-resistance to MCNU, and MCNU-resistant (9L/MCNU) cells to ACNU. Drug sensitivity to other DNA-damaging agents (BLM, NCS, CDDP, etoposide) than CENUs fluctuated to a lesser extent among 9L parent, 9L/ACNU, and 9L/MCNU cells. These data suggest clinical disadvantage of prolonged adjuvant CENU chemotherapy and advantage of combined CENU chemotherapy with other agents than CENUs in brain tumours.