Retrovirally transduced Escherichia coli gpt genes combine selectability with chemosensitivity capable of mediating tumor eradication.
"Suicide genes" encoding exceptional sensitivity to chemotherapeutic agents can potentially improve the selectivity of cancer therapy. As a component of a retroviral gene therapy vector, a suicide gene might also improve the safety of gene therapy by permitting the subsequent ablation of transduced cells exhibiting neoplastic or other aberrant behavior. An extra gene, however, cannot easily be added to vectors already carrying a therapeutic gene and a selectable drug resistance marker without compromising gene expression. To circumvent this obstacle, we have investigated a retrovirally transduced Escherichia coli gpt gene on the basis of evidence that it might subserve a dual sensitivity/resistance function. A gpt vector was used to transduce the gene into murine K3T3 sarcoma cells. In vitro, gpt-positive K3T3 clones could be selected on the basis of resistance to a regimen containing mycophenolic acid and xanthine; the same clones were 18 to 86 times as sensitive to 6-thioxanthine (6TX) as their gpt-negative counterparts. In mice, systemic 6TX therapy induced durable regressions in 19/20 gpt-positive K3T3 sarcomas without affecting gpt-negative tumors. These results indicate that selectability and in vivo chemosensitivity can be expressed in the same cell population from a single retrovirally transduced gene and imply the additional possibility of fusing the gpt gene with a therapeutic gene to create vectors expressing three important functions from a single gene.
Mroz
P J
PJ
Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA 01730.
Moolten
F L
FL
D000818:Animals; D002460:Cell Line; D004351:Drug Resistance / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010430:Pentosyltransferases / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics*; D012513:Sarcoma, Experimental / Q000628:therapy*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000494:pharmacology
D014970:Xanthines; C054700:6-thioxanthine; D010430:Pentosyltransferases; C024827:xanthine phosphoribosyltransferase