Six Degrees of Separation: The Oxygen Effect in the Development of Radiosensitizers

Abstract

The popular theory six degrees of separation is used in this review as an analogy to relate all radiosensitization to oxygen. As the prime mover of all radiosensitizers, the pervasive influence of oxygen has consciously or unconsciously influenced the direction of research and development and provided the benchmark against which all other compounds and approaches are measured. It is the aim of this review to develop the six degrees of separation from oxygen analogy as a unifying framework for conceptually organizing the field and for giving context to its varied subspecializations and theories. Under such a framework, it would become possible for one area to consider questions and problems found in other areas of radiosensitization, using a common analogy, that would allow for further development and unification of this multifaceted discipline. In this review, approaches to the development of radiosensitizers and the current state of research in this field are discussed, including promising new agents in various stages of clinical development.

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

“…The apparent lack of efficacy has also diminished the urgency for future work in this area and stalled efforts to improve outcomes in radiation therapy by overcoming the effects of hypoxia. The development of hypoxia amelioration strategies for patients with radioresistant tumors is an unmet medical need, especially considering the high percentage of cancer patients who undergo radiotherapy as a part of their treatment (211). In recognizing the potential increase in cure rates and OS by coupling radiation therapy with radiosensitizers, the NCI-RTOG recently published strategic guidelines for the early-stage development of radiosensitizers to accelerate drug development with radiation (159).…”

“…Biomarkers may also aid in the monitoring of therapy to assess the response to therapy. The incorporation of hypoxia assessment for patient stratification can be valuable to radiation oncologists, surgeons, and biotechnology and pharmaceutical companies who are developing tumor hypoxia therapies or other new treatment strategies for treating hypoxic tumors (13,17,26,130,192,211,214,230).…”

Targeting Tumor Hypoxia in Radiotherapy: A Brief Review of Historical Background and Recent Progress

“…In hypoxic tumor cells, nitroimidazoles undergo a series of enzymatic reductions mediated by nitroreductase enzymes that are expressed under hypoxic conditions, leading to the generation of highly reactive anion radicals, which then bind to thiol-containing cellular molecules. [86] In preclinical studies, misonidazole had a higher electron affinity and was more effective in sensitization of tumors to radiation without concomitant effects in normal tissues than the 5-nitroimidazole, metronidazole. [87,88] However, misonidazole performed poorly clinically due to dose-limiting neural toxicity of the radiosensitizers, which necessitated the employment of inadequate therapeutic doses.…”

Molecular features of thymidine analogues governing the activity of human thymidine kinase

“…The efficacy of radiotherapy, one of the most common modalities used to combat cancer [1], is impaired by the fact that solid tumour cells suffer from hypoxia, which make them radioresistant [2]. In order to overcome this therapeutically undesirable effect, radiosensitisation is necessary.…”