Use of transcriptional regulatory elements of the MUC1 and ERBB2 genes to drive tumour-selective expression of a prodrug activating enzyme.
In order to exploit differences in gene expression between normal and malignant cells for genetic prodrug-activation therapy, we have generated recombinant retroviruses containing the herpes simplex virus thymidine kinase coding region cloned downstream of sequences derived from the 5'-flanking regions of the MUC1 and ERBB2 genes. Transduction with retroviruses containing MUC1 promoters resulted in an increase in GCV sensitivity in MUC1 positive cells. A further increase in GCV sensitivity was achieved when MUC1-positive cells were transduced with retroviruses containing chimeric-MUC1/ERBB2 promoters. No significant sensitization to GCV was observed when MUC1-negative cells were transduced with these recombinant retroviruses. These results suggest that one may be able to develop a tumour-selective therapy by utilizing the transcriptional regulatory regions of the MUC1 and ERBB2 genes to drive the expression of suicide genes.
Ring
C J
CJ
Imperial Cancer Research Fund Molecular Oncology Unit, Imperial College School of Medicine at Hammersmith, Hammersmith Hospital, London, UK.
Blouin
P
P
Martin
L A
LA
Hurst
H C
HC
Lemoine
N R
NR
D000998:Antiviral Agents / Q000494:pharmacology; D015152:Blotting, Northern; D002470:Cell Survival / Q000187:drug effects; D015774:Ganciclovir / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D018396:Mucin-1 / Q000235:genetics*; D011355:Prodrugs / Q000378:metabolism*; D012190:Retroviridae / Q000201:enzymology / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000998:Antiviral Agents; D018396:Mucin-1; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir