Abstract:
:Autonomous parvoviruses are small, single strand DNA viruses which preferentially replicate in transformed and tumor cells, causing cell death by expression of the cytotoxic nonstructural protein, NS1. Several parvoviruses of the rodent group, including LuIII, efficiently infect human transformed cell lines. The potential for systemic use of these viruses in targeting metastases might be enhanced if NS1 expression and viral replication could be controlled by an innocuous drug such as tetracycline. We therefore substituted prokaryotic tetracycline operator sequences for part of P4 of LuIII, the promoter responsible for transcription of the mRNAs for nonstructural proteins. The resulting construct unexpectedly showed constitutive expression in transiently transfected cells, as indicated by efficient excision and amplification of viral replicative form (RF) DNA. This was apparently due to self-stimulatory transcriptional transactivation by NS1. This problem was overcome by cotransfection with a plasmid expressing a chimera of the repressor of the tetracycline operon with a KRAB transrepression domain. These conditions allowed efficient control of transcription and RF amplification by the tetracycline derivative, doxycycline. These observations form a basis for developing a therapeutic agent based on a drug-controlled parvovirus.
journal_name
Gene Therjournal_title
Gene therapyauthors
Maxwell IH,Maxwell Fdoi
10.1038/sj.gt.3300832keywords:
subject
Has Abstractpub_date
1999-03-01 00:00:00pages
309-13issue
3eissn
0969-7128issn
1476-5462journal_volume
6pub_type
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