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

Abstract

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.

A novel chimeric promoter that is highly responsive to hypoxia and metals

“…Moreover, targeting gene expression to the hypoxic regions of solid tumors will allow the use of lower doses of the vector and decrease the risk of side effects. 26,27 In this respect, the successful performance of the E-M-H vector in LLC1 carcinoma cells should be noted.…”

Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1

“…The critical changes in the cellular microenvironment are due to an inadequate oxygen supply and the resultant hypoxia (2). The hypoxic tumor environment results in aggressive and metastatic cancer phenotypes that are associated with resistance to radiation therapy, chemotherapy, and a poor treatment outcome (3,4). Hypoxia detected in the central regions of solid tumors can be a leading cause of angiogenesis, a fundamental determinant of malignant tumor progression, by activating the expression of angiogenic factors (5,6).…”

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

“…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.…”