Tissue specific promoters in targeting systemically delivered gene therapy.
Melanin biosynthesis is restricted to melanocytes partly as a consequence of transcriptional regulation of the mRNA coding for those enzymes involved in this biochemical pathway. Promoter sequences of these genes may be used to regulate expression of complementary DNA coding for therapeutic genes so as to provide transcriptional targeting. As a model system we have used the 5'-flanking sequences of the murine tyrosinase or tyrosinase-related protein 1 (TRP-1) genes to show that such transcriptional targeting can be accomplished both in vitro and in vivo. Using interleukin-2 (IL-2) as an example of an immunostimulatory gene and herpes simplex virus thymidine kinase (HSVTK), as an example of a prodrug-activating gene we have shown, in murine model systems, that marked antitumour effects can be achieved by targeted gene therapy approaches. Because other tumor types produce particular proteins as a consequence of specific transcription it is possible that this approach may provide a way of targeting therapeutic genes to various cancers.
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Richard Dimbleby Department of Cancer Research, St. Thomas' Hospital, London, England.
D000818:Animals; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000628:therapy; D008562:Membrane Glycoproteins; D014442:Monophenol Monooxygenase / Q000235:genetics; D009369:Neoplasms / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000628:therapy; D010088:Oxidoreductases; D011471:Prostatic Neoplasms / Q000628:therapy; D011506:Proteins / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics
D007375:Interleukin-1; D008562:Membrane Glycoproteins; D011506:Proteins; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; D013937:Thymidine Kinase