We have investigated the mechanism of
TOP-53 distribution to the lung and lung-localized
tumor. In contrast to
etoposide (VP-16),
TOP-53 contains a basic aminoalkyl group that may predispose it to interact specifically with
phospholipids, consequently leading to an increase of
drug accumulation in the tissues. Therefore, we have studied its interaction with
phospholipids in vitro using an organic
solvent-water partition system.
TOP-53 appeared to have the most potent binding affinity (Ka = 563 x 10(-2) microM) to
phosphatidylserine (PhS), whereas
VP-16 showed no interaction with any
phospholipid tested. PhS content determined after HPLC separation varied among tested tissues; however, large quantities were found in normal lung and
lung cancer tissues far exceeding those present in the liver and kidney. The predicted tissue-to-plasma partition coefficient values, estimated based on PhS content and its binding affinity, resembled those experimentally determined. We concluded that tissue distribution of
TOP-53 is determined by PhS content in the tissues and by binding affinity. As a result of specific accumulation in the lung,
TOP-53 appeared to show a strong antitumor activity (increase of life span = 171%) against
cancer metastasizing to the lung, whereas
VP-16 was less effective (increase of life span = 78%). These results suggest that
TOP-53 may have an advantage over
VP-16 in the treatment of
lung cancers in patients.