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 degrees 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 degrees 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.