Comparative cytotoxicity of carmustine (BCNU), nimustine (ACNU) and elmustine (HeCNU) after depletion of O6-alkylguanine-DNA alkyltransferase (O6-AGT).
BCNU was reported to have about a 6- to 8- fold lower cytotoxic potency than ACNU in cell lines naturally deficient in O6-AGT. In seven tumor cell lines with an O6-AGT activity ranging from 40 to 360 fmol/mg the cytotoxic potency of BCNU, ACNU and HeCNU, without and after O6-AGT depletion by O6-BG, was determined. Without O6-AGT depletion, BCNU was superior to both other drugs in tumor cells with high O6-AGT activity. After O6-AGT depletion, the cytotoxic potency (comparison of IC50 values) of ACNU was higher than that of BCNU (p=0.016) or that of HeCNU (p=0.016) in all tumor cell lines. We conclude that (without O6-AGT depletion) BCNU is the drug of choice especially in tumor cells with high transferase activity. The higher cytotoxic potency of ACNU after O6-AGT depletion as compared to BCNU after O6-AGT depletion is countered by the higher toxicity of ACNU in patients necessitating a clinical dose reduction as compared to BCNU. Thus, we would not expect superiority of ACNU + O6-BG over BCNU+ O6-BG after systemic administration.
Büch
T R
TR
German Cancer Research Center Heidelberg (DKFZ).
Zeller
W J
WJ
D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D002330:Carmustine / Q000633:toxicity; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015376:Nimustine / Q000633:toxicity; D009607:Nitrosourea Compounds / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000172:deficiency* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D009607:Nitrosourea Compounds; C064976:O(6)-benzylguanine; D015376:Nimustine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C013876:elmustine; D002330:Carmustine