Use of Razoxane as a radiosensitizer for the treatment of soft tissue sarcomas

Razoxane, discovered in the 1960s, was evaluated as a topoisomerase II inhibitor to treat cancer. Cancer therapeutic models of the mid-1900's were based on the following three assumptions: treatment agents should demonstrate activity as a single agent, should reduce tumor size, or could exacerbate tumor hypoxia. Razoxane fulfilled none of these requirements.

Although well-tolerated, safe, and approved for cancer treatment, Razoxane lacks the cell-killing activity exhibited by other agents and was a commercial failure. It blocks the cell cycle at G2/M boundary, leading to cell cycle synchrony where radiation and chemotherapeutics are most effective. Daughter chromatid separation is inhibited; metaphase clefts do not form; and cells continue to synthesize DNA and become polyploidal, polynucleate, and hypertrophic, demonstrating a senescent phenotype where weakened cells are removed. Cell proliferation halts, allowing neovasculature to mature with structured endothelial lining and reduced sinusoids, thus eliminating a major route by which tumor cells enter the bloodstream and metastasize.

Blockade of the cell cycle at G2/M maximizes DNA alteration in response to therapy; improved oxygenation enhances the generation of reactive oxygen species during polytherapy; and increased vascularity facilitates synergy with radiation and chemotherapy by improving drug delivery.