Modelling the contributing factors of hypoxic fractions in human solid tumors
Hypoxia is one of the primary causes of radioresistance in human solid tumors. There are a series of contributing factors such as blood-flow rate, oxygen consumption rate, arterial pO2, and microvascular arrangement. In this study, blood-flow rate, oxygen consumption rate (OCR), and arterial pO2 are simulated to analyze their effects on hypoxia. A Green’s function method is applied in a densely vascularized tumor region to predict oxygen delivery. The results indicate that changes in OCR lead to greater changes in hypoxia. A 30% reduction in oxygen consumption rate leads to a 21% reduction in the hypoxic fraction. However, a 30% increase in blood-flow rate and arterial pO2 results in a 6% and 13% reduction in hypoxic fraction respectively. A 20% reduction in oxygen consumption rate plus a 20% increase in arterial pO2 causes a 40% decrease in hypoxic fraction. With increasing blood-flow rate and arterial pO2, hypoxic fraction reaches a plateau. As a result, hypoxia is more sensitive to OCR. In the second phase of this work, modeling results were compared to experimental data indicating the effect of papaverine in modulating tumor hypoxia. Papaverine is an FDA (Food and Drug Administration)-approved drug that can effectively decrease oxygen consumption rate and thus potentially decrease hypoxic fraction (~14%) at 2 mg/kg. At 4mg/kg, the addition of papaverine did not lead to a decrease in hypoxic fraction. This result fits the hypothesis that the oxygen consumption rate may be balanced by the effects of vasodilation which may induce more tumor shunting and poor perfusion. However, the results shown here are limited to few animals. A larger number of animals in each group, combined with other types of evidence such as perfusion staining is conducive to get a more accurate result and a better understanding of the underlying mechanism. Therefore, these experiments can be regarded as preliminary results and suggest opportunities for future experimental work.
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