A COMPARISON OF THE PROPERTIES OF DIFFERENT RETROVIRAL VECTORS CONTAINING THE MURINE TYROSINASE PROMOTER TO ACHIEVE TRANSCRIPTIONALLY TARGETED EXPRESSION OF THE HSVTK OR IL-2 GENES

To target therapeutic genes specifically to melanoma cells, we have co nstructed recombinant retroviruses where transcriptional control of th e murine interleukin-2 (mIL-2) or herpes simplex virus thymidine kinas e (HSVtk) genes is provided by the 5' promoter region of the murine ty rosinase gene. Tissue-specific expression of these genes is observed b oth at the mRNA and protein levels in the B16 melanoma line compared w ith NIH3T3 fibroblasts. Thus, B16 cells infected with one such retrovi rus containing the HSVtk gene exhibited a > 90% reduction in colony-fo rming efficiency after exposure to 1 mu g/ml ganciclovir, relative to controls, whereas similarly infected NIH3T3 cells showed < 10% reducti on in colony-forming efficiency under comparable conditions. The degre e of preservation of tissue-specific expression from the internal tyro sinase promoter depended upon the exact molecular design of the vector , possibly as a consequence of the interference between closely juxtap osed promoters within the provirus. Our results show that retroviral v ectors can be prepared with the capacity to regulate expression of ins erted genes specifically in a particular cell type and may be useful f or developing efficient, targeted vectors for the in vivo delivery of genetic therapies for malignant melanoma.