Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours

Patterson, Adam V.; Williams, Kaye J.; Cowen, Rachel L.; Jaffar, Mohammed; Telfer, Brian A.; Saunders, Mark; Airley, Rachel; Honess, Davina J.; Kogel, Albert J. van der; Wolf, Charles; Stratford, Ian J.

doi:10.1038/sj.gt.3301702

Cited by 61 publications

(44 citation statements)

References 20 publications

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“…In HT1080 cells transfected with the P450R CDS under the control of a murine PGK-1 HRE trimer upstream of the SV40 minimal promoter, 18 h anoxic incubation produced a 30-fold enhancement of in vitro hypoxic cytotoxicity of RSU1069 (Patterson et al, 2002). HT1080 tumor xenografts treated with a combination of a single 10 Gy X-ray dose and RB6145 (250 mg/kg), a precursor of RSU1069, displayed a 50% cure rate at 100 days after therapy (Patterson et al, 2002). A hypoxia-inducible GFP control was refractory to 10 Gy, RB6145 alone, or the combination, with 100% mortality at 100 days.…”

Section: Hre-directed Gene Therapymentioning

confidence: 99%

“…P450R overexpression in human fibrosarcoma (HT1080) or breast cancer (MDA231) cells conferred increased sensitivity to the bioreductive drugs tirapazamine, RSU1069 (1-3-aziridinyl-2-hydroypropyl-2-nitroimidazole), mitomycin C, and porfiromycin Saunders et al, 2000). In HT1080 cells transfected with the P450R CDS under the control of a murine PGK-1 HRE trimer upstream of the SV40 minimal promoter, 18 h anoxic incubation produced a 30-fold enhancement of in vitro hypoxic cytotoxicity of RSU1069 (Patterson et al, 2002). HT1080 tumor xenografts treated with a combination of a single 10 Gy X-ray dose and RB6145 (250 mg/kg), a precursor of RSU1069, displayed a 50% cure rate at 100 days after therapy (Patterson et al, 2002).…”

Section: Hre-directed Gene Therapymentioning

confidence: 99%

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How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

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Section: Hre-directed Gene Therapymentioning

confidence: 99%

Section: Hre-directed Gene Therapymentioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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“…Semiquantitative RT-PCR analysis showed that HIF-1a mRNA was unchanged in the AIF knockdown cells (results not shown). Extending these findings, we used an HIF-1a reporter construct 19 and show that HIF-1a protein in cell lines AIF-1-10 and AIF-2-4 was transcriptionally active, with reporter levels 42-fold higher in both AIF-silenced cell lines compared to the pU6-2 control (Figure 1e (ii)). Overall, these data suggested that the increased levels of HIF-1a protein in the AIF-silenced cells were a direct consequence of the increased levels of ROS.…”

mentioning

confidence: 99%

Loss of apoptosis-inducing factor leads to an increase in reactive oxygen species, and an impairment of respiration that can be reversed by antioxidants

et al. 2005

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“…The authors speculated that one factor was the number of cells within the tumours at oxygen tensions low enough to inhibit killing by radiation but insufficiently low to activate P450 reductase. 26 From our data, the heterogeneous response in the group with HREdriven stromal TK(SR39) correlated with starting tumour volume. Nonresponders grew similarly to the group that did not receive GCV and started at a mean volume of approximately 100 mm 3 .…”

Section: Discussionmentioning

confidence: 98%

Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy

Ingram

Porter

2005

Gene Ther

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Deregulated tumour growth and neovascularization result in an inadequate tumour blood supply, leading to areas of chronic hypoxia and necrosis. Irregular vascular structure and abnormal tumour physiology also cause erratic blood flow in tumour vessels. We reasoned that tumour stroma, including vascular endothelial cells, would consequently experience transient hypoxia that may allow transcriptional targeting as part of an antivascular gene therapy approach to cancer. To exploit hypoxia for transcriptional regulation, retroviral vectors were generated with modified LTRs: a 6-mer of hypoxia response elements in place of the viral enhancer produced near wild-type levels of expression in hypoxia but was functionally inert in normoxia. In a tumour xenograft model, expression was mainly around areas of necrosis, which were shown to be hypoxic; no expression was detected in tumour stroma. Time-course experiments in vitro demonstrated that expression was transient in response to a hypoxic episode, such that a reporter gene would be insensitive to acute hypoxia in vivo. In contrast, a significant therapeutic effect was seen upon ganciclovir administration with a vector expressing thymidine kinase (TK) in the tumour stroma. Expression of TK was more effective when targeted to acute hypoxia in the stroma compared to chronic hypoxia in the poorly vascularized regions of the tumour cell compartment. The data presented here are evidence that hypoxia in the stromal compartment does occur and that transient hypoxia constitutes a valid therapeutic target.

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Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours

Cited by 61 publications

References 20 publications

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Loss of apoptosis-inducing factor leads to an increase in reactive oxygen species, and an impairment of respiration that can be reversed by antioxidants

Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy

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