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Comparative Analyses of Transgene Delivery and Expression in Tumors Inoculated with a Replication-conditional or -defective Viral Vector¹

Molecular Neuro-oncology Laboratory, Neurosurgery Service, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Viral vectors for cancer can be classified into those that do not replicate (replication-defective vectors) and those that selectively replicate in neoplastic cells (replication-conditional or oncolytic vectors). Both of these can deliver anticancer cDNAs for therapeutic purposes. Opposite hypotheses can be made regarding the advantages of each vector type with regard to anatomic 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 functions may occur. For the latter vector, active viral replication may permit 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 ß-galactosidase and for neoplastic viral titers. We find that lacZ cDNA expression is observed in approximately 40% of the tumor area 3, 7, and 14 days after injection with the replication-conditional vector, whereas approximately 10% of the tumor area expresses the transgene 3 days after injection with the replication-defective vector, with a rapid decline in expression thereafter. Titers of the replication-conditional 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 the replication-defective vector decrease rapidly after injection (to a value of 1:100,000 of the initial injection dose). Taken in conjunction, these studies show that transgene delivery and expression in tumors last longer and are found throughout an anatomically more extensive area after injection with replication-conditional gene therapy vectors than after injection with replication-defective gene therapy vectors.

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