A texaphyrin-oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells.
A texaphyrin-oxaliplatin conjugate, oxaliTEX, was designed to test the concept that a platinum analog can overcome defects in drug accumulation and p53-dependent DNA damage response in a tumor model expressing multifactorial mechanisms of cisplatin resistance. Cytotoxic studies resulted in a resistance factor of only 1.2, which essentially indicated complete reversal of resistance in 2780CP cells expressing a factor of 22 with cisplatin. Unlike cisplatin, oxaliTEX accumulated and formed DNA adducts, stabilized and activated p53 at similar levels in both sensitive and resistant cells, and induced apoptosis in both models. The ability and importance of a designer drug, such as oxaliTEX, to overcome cisplatin resistance by targeting two dominant resistance mechanisms is discussed.
Department of Chemistry and Biochemistry, Texas Institute for Diagnostics and Drug Development, The University of Texas, 1 University Station-A5300, Austin, TX 78712-0165, USA. ; Tel: +1 512 471 5009 ; Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 353, Houston, TX 77030, USA. Fax: +1 713 792 1204; Tel: +1 713 792 7746.
Jonathan F
JF
Arambula
Jonathan L
JL
Sessler
Zahid H
ZH
Siddik