O6-methylguanine and temozolomide can reverse the resistance to chloroethylnitrosoureas of a mouse L1210 leukemia.
Using L1210 and a subline resistance to chloroethylnitrosoureas (L1210/BCNU), we found that the resistance to 1-(2-chloroethyl)-1-nitrosourea (CNU) or to diethyl-1-3-(2-chloroethyl)-3-nitrosoureido ethyl phosphonate (fotemustine) can be reversed by a pretreatment with O6-methyl Guanine (O6-mGua) or temozolomide. In L1210/BCNU but not in L1210 the pretreatment with O6mGua caused an increased peak level of CNU-induced DNA-interstrand crosslinks. We then evaluated whether the resistance to BCNU could be counteracted in vivo by i.p. O6mGua treatment of L1210/BCNU bearing mice. The results were negative due to the fact that O6mGua, which was not toxic when given alone, caused a high toxicity when associated with BCNU.
D'Incalci
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Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D009607:Nitrosourea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077204:Temozolomide
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C017139:1-(2-chloroethyl)-1-nitrosourea; D006147:Guanine; D003606:Dacarbazine; C008449:O-(6)-methylguanine; C054368:fotemustine; D005038:Ethylnitrosourea; D002330:Carmustine; D000077204:Temozolomide