Role of p53 in the ability of 1,2-diaminocyclohexane-diacetato-dichloro-Pt(IV) to circumvent cisplatin resistance.
Several reports indicate that the mechanism of resistance to cisplatin is multifactorial. However, DNA damage tolerance appears to be the more significant mechanism. It is clear that resistance in general is a major clinical concern, and a number of approaches have been taken to circumvent this clinical impediment. One approach is through analog development, and we have identified 1,2-diaminocyclohexane-diacetatodichloro-platinum(IV) as an analog with activity in cisplatin resistance. The activity is greatest against ovarian tumor cell lines where the latent, non-inducible wild-type p53 function can be reactivated by the analog. This functional activation of p53 also corresponds to a reduced threshold for tolerance to DNA damage induced by the analog. Interestingly, cell lines with mutant or null p53 are cross-resistant to the analog. The data indicate that cisplatin resistance due to an increase in DNA damage tolerance can arise through a loss of p53 function, and that functional activation of latent wild-type p53 by the analog facilitates cell death and circumvents this resistance mechanism.
Siddik
Z H
ZH
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX 77030, USA. zsiddik@mdanderson.org
Hagopian
G S
GS
Thai
G
G
Tomisaki
S
S
Toyomasu
T
T
Khokhar
A R
AR
D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics*
C119451:(diaminocyclohexane)(diacetato)(dichloro)platinum; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; C049777:ormaplatin