Cross-sensitivity of methylating agents, hydroxyurea, and methotrexate in human tumor cells of the Mer- phenotype.

Five human tumor cell lines of the Mer- phenotype sensitive to killing by the methylating agent 5-(3-methyl-1-triazeno)imidazole-4-carboxamide were sensitive to hydroxyurea (HU) compared with 15 cell lines resistant to methylating agents (Mer+ phenotype). In a study using fewer cell lines, Mer- cells were also sensitive to methotrexate but not to seven other agents including the antimetabolites 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil. Cells sensitive to HU were designated the Hu- phenotype. Five autologous Mer+ lines, derived in vitro by treating Mer- lines with methylating agents, did not become resistant to HU or methotrexate (Mer+ Hu- phenotype). All Mer+ lines studied had enhanced ability to reactive methylated adenovirus. Adenovirus was inactivated by prolonged treatment with HU, but no enhanced reactivation of HU-treated virus was found in Mer+ cell lines. Cell survival after 5-(3-methyl-1-triazeno)imidazole-4-carboxamide treatment was not significantly decreased by HU, nor was replication of methylated adenovirus inhibited by HU in Mer- or Mer+ lines. Replication of untreated adenovirus was poor in Mer- cells treated with HU, indicating that sensitivity of cells to HU was associated with inhibition of DNA synthesis. These results suggest that cell sensitivity to deoxynucleotide depletion is linked, perhaps coincidentally, to the Mer- phenotype. The retention of HU and methotrexate sensitivity by cells after development of resistance to 5-(3-methyl-1-triazeno)imidazole-4-carboxamide may have therapeutic implications.