Specific distribution of TOP-53 to the lung and lung-localized tumor is determined by its interaction with phospholipids.
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.
Yoshida
M
M
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Hanno-City, Saitama, Japan.
Kobunai
T
T
Aoyagi
K
K
Saito
H
H
Utsugi
T
T
Wierzba
K
K
Yamada
Y
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D005047:Etoposide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism*; D011802:Quinidine / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D010743:Phospholipids; C099874:TOP 53; D005047:Etoposide; D011802:Quinidine