Cytotoxic and DNA-damaging effects of 1,2-bis(sulfonyl)hydrazines on human cells of the Mer+ and Mer- phenotype.
A series of 1,2-bis(sulfonyl)hydrazines with the capacity to function as alkylating agents have been evaluated for their toxicity towards Mer- HT29 and Mer- BE cells, and for their ability to produce DNA damage expressed as single-strand breaks and DNA interstrand cross-links. Compounds of this class with methylating potential showed a marked difference in their capacity to inhibit the growth of Mer- and Mer+ cells, being considerably more toxic to BE Mer- cells. Dose-dependent DNA single-strand breaks were induced by these agents, with the quantity of breaks produced in Mer- and Mer+ cells being essentially the same. Maintenance of these lesions did not appear to explain the differential in toxicity to BE and HT29 cells. A chloroethylating compound of this class was also more toxic to Mer- BE cells than to Mer+ HT29 cells, but the differential toxicity was considerably less than that of the methylating agents of the series. The chloroethylating agent did not produce measurable single-strand breaks of the DNA of treated cells, but caused more DNA interstrand cross-links in Mer- cells than in Mer+ cells. Thus, DNA interstrand cross-links may be at least in part responsible for the cell kill produced by this agent. The findings suggest that methylating and chloroethylating derivatives of the 1,2-bis(sulfonyl)hydrazine family have different biochemical determinants of their cytodestructive actions.
Pratviel
G
G
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Shyam
K
K
Sartorelli
A C
AC
D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D003110:Colonic Neoplasms; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010641:Phenotype; D013450:Sulfones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D006834:Hydrazines; D009363:Neoplasm Proteins; D013450:Sulfones; D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase