Biomodulation by hyperthermia of topoisomerase II-targeting drugs in human colorectal cancer cells.
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.
Hirohashi
Y
Y
Department of Surgery, Saga Medical School.
Hidaka
K
K
Sato
S
S
Kuwano
M
M
Kohno
K
K
Hisatsugu
T
T
D000230:Adenocarcinoma / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D006358:Hot Temperature; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D013713:Teniposide / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014750:Vincristine; D005047:Etoposide; D013713:Teniposide; D002166:Camptothecin