[Modulation of the antitumor activity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosoure a by O(6)-methyl-2'-deoxyguanosine--a new inhibitor of O(6)-alkylguanine-DNA-alkyltransferase].
O6-Methyl-2'-deoxyguanosine (O6-MedG), a novel inhibitor of O6-alkylguanine-DNA alkyltransferase (O6-AGT), has been synthesized. The ability of O6-MedG to deplete the O6-AGT activity in leukemia L1210 and melanoma B16 cells in vivo has been studied. After intraperitoneal administration of O6-MedG to mice bearing leukemia L1210 or melanoma B16, the activity of O6-AGT in tumour cells decreased by 50%. Pretreatment of leukemia L1210 bearing mice with O6-MedG (200 mg/kg) 24 hours prior to ACNU (15 mg/kg) administration resulted in six out of seven 60-day survivors. Treatment of mice with ACNU (15 mg/kg) alone increased the life span by 200%. Treatment of melanoma B16 bearing mice with O6-MedG and 3 hours thereafter with ACNU resulted in a 50% inhibition of tumour growth, whereas the inhibiting effect of ACNU alone was 16%. There was no difference in leukemia growth when L1210/BCNU bearing mice were treated with O6-MedG followed by ACNU treatment. In vivo ACNU (15 mg/kg) produced a deep and prolonged inhibition of DNA, RNA and protein synthesis in leukemia L1210 cells. The DNA synthesis in leukemia L1210/BCNU cells was shown to recover more rapidly than in L1210 cells. The activities of DNA-polymerases alpha and beta and, especially, of O6-AGT were elevated in ACNU-resistant leukemia cells as compared with ACNU-sensitive cells. The activation of some repairing enzymes, such as O6-AGT, DNA-polymerases alpha and beta as well as increased levels of GSH may play a role in the development of drug resistance to ACNU.
Dederer
L Iu
LIu
Sokolova
I S
IS
Bakhmedova
A A
AA
Miniker
T D
TD
Mel'nik
S Ia
SIa
Gorbacheva
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D007939:Leukemia L1210 / Q000201:enzymology / Q000473:pathology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015376:Nimustine / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015376:Nimustine; C015558:O(6)-methyl-2'-deoxyguanosine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004259:DNA-Directed DNA Polymerase; D003849:Deoxyguanosine
Moduliatsiia protivoopukholevoĭ aktivnosti 1-(4-amino-2-metil-5-pirimidinil)metil-3-(2-khlorétil)-3-nitrozomochev iny O(6)-metil-2'-dezoksiguanozinom--novym ingibitorom O(6)-alkilguanin-DNK-alkiltransferazy.