Genotoxic and cytotoxic effects of 4-aroyl-1-nitrosohydrazine-carboxamides on O6-alkylguanine-DNA alkyltransferase-positive and -negative human cell lines.
Five different representatives (I-V) of a new class of bifunctional alkylating agents, the 4-aroyl-1-nitrosohydrazinecarboxamides ("nitrososemicarbazides"), were evaluated for their potential interaction with DNA and for their cytotoxic activity in vitro to O6-alkylguanine-DNA alkyltransferase-positive (Mer+) and -negative (Mer-) human cell lines. The HeLa MR cell line (Mer-) showed up to 20-fold higher sensitivity 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 assay. 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 nearly the same effects as carmustine. Whether compounds I-V produce DNA strand breaks and/or DNA-protein cross-links was investigated using an alkaline filter elution technique. In this assay all compounds produced DNA single-strand breaks; no correlation could be detected between the strand breakage frequency and cytostatic, mutagenic and antitumor activity.
Schell
C
C
Institute of Hygiene and Occupational Medicine, University Medical Center, Essen, Germany.
Lantermann
O
O
Popp
W
W
Vahrenholz
C
C
Thomale
J
J
Gugova
R
R
Golovinsky
E
E
Norpoth
K
K
D002330:Carmustine / Q000633:toxicity; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D009152:Mutagenicity Tests; D009603:Nitroso Compounds / Q000633:toxicity*; D009607:Nitrosourea Compounds / Q000737:chemistry / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D012663:Semicarbazides / Q000633:toxicity*; D014410:Tumor Stem Cell Assay
D009603:Nitroso Compounds; D009607:Nitrosourea Compounds; D012663:Semicarbazides; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine