Be. Huber et al., VDEPT - AN ENZYME PRODRUG GENE-THERAPY APPROACH FOR THE TREATMENT OF METASTATIC COLORECTAL-CANCER, Advanced drug delivery reviews, 17(3), 1995, pp. 279-292
Colorectal carcinoma (CRC) remains a significant medical challenge wit
h an expected 350000 new cases per year. Although the primary cancer c
an be successfully controlled by surgical resection, metastatic diseas
e to the liver is the most common demise of the CRC patient. New innov
ative approaches must be developed for the treatment of CRC hepatic me
tastasis if the overall 2- and 5-year survival rates and quality of li
fe assessments are to improved. We now describe an innovative gene the
rapy approach for the treatment of metastatic CRC, an approach called
VDEPT. In this approach, an artificial chimeric gene is created which
consists of two components: (1) the transcriptional regulatory sequenc
e (TRS) of the human carcinoembryonic antigen gene (CEA); and (2) the
protein coding domain of the nonmammlian cytosine deaminase gene (CD).
This artificial gene will express CD only in cells which naturally ex
press CEA. Expression of CD in CEA-positive cells is, by itself, nonto
xic. However, CD can convert the nontoxic prodrug, 5-fluorocytosine (5
-FCyt), to the toxic anabolite, 5-fluorouracil (5-FUra). Hence, the to
xic compound, 5-FUra, will be selectively produced in cells which expr
ess CD. Since expression of CD is restricted to CEA-positive cells, 5-
FUra will be selectively produced in CEA-positive cells. Hence, tumor-
specific expression of CD permits the tumor-specific production of 5-F
Ura at high concentrations for extended periods of time directly at th
e tumor site. The artificial, chimeric gene can be delivered to CEA-po
sitive tumors via a replication-defective retroviral vector. Chimeric
genes composed of the human CEA promoter and the coding sequence of CD
were created and engineered into a retroviral gene delivery vector. T
hese chimeric genes selectively expressed CD in CEA-positive cells whi
ch resulted in the selective conversion of 5-FCyt to 5-FUra in the CEA
-positive tumor cells. Human tumor xenografts demonstrated that expres
sion of CD in solid tumors can generate complete cures if only 4% of t
he solid tumor cell mass expressed this enzyme. In vivo gene transfer
has indicated that retroviral vectors can delivery and express CD chim
eric genes in liver tumors at this 4% level.