Papaverine Derivatives that are Effective Hypoxic Tumor Radiosensitizers
Dr. Nicholas Denko and colleagues at The Ohio State University have developed papaverine derivatives that can be used as metabolic radiosensitizers in hypoxic tumors. The compounds make cancer cells more sensitive to radiation therapy without the concomitant toxicity issues that can occur as a side-effect of papaverine.
Radiation therapy is a common treatment for cancerous tumors. However, environmental conditions in the tumor can influence sensitivity to radiation therapy, and some cells are resistant to treatment. For example, hypoxic cells (those with low levels of oxygen) in tumors such as lung, glioblastoma, bladder , or head and neck do not respond well to radiation therapy. Radiosensitizers can make radiation therapy more effective on such cancers.
This novel strategy is aimed at increasing tumor oxygenation by reducing oxygen consumption (OCR) in tumor cells by reducing mitochondrial oxidative phosphorylation (oxygen consumption/cellular respiration). Preclinical studies with these novel molecules have shown this is a safe and effective way to improved radiotherapy.
Unfortunately, papaverine is also a phosphodiesterase 10A (PDE10A) inhibitor and its use has other effects on blood pressure and vascular tone which could be negative side-effects, especially in patients with cardiovascular co-morbidities.
Dr. Denko’s team have derived papaverine compounds that retain the ability to inhibit mitochondrial complex 1 of the respiratory chain without inhibiting the PDE10A protein. With this alteration, tumor oxygenation is increased which makes them more sensitive to radiation therapy without the negative side-effects that may occur with PDE10 inhibition. The two lead compounds, SMV-37 and SMV-32, have separated the OCR and PDE inhibition activity by over 10-fold in vitro.