Detection and Specific Targeting of Hypoxic Regions within Solid Tumors: Current Preclinical and Clinical Strategies (original) (raw)

Hypoxia in head and neck cancer: How much, how important?

Head & Neck, 2005

Background. Hypoxia develops in tumors because of a less ordered, often chaotic, and leaky vascular supply compared with that in normal tissues. In preclinical models, hypoxia has been shown to be associated with treatment resistance and increased malignant potential. In the clinic, several reports show the presence and extent of tumor hypoxia as a negative prognostic indicator. This article reviews the biology and importance of hypoxia in head and neck cancer.

Hypoxia in cancer: significance and impact on clinical outcome

Cancer and Metastasis Reviews, 2007

Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O 2 sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1!, GLUT-1, CA IX) or exogenous bioreductive drugs. In many-albeit not in all-studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.

Imaging of Tumor Hypoxia to Predict Treatment Sensitivity

Current Pharmaceutical Design, 2008

Non-invasive detection of tumor hypoxia using radiolabeled 2-nitroimidazoles has been a major effort during the last two decades. Recent years have witnessed the introduction of several new compounds which are chemically related to [ 18 F]fluoromisonidazole (FMISO) but show slight but distinct differences in biodistribution and metabolic clearance. Although [ 18 F]FMISO has shown clinical potential it suffers from suboptimal oxygen dependent tissue contrast and newer agents seek to improve this essential feature. The limited data on other interesting tracers keeps the investigators busy at demonstrating the potential advantages over [ 18 F]FMISO while efforts should start to concentrate on proving the clinical significance of such techniques in the form of outcome data from image-guided therapy modification. We review here our experiences with two hypoxia-avid agents [ 18 F]fluoroerythronitromidazole (FETNIM) and [ 18 F] 2-(2-nitro-1-Himidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) and focus on the similarities and differences of these two tracers in comparison to other radiolabeled 2-nitroimidazoles. It is recognized that only [ 18 F]FMISO has thus far shown clinical utility and newer tracers need to be tested against this circumstance.

An insight into tumoral hypoxia: the radiomarkers and clinical applications

Oncology Reviews, 2009

Tumoral hypoxia is related to severe structural abnormalities of tumor microvessels, leading to deteriorated O 2 diffusion. This decreased O 2 concentration in cancer cells compromises cellular functions, besides being responsible for resistance to radiation therapy. Consequently, it is very important to know the hypoxic status of a tumor. In this review, the different methodologies available for evaluating cellular hypoxia in vivo are discussed, particularly those in which the hypoxia information is obtained through imaging. Among these the nuclear medicine approach uses ligands to complex with radionuclides. The resulting radioactive complexes which may be single photon or positron emitters, are very useful as imaging probes. The nature of ligands and their corresponding complexes, with application or potential application as hypoxia detectors, will be described. A summary of the most significant results so far obtained in clinical or preclinical applications will also be discussed.

PET and Planar Imaging of Tumor Hypoxia With Labeled Metronidazole

Academic Radiology, 2006

This study was aimed to develop 99m Tc-and 68 Ga-labeled metronidazole (MN) using ethylenedicysteine (EC) as a chelator and evaluate their potential use to assess tumor hypoxia. Materials and Methods: EC-MN was labeled with 99m Tc in the presence of tin (II) chloride. Labeling EC-MN with 68 Ga was achieved by adding 68 GaCl 3 (2 mCi with 3.4 g cold GaCl 3). In vitro cellular uptakes of 99m Tc-and 68 Ga-EC-MN were obtained in various types of tumor cells at 0.5-4 hours. Tissue distribution and PET imaging of 99m Tc and 68 Ga-EC-MN were evaluated in breast tumor-bearing rats at 0.5-4 hours. Tumor oxygen tension was measured using an oxygen probe. Results: There were similar cellular uptakes (2-10%) between 99m Tc-and 68 Ga-EC-MN at 0.5-4 hours. In vivo biodistribution of 99m Tc-and 68 Ga-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Positron emission tomography images confirmed that the tumors could be visualized clearly with 68 Ga-EC-MN. Oxygen tension in tumor tissue was determined to be 6-10 mm Hg compared with 40-50 mm Hg in normal muscle tissue. Conclusions: The results indicated that it is feasible to use 99m Tc-and 68 Ga-EC-MN for assessment of tumor hypoxia. These agents may be useful in selecting and evaluating cancer therapy.