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2015 ; 45
(2
): 163-76
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Optimizing hypoxia detection and treatment strategies
#MMPMID25704388
Koch CJ
; Evans SM
Semin Nucl Med
2015[Mar]; 45
(2
): 163-76
PMID25704388
show ga
Clinical studies using Eppendorf needle sensors have invariably documented the
resistance of hypoxic human tumors to therapy. These studies first documented the
need for individual patient measurement of hypoxia, as hypoxia varied from tumor
to tumor. Furthermore, hypoxia in sarcomas and cervical cancer leads to distant
metastasis or local or regional spread, respectively. For various reasons, the
field has moved away from direct needle sensor oxygen measurements to indirect
assays (hypoxia-inducible factor-related changes and bioreductive metabolism) and
the latter can be imaged noninvasively. Many of hypoxia's detrimental therapeutic
effects are reversible in mice but little treatment improvement in hypoxic human
tumors has been seen. The question is why? What factors cause human tumors to be
refractory to antihypoxia strategies? We suggest the primary cause to be the
complexity of hypoxia formation and its characteristics. Three basic types of
hypoxia exist, encompassing various diffusional (distance from perfused vessel),
temporal (on or off cycling), and perfusional (blood flow efficiency)
limitations. Surprisingly, there is no current information on their relative
prevalence in human tumors and even animal models. This is important because
different hypoxia subtypes are predicted to require different diagnostic and
therapeutic approaches, but the implications of this remain unknown. Even more
challenging, no agreement exists for the best way to measure hypoxia. Some
results even suggest that hypoxia is unlikely to be targetable therapeutically.
In this review, the authors revisit various critical aspects of this field that
are sometimes forgotten or misrepresented in the recent literature. As most
current noninvasive imaging studies involve PET-isotope-labeled
2-nitroimidazoles, we emphasize key findings made in our studies using
2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and
F-18-labeled EF5. These show the importance of differentiating hypoxia subtypes,
optimizing drug pharmacology, ensuring drug and isotope stability, identifying
key biochemical and physiological variables in tumors, and suggesting therapeutic
strategies that are most likely to succeed.
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