Adenoviral transfer of antisenses or ribozyme to O6-methylguanine-DNA methyltransferase mRNA in brain-tumor model resistant to chloroethyl-nitrosourea.
Chloroethyl-nitrosourea is a potent chemotherapeutic agent for brain tumors. However, acquired resistance to this drug has become a serious problem for the treatment of patients. Previously, we established an animal model resistant to nitrosourea (Anticancer Res 19: 5313-5318, 1999). In this study, we evaluate the efficacies of antisense sequences and ribozyme transduction by an adenoviral vector utilizing this model. Adenoviral vectors encoding antisense sequences or ribozyme to MGMT mRNA were constructed, then MGMT-expressing glioma cells were infected with these viruses and 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) sensitivities were quantified. The adenoviral transfer of antisense RNA and ribozyme down-regulated the transcription and expression of MGMT in vitro. It also conferred sensitivity to nitrosourea in vitro and in vivo. However, the effect was minimal. These data suggest that incomplete depletion of MGMT is not sufficient to overcome the resistance and that additional optimization will be required for the complete reversion of drug resistance.
Manome
Yoshinobu
Y
Department of Microbiology, Jikei University School of Medicine, Tokyo, Japan. manome@jikei.ac.jp
Yoshinaga
Hisao
H
Watanabe
Michiko
M
Ohno
Tsuneya
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018014:Gene Transfer Techniques; D005910:Glioma / Q000188:drug therapy / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D016337:RNA, Catalytic / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D016337:RNA, Catalytic; D012333:RNA, Messenger; C017139:1-(2-chloroethyl)-1-nitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005038:Ethylnitrosourea