Lethal and Kinetic Effects of AMSA in a Range of Human Tumour Cell Lines and its Value in Overcoming Induced Drug Resistance in a Series of Murine L5178Y Lymphoma Sublines in Vitro

Abstract

4’-(9-acridinylamino)methanesulfon-m-anisidide (AMSA), currently undergoing Phase II clinical trials, shows activity in childhood leukaemia. The drug’s lethal and kinetic effects were investigated in Syrian hamster ovary cells (NIL8) and a human neuroblastoma line (CHP100), Cytotoxicity increased exponentially with drug concentration and duration of exposure. Plateau-phase cells were significantly more resistant to AMSA than log-growing cells. Lethal effects of AMSA on synchronised cells showed no cell cycle specificity in contrast to adriamycin which kills cells predominantly in late S and G₂. Flow microfluorimetric analyses of asynchronous cells provided no evidence of delay or arrest in cell cycle progression by AMSA. To identify any value for AMSA in overcoming resistance to other antitumour drugs we screened (i) a range of in vitro selected resistant sublines of the murine L5178Y lymphoma and (ii) a series of human neuroblastoma, prostate, colon and breast tumour cell lines. AMSA proved effective against murine cells resistant to methotrexate, 5-fluorouracil, vincristine and cis-platinum but showed complete cross resistance with adriamycin. In contrast, no positive correlations were found with the human tumour cell lines where IC50 values varied 12-fold for a 24 hour exposure to AMSA. These studies provide evidence of differing responses to AMSA depending on the model system adopted for screening and caution against general extrapolation of data from a single test system.