A novel gene therapy for cancer has been discovered, which unlike most
prior approaches, does not require specific knowledge of the cancer
cells, but instead targets a general characteristic that distinguishes
cancer cells from normal cells, i.e., elevated eIF4E expression. The
expression of a toxin or conditional toxin such as HTK is translationally
repressed in normal cells by placing a complex 5' UTR in front of its
reading frame. In prototype experiments, this HTK mRNA, a transcriptional
product of the BK-UTK vector, was translationally regulated so as to
largely inhibit its production in normal murine and human cells, while
cancer cells efficiently translated the protein, which a resulting
increased sensitivity to GCV. Synthesis of the HTK protein from the
BK-UTK vector (containing the 5' UTR of Fibroblast growth factor-2
("FGF-2") readily occurred in a panel of murine and human breast
carcinoma lines, but not in normal cell lines. Subcutaneous tumors and
experimental lung metastases of the breast carcinoma line MM2MT in BALB/c
mice were greatly reduced by transfection with the BK-UTK vector,
followed by GCV administration. Both the BK-UTK and the BK-TK (control)
vectors were effective in reducing lung metastasis following systemic
delivery of the vectors and subsequent GCV administration. However, the
BK-TK vector was highly toxic to mice while little to no toxicity was
seen in mice treated with the BK-UTK vector.