Strategy for achieving selective killing of carcinomas.
Carcinomas are malignancies derived from epithelial cells that frequently respond poorly to conventional chemotherapy. Selective expression or transduction of toxin genes to carcinomas, i.e. molecular chemotherapy, may offer important advantages over conventional chemotherapy. As one approach to developing a means of selectively expressing toxin genes, the transcriptional regulatory sequences of a gene expressed in multiple carcinomas were used to direct expression of the herpes simplex virus thymidine kinase (HSVtk) coding sequences. The secretory leukoprotease inhibitor (SLPI) gene was found to be expressed in lung, breast, oropharyngeal, bladder, endometrial, ovarian and colorectal carcinomas. The tissue-specific transcriptional regulatory sequences were isolated and used to construct a chimeric gene in which the SLPI sequences directed HSVtk expression. SLPI-expressing carcinomas were reduced in number by transduction of the SLPI-directed toxin plasmid plus ganciclovir, but the same treatment had no effect on a cell line that did not express SLPI. These results suggest that SLPI-directed therapeutic genes could be used for directing toxicity to carcinoma tissues, especially if combined with other targeting strategies.
Garver
R I
RI
Division of Pulmonary and Critical Care Medicine, UAB School of Medicine 35294, USA.
Goldsmith
K T
KT
Rodu
B
B
Hu
P C
PC
Sorscher
E J
EJ
Curiel
D T
DT
D000256:Adenoviridae / Q000235:genetics; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics / Q000628:therapy*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008969:Molecular Sequence Data; D010957:Plasmids / Q000235:genetics; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014118:Toxins, Biological / Q000235:genetics* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011993:Recombinant Fusion Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; D014118:Toxins, Biological; D013937:Thymidine Kinase