RESPONSE OF PURIFIED MITOCHONDRIAL-DNA TOPOISOMERASE-I FROM BOVINE LIVER TO CAMPTOTHECIN AND M-AMSA

The type I DNA topoisomerase isolated from bovine liver mitochondria i s demonstrated here to be inhibited by camptothecin, a plant alkaloid previously shown to target the nuclear type I topoisomerase in mammali an cells. The antitumor drug reduces the ability of the mitochondrial enzyme to relax positive as well as negative supercoils although the i nhibition of the former process requires more than 60-fold more drug t han the latter process. A similar response is seen with the nuclear to poisomerase I. Camptothecin also stimulates the mitochondrial topoisom erase-induced cleavage of pUC19 at numerous, discrete sites. The antit umor drug 4'-(9-acridinylamino)-methanesulfon-m-anisidide, which has b een shown to target the nuclear topoisomerase II, inhibited the mitoch ondrial type I topoisomerase relaxation activity, but this effect was found to be the result of the drug intercalating into the negatively s upercoiled DNA rather than from a specific interaction with the mitoch ondrial enzyme. VM-26, a nonintercalating topoisomerase II poison, sho wed no inhibitory effect up to a concentration of 50 mu M. (C) 1996 Ac ademic Press, Inc.