O6-methylguanine as a modulator of antitumor activity of N-alkyl-N-nitrosoureas in vivo.
The effect of O6-methylguanine (O6-MeG) on the therapeutic efficiency of 1-methyl-1-nitrosourea (MNU) and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) against the murine L1210 leukemia and B16 melanoma was studied in vivo. Although the level of O6-alkylguanine-DNA alkyltransferase (AGT) in L1210/BCNU leukemia cells was three times higher than in L1210 leukemia cells, no enhancement of the antitumor activity of MNU and BCNU in L1210 leukemia or B16 melanoma with O6-MeG or MNU potentiated markedly the cytotoxic effects of MNU and BCNU. Administration of O6-MeG to mice bearing L1210 leukemia led to delayed inhibition of DNA synthesis and appearance of long-term single-strand breaks in DNA of tumor cells.
Gorbacheva
L B
LB
Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow.
Kukushkina
G V
GV
Elksne
S J
SJ
Miniker
T D
TD
Melnik SYa
Preobrazhenskaya
M N
MN
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004347:Drug Interactions; D004351:Drug Resistance; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009690:Nucleic Acid Conformation / Q000187:drug effects; D013997:Time Factors
D004273:DNA, Neoplasm; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine; D002330:Carmustine