Effect of hyperthermia on the activity of 1-[(4'-hydroxy-2'-butenoxy)methyl]-2-nitroimidazole, which is cytotoxic to hypoxic cells.
The effect on EMT6/KU cells of a newly synthesized hypoxic cell sensitizer, 1-[(4'-hydroxy-2'-butenoxy)methyl]-2-nitroimidazole (RK28), combined with heat was determined in vitro under conditions of hypoxia. As compared with aerobic conditions, hypoxia produced a 1.30-fold increase in the cytotoxicity of the drug for mouse mammary EMT6/KU cells induced by 1 h heat treatment at 43 degrees C in medium with a normal pH. Hypoxia also reduced the surviving fraction of cells treated with both RK28 alone for 2 h and the same concentrations of RK28 and heat (43 degrees C) in combination. Those enhancement ratios corresponded to a 20.3- and > 345-fold increase, respectively. Moreover, concomitant treatment with RK28 and heat greatly inhibited the clonogenic activity of the EMT6/KU cells under conditions of in vitro hypoxia and in all experimental groups; there was a statistically significant difference in the time-response curves (P < 0.05). As hypoxic cells in a solid tumor are resistant to various anticancer drugs, RK28 combined with hyperthermia deserves further study for possible clinical applications.
Kusumoto
T
T
Clinical Research Division, National Kyushu Cancer Center, Fukuoka, Japan.
Maehara
Y
Y
Emi
Y
Y
Sakaguchi
Y
Y
Baba
H
H
Sakaguchi
M
M
Sugimachi
K
K
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006979:Hyperthermia, Induced; D008325:Mammary Neoplasms, Experimental / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D011838:Radiation-Sensitizing Agents; C047778:1-(4'-hydroxy-2'-butenoxy)methyl-2-nitroimidazole; D008920:Misonidazole