Molecular Pathways: A Novel Approach to Targeting Hypoxia and Improving Radiotherapy Efficacy via Reduction in Oxygen Demand

摘要

Abstract Tumor hypoxia presents a unique therapeutic challenge in the treatment of solid malignancies. Its presence has been established to be a poor prognostic factor in multiple cancer types, and past hypoxia-directed approaches have yielded generally disappointing results. Previous approaches have centered on either increasing oxygen delivery or administering agents that preferentially radiosensitize or kill hypoxic cells. However, a novel and potentially more effective method may be to increase therapeutic benefit by decreasing tumor oxygen consumption via agents such as metformin or nelfinavir in a patient population that is enriched for tumor hypoxia. This promising approach is currently being investigated in clinical trials and the subject of this article. Background Hypoxia/anoxia is a well-characterized component of the solid tumor microenvironment. In their comprehensive review of studies in the literature examining tumor hypoxia using polarographic needle electrode systems, Vaupel and colleagues (1) found that the overall median pO2 levels in malignant brain tumors and cancers of the uterine cervix, head and neck, and breast were 10-mm Hg with the hypoxic fraction (percentage of tumor with pO2 < 2.5 mm Hg) approximately 20% to 30%. In general there is not a correlation between tumor diameter and median pO2 or hypoxic fraction. For many tumors, there is spatial heterogeneity of hypoxia, i.e. there is no characteristic topologic distribution of pO2 within tumors (periphery vs. center). For example, Evans and colleagues (2) showed that there was substantial intra- and intertumoral hypoxic heterogeneity within human grade 4 glial neoplasms. The majority of cells within these tumors had levels of hypoxia that were mild to moderate (defined as 10%-0.5% pO2) rather than severe (approximately 0.1% pO2). Even if only a minority of cells within a tumor are hypoxic, this can have a negative effect on outcome (3). Hypoxia is associated with chemoresistance, increased genomic instability, and the propensity for invasion and metastasis (4). Hypoxic cells are more resistant to radiotherapy because O2 must be present for optimal fixation of DNA damage induced by ionizing radiation (5). Hypoxic cells are relatively resistant to radiotherapy, requiring 2.5 to 3 times the radiation dose as normoxic cells to result in the same level of cell killing (5).