Tumor Hypoxia and Papaverine: A New Use for an Old Drug?

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Papaverine was found to sensitize tumors in a way that could potentially improve their response to radiation therapy in patients with certain tumor types.
Papaverine was found to sensitize tumors in a way that could potentially improve their response to radiation therapy in patients with certain tumor types.

Solid tumors can be treated with surgery, chemotherapy and/or radiation, depending on a multitude of factors such as cancer type, location, and a patient's overall clinic status. As solid tumors develop, they can frequently outgrow their oxygen supply based on the level of metabolism required for malignant cells. This can lead to a relatively hypoxic environment for the solid tumor, at which point different pathways are utilized to maintain growth.1

One such pathway is through the vascular endothelial growth factor (VEGF) receptor. VEGF-A is one of the primary regulators of angiogenesis and works through multiple mechanisms including increased vascular permeability and promotion of endothelial cell growth and survival.2 VEGF-A is predominantly regulated by hypoxia, with lower levels of oxygen promoting increased levels of VEGF-A via hypoxia-inducible transcription factors (HIFs).3 Hypoxia can also increase VEGF-A levels by additional mechanisms outside of HIFs including induction of interleukin-8 (IL-8), cyclooxygenase-2 (COX-2) and cytokines such as transforming growth factor beta (TGF-β) and epidermal growth factor (EGF).4,5

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Numerous drug-development programs have revolved around medications aimed at the above pathways in hopes of inhibiting angiogenesis and tumor growth. In addition to chemotherapy, the role of radiation as a treatment option in certain solid tumors is impacted by hypoxia. The blood vessels that are formed as a result of hypoxia-induced angiogenesis are typically less “effective” than the traditional vasculature. Therefore, it is more difficult to deliver molecular oxygen (O2) to the tumor, which can help augment the response to radiation.7 Most previous attempts at rectifying this issue have been aimed at increasing the dose of therapeutic O2, however based on the lack of adequate surrounding vasculature, these approaches haven't shown much success. A recent study published by Benej and colleagues evaluated a unique approach to increasing oxygen delivery and resulting response to radiation therapy (RT) by utilizing papaverine (PPV).7

PPV promotes smooth muscle relaxation leading to vasodilation. PPV is an older medication that has been used for numerous vascular indications (both approved by the US Food and Drug Administration and non–FDA-approved), including erectile dysfunction, vascular spasm (in the setting of stroke or clot), and mesenteric ischemia. Benej and colleagues proposed that PPV could inhibit mitochondrial function within tumor cells leading to less hypoxia, which would, in turn, theoretically work as a “primer” for radiation treatment.

This is a different way to counter tumor hypoxia than previously studied, as most prior attempts were aimed at increasing supply of O2, which as noted prior, is typically not effective based on the poor quality of the vasculature created by hypoxia-induced angiogenesis. The utilization of PPV was hypothesized to reduce the oxygen demand within the tumor, leading to an improved response to radiation. 

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