Biomodulation by Hyperthermia of Topoisomerase II‐Targeting Drugs in Human Colorectal Cancer Cells

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Abstract
We examined whether heat stress could enhance the sensitivity of human colon cancer WiDr cells to topoisomerase II‐targeting anticancer agents, etoposide (VP‐16) and teniposide (VM‐26), and also determined the most effective timing for the drug administration after exposure to hyperthermia. Both topoisomerase II contents and topoisomerase II activity were significantly increased in WiDr cells 3 to 12 h after heat stress at 43°C for 1 h, in comparison with those immediately after the heat stress. Cytotoxicity by VP‐16 was most significantly enhanced 3 to 12 h after exposure to 43°C for 1 h, but no synergistic effect was observed when the drug was administered immediately after the heat stress. A combination of VM‐26 with heat stress, but not that of a topoisomerase I‐targeting camptothecin derivative (CPT‐11), or vincristine, showed a synergistic cytotoxic effect on WiDr cells. VP‐16 alone induced cellular accumulation at the G2+M phase, whereas the combination of VP‐16 and heat stress further increased the cell population at the G2+M phase, and decreased S‐phase cells. A possible application of the combination of VP‐16 and hyperthermia in clinical use is discussed.