Targeting tumors with hypoxia-activated cytotoxins

Ahn, G‐One; Brown, Martin

doi:10.2741/2329

Cited by 50 publications

(40 citation statements)

References 143 publications

(108 reference statements)

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“…A related approach is based on the targeting of hypoxia. Hypoxia-activated prodrugs or bioreductive drugs are designed to deliver a cytotoxic agent to hypoxic areas within a tumour [140][141][142][143]. Several clinical trials have shown promising results for this class of drugs, e.g.…”

Section: Exploiting the Ph/tumour Microenvironment/ Metabolism Inter-mentioning

confidence: 99%

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Andersen

Moreira

Pedersen

2014

Phil. Trans. R. Soc. B

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Major changes in intra-and extracellular pH homoeostasis are shared features of most solid tumours. These changes stem in large part from the metabolic shift of most cancer cells towards glycolytic metabolism and other processes associated with net acid production. In combination with oncogenic signalling and impact from factors in the tumour microenvironment, this upregulates acid-extruding plasma membrane transport proteins which maintain intracellular pH normal or even more alkaline compared with that of normal cells, while in turn acidifying the external microenvironment. Mounting evidence strongly indicates that this contributes significantly to cancer development by favouring e.g. cancer cell migration, invasion and chemotherapy resistance. Finally, while still under-explored, it seems likely that non-cancer cells in the tumour microenvironment also exhibit altered pH regulation and that this may contribute to their malignant properties. Thus, the physical tumour microenvironment and the cancer and stromal cells within it undergo important reciprocal interactions which modulate the tumour pH profile, in turn severely impacting on the course of cancer progression. Here, we summarize recent knowledge of tumour metabolism and the tumour microenvironment, placing it in the context of tumour pH regulation, and discuss how interfering with these properties may be exploited clinically.

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Section: Exploiting the Ph/tumour Microenvironment/ Metabolism Inter-mentioning

confidence: 99%

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Andersen

Moreira

Pedersen

2014

Phil. Trans. R. Soc. B

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“…HSVtk/GCV and NTR/CB1954 have been widely used in a number of cytotoxic gene therapy studies, including therapies targeting hypoxia. [21][22][23][24] Only a few studies have compared both HSVtk and NTR systems in parallel, but none of these comparisons has been under hypoxic conditions with different transcriptional regulation. In one study, HSVtk/GCV showed the widest therapeutic index, whereas NTR/CB1954 demonstrated a stronger bystander effect in a retroviral vector.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

et al. 2011

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Hypoxia is an important factor in tumor growth. It is associated with resistance to conventional anticancer treatments. Gene therapy targeting hypoxic tumor cells therefore has the potential to enhance the efficacy of treatment of solid tumors. Transfection of a panel of tumor cell lines with plasmid constructs containing hypoxia-responsive promoter elements from the genes, vascular endothelial growth factor (VEGF) and erythropoietin, linked to the minimal cytomegalovirus (mCMV) or minimal interleukin-2 (mIL-2) promoters showed optimum hypoxia-inducible luciferase reporter gene expression with five repeats of VEGF hypoxic-response element linked to the mCMV promoter. Adenoviral vectors using this hypoxia-inducible promoter to drive therapeutic transgenes produced hypoxia-specific cell kill of HT1080 and HCT116 cells in the presence of prodrug with both herpes simplex virus thymidine kinase/ganciclovir and nitroreductase (NTR)/CB1954 prodrug-activating systems. Significant cytotoxic effects were also observed in patient-derived human ovarian cancer cells. The NTR/CB1954 system provided more readily controllable transgene expression and so was used for in vivo experiments of human HCT116 xenografts in nude mice. Subjects treated intratumorally with Ad-VEGFmCMV-NTR and intraperitoneal injection of CB1954 demonstrated a statistically significant reduction in tumor growth. Immunohistochemistry of treated xenografts showed a good correlation between transgene expression and hypoxic areas. Further investigation of these hypoxia-inducible adenoviral vectors, alone or in combination with existing modalities of cancer therapy, may aid in the future development of successful Gene-Directed Enzyme Prodrug Therapy systems, which are much needed for targeting solid tumors.

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“…Subsequently, a large body of evidence has been accrued that establishes hypoxic regions within tumors as being populated by cells that are chemo-and radio-resistant. 1,2,29,30 Hence, the design of therapeutic agents that specifically target hypoxic tumor regions has been considered an important cancer therapy. Strategies include radiosensitizers and bioreductive drugs, which are developed on the basis that hypoxic cells have increased reductive potential.…”

Section: Discussionmentioning

confidence: 99%

“…This enhanced survival likely promotes malignant transformation and generates the characteristic chemoand radio-resistance properties that hinder therapeutic intervention. 2 The modulation of gene expression by HIF-1a and HIF-2a is mediated by their binding to HREs within the promoter and the 3 0 UTR regions of target genes. 3,12 The use of synthetic variants of this element, usually as a tandem oligomer, fused to a minimal promoter has now been extensively reported for hypoxia-inducible transgene expression.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 In this respect, the use of bioreductive alkylating drugs has shown promise due to the enhanced reducing potential of the intracellular compartment of hypoxic cells. A more recent strategy has been the use of hypoxia-inducible gene therapies where the expression of a cytotoxic gene is modulated by a hypoxia response element (HRE)-based promoter.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia-induced human endonuclease G expression suppresses tumor growth in a xenograft model

et al. 2008

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We have developed a hypoxia-inducible gene therapy approach for the expression of the mature form of human endonuclease G to facilitate cell death in hypoxic regions of the tumor. The chimeric therapeutic gene is placed under the control of a hypoxia response element based promoter and contains a translocation motif linked in frame to an oxygen-dependent degradation domain and the endonuclease G gene. Transient expression of the chimeric therapeutic gene in breast and prostate cancer cell lines resulted in efficient cell death under hypoxia-mimetic conditions. Stable MDA-MB-435 cells expressing the chimeric therapeutic gene under 1% O 2 showed an increase in stable HIF-1a protein levels and synthesis of the endonuclease G protein in a time-dependent manner. In normoxic conditions, these stable transgenic cells exhibited no change in growth rate, invasion and motility when compared to parental cells. Moreover, xenografts generated using the transgenic cells exhibited highly significant suppression of tumor growth in a preclinical cancer model compared to the parental cell line. Thus, the hypoxia-modulated endonuclease G expression has the potential to be used as a gene-based-therapy system to kill malignant cells within hypoxic regions of tumors.

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Targeting tumors with hypoxia-activated cytotoxins

Cited by 50 publications

References 143 publications

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

Hypoxia-induced human endonuclease G expression suppresses tumor growth in a xenograft model

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