Hypoxia reduces adenoviral replication in cancer cells by downregulation of viral protein expression

Abstract

Successful cancer therapy using replicating viral vectors relies on the spread of virus from infected to uninfected cells. To date, there has been limited clinical success in the use of replicating adenoviruses. In animal models, established xenograft tumors are rarely eliminated despite the persistence of high viral titers within the tumor. Hypoxia is a prevalent characteristic of solid tumors, whereas adenovirus naturally infects tissues exposed to ambient oxygen concentrations. Here, we report that hypoxia (1% oxygen) reduces adenoviral replication in H1299 and A549 lung cancer cells, BxPC-3 pancreatic cancer cells, LNCaP prostate cancer cells and HCT116 colon cancer cells. However, hypoxia does not reduce cell viability or restrict S-phase entry. Importantly, the production of E1a and fiber proteins under hypoxic conditions was substantially decreased at 24 and 48 h compared to room air controls. In contrast, Northern analysis showed similar levels of E1a mRNA in room air and hypoxic conditions. In conclusion, a level of hypoxia similar to that found within solid tumors reduces the replication of adenoviral vectors by reduction of viral protein expression without a reduction in mRNA levels. To further improve oncolytic therapy using a replicating adenovirus, it is important to understand the mechanism through which hypoxia and the virus interact to control expression of viral and cellular proteins, and consequently to develop means to overcome decreased viral production in hypoxic conditions. Gene Therapy (2005) 12, 911-917.

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

“…36 In this context, our group has recently shown that hypoxia impairs viral replication, and the hypoxic environment within the center of a tumor may be a contributing factor to the insufficiency of viral spread. 51 Clearly, the specific mechanisms that restrict viral spread need to be further elucidated. However, transgene expression or other modifications that lead to more rapid and effective tumor cell lysis are valuable option to improve viral spread and oncolytic efficacy.…”

The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

“…75 In recent studies, we have shown that the alcohol form of PR-104 is also an excellent substrate for NTR and displays marked activity in the WiDr mixed tumor model. Given the observations that hypoxia is an impediment to CRAd replication 85,86 and a common feature of solid tumors, 87 the independent co-activation of PR-104 by hypoxia and NTR may be of significant therapeutic value. We are currently evaluating whether PR-104 provides efficacy similar to SN 28343 in combination with ONYX-411 NTR and thus whether it has potential clinical utility in this context.…”

Downregulation of the coxsackie and adenovirus receptor in cancer cells by hypoxia depends on HIF-1α

“…27,31 Moreover, considering the variety of pathways that have been linked to the loss of CAR in cancers, 8,[21][22][23] our data do also underline the need for modified adenoviruses that bind to the cell surface independently of CAR in novel concept for cancer treatment. 32 Abbreviations CAR, coxsackie and adenovirus receptor; TJ, tight junctions; HIF-1a, hypoxia-inducible factor-1a; FCS, fetal calf serum; GFP, green fluorescent protein . …”