Comparative analyses of transgene delivery and expression in tumors inoculated with a replication-conditional or -defective viral vector

Viral vectors for cancer can be classified into those that do not replicate (replication-defective vectors) and those that selectively replicate in ne oplastic cells (replication-conditional or oncolytic vectors). Both of thes e can deliver anticancer cDNAs for therapeutic purposes, Opposite hypothese s can be made regarding the advantages of each vector type with regard to a natomic transgene expression. For the former vector, because cDNA delivery occurs in neoplastic cells that have the ability to migrate into the tumor mass, relatively extensive anatomic and temporal expression of anticancer f unctions may occur. For the latter vector, active viral replication may per mit anatomically and temporally extensive delivery of the foreign cDNA into the tumor mass. Herein, we performed a simple comparative analysis to test which of these hypotheses is valid. Direct inoculation of s.c. tumors with a replication-conditional or a replication-defective viral vector, each of which expressed lacZ cDNA, was performed. Tumors were excised and analyzed for anatomic delivery of beta -galactosidase and for neoplastic viral tite rs. We find that lacZ cDNA expression is observed in approximately 40% of t he tumor area 3, 7, and 14 days after injection with the replication-condit ional vector, whereas approximately 10% of the tumor area expresses the tra nsgene 3 days after injection with the replication-defective vector, with a rapid decline in expression thereafter, Titers of the replication-conditio nal virus remain stable within injected tumors for the 14 days of the assay (approximately 1:1,000 of the initial injection dose), whereas titers of t he replication-defective vector decrease rapidly after injection (to a valu e of 1:100,000 of the initial injection dose). Taken in conjunction, these studies show that transgene delivery and expression in tumors last longer a nd are found throughout an anatomically more extensive area after injection with replication-conditional gene therapy vectors than after injection wit h replication-defective gene therapy vectors.