The one-ring open hydrolysis intermediates of the cardioprotective agent dexrazoxane (ICRF-187) do not inhibit the growth of Chinese hamster ovary cells or the catalytic activity of DNA topoisomerase II.
Dexrazoxane (ICRF-187), which is clinically used to reduce doxorubicin-induced cardiotoxicity, has growth inhibitory properties through its ability to inhibit the catalytic activity of DNA topoisomerase II. Because the bisdioxopiperazine dexrazoxane undergoes significant ring-opening hydrolysis under physiological conditions to form two one-ring open hydrolysis intermediates, a study was undertaken to determine if these two intermediates had either any growth inhibitory or topoisomerase II inhibitory effects. Neither of the one-ring open intermediates exhibited growth inhibitory effects towards Chinese hamster ovary cells nor were they able to inhibit topoisomerase II. Thus, it was concluded that only intact dexrazoxane is able to inhibit the catalytic activity of topoisomerase II.
Hasinoff
B B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Kuschak
T I
TI
Fattman
C L
CL
Yalowich
J C
JC
D000818:Animals; D016466:CHO Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D002317:Cardiovascular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002384:Catalysis; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004278:DNA, Superhelical / Q000037:antagonists & inhibitors / Q000378:metabolism; D006868:Hydrolysis; D011929:Razoxane / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D002317:Cardiovascular Agents; D004278:DNA, Superhelical; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D004250:DNA Topoisomerases, Type II