GENOTOXIC AND CYTOTOXIC EFFECTS OF 4-AROYL-1-NITROSOHYDRAZINE-CARBOXAMIDES ON O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE-POSITIVE AND ALKYLTRANSFERASE-NEGATIVE HUMAN CELL-LINES

Five different representatives (I-V) of a new class of bifunctional al kylating agents, the 4-aroyl-1-nitrosohydrazinecarboxamides (''nitroso semicarbazides''), were evaluated for their potential interaction with DNA and for their cytotoxic activity in vitro to O-6-alkylguanine-DNA alkyltransferase-positive (Mer(+)) and -negative (Mer(-)) human cell lines. The HeLa MR cell line (Mer(-)) showed up to 20-fold higher sens itivity at IC50 (dose that inhibits colony formation by 50%) to agents I-V than did the HeLa S3 cell line (Mer(+)) in a colony-formation ass ay. These data were compared to those obtained by treatment of the two cell lines with carmustine, a currently used antitumor drug. In Mer() cells comparable results to those with carmustine were obtained with compounds III, IV and V; in Mer(-) cells compounds I and II showed ne arly the same effects as carmustine. Whether compounds I-V produce DNA strand breaks and/or DNA-protein cross-links was investigated using a n alkaline filter elution technique. In this assay all compounds produ ced DNA single-strand breaks; no correlation could be detected between the strand breakage frequency and cytostatic, mutagenic and antitumor activity.