Sensitivity of human neuroblastoma to activated dacarbazine: relationships between cell survival, methyltransferase activity and activation of adenovirus-5.

Early passage cultures of neuroblastoma cells were tested for (i) cellular sensitivity to the methylating agent 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC); (ii) ability to reactivate MTIC-damaged adenovirus (Mer+ phenotype); and (iii) methyltransferase activity. Seven of eight lines were resistant to MTIC. One line had an intermediate level of cellular resistance to MTIC, when compared with Mer+ and Mer- control lines. Methyltransferase activity of the neuroblastomas was intermediate between Mer+ and Mer- control. Unlike other methylation-resistant cell types, the neuroblastomas showed an initial decline in the MTIC dose-response profile for cell survival followed by a plateau at higher doses. In the virus reactivation assay (HCR), the slope (D0) of the virus survival curve at high MTIC doses for cells from three of 10 patients was similar to that of Mer- controls. The D0 for the remaining seven was also much less than for Mer+ controls. However, due to shoulders on the survival curves, all of the neuroblastomas could be classified as Mer+ at low levels of MTIC damage. Overall, the neuroblastoma cells appeared to form a new, though heterogeneous, methylation-resistant group, with cell survival not paralleled by methyltransferase activity or virus reactivation at high methylation levels.