Efficient oncolysis by a replicating adenovirus (ad) in vivo is critically dependent on tumor expression of primary ad receptors.
Replicating adenoviruses (Ads) are designed to replicate in and destroy cancer cells, generating viral progeny that spread within the tumor. To address the importance of the primary cellular receptor for Ads, the coxsackievirus and Ad receptor (CAR), in permitting intratumoral spread of a replicating Ad, we have used a pair of tumor cell lines differing only in the expression of a primary receptor for Ad5. This novel system thus allowed the first direct evaluation of the relationship between the efficacy of a replicating Ad and the primary receptor levels of the host cell without the confounding influence of other variable cellular factors. We demonstrate that the absence of the primary cellular receptor on the tumor cells restricts the oncolytic potency of a replicating Ad both in vitro and in vivo. Based on these findings, it is apparent that the potential therapeutic advantages afforded by viral replication would be negated by poor intratumoral spread of the viral progeny due to the failure to infect neighboring tumor cells. Because a number of studies have reported that primary cancer cells express only low levels of CAR, our results suggest that strategies to redirect Ads to achieve CAR-independent infection will be necessary to realize the full potential of replicating Ads in the clinical setting.
Douglas
J T
JT
Department of Medicine, Gene Therapy Center University of Alabama at Bermingham, 35294, USA. Joanne.Douglas@ccc.uab.edu
Kim
M
M
Sumerel
L A
LA
Carey
D E
DE
Curiel
D T
DT
D000260:Adenoviruses, Human / Q000472:pathogenicity / Q000502:physiology*; D000818:Animals; D002213:Capsid / Q000032:analysis; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003588:Cytopathogenic Effect, Viral; D004279:DNA, Viral / Q000096:biosynthesis; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000628:therapy / Q000821:virology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011991:Receptors, Virus / Q000096:biosynthesis* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D018406:Virus Physiological Phenomena; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004279:DNA, Viral; D011991:Receptors, Virus; C085301:adenovirus receptor