The binding affinity of HMG1 protein to DNA modified by cis-platin and its analogs correlates with their antitumor activity.
The antitumor activity of cis-platin is believed to result from its interaction with cellular DNA and subsequent processing of DNA adducts by damage recognition proteins. Among them are the high mobility group (HMG) proteins 1 and 2, which have been hypothesized to mediate the effect of cis-platin. One possibility suggests that the tight binding of HMG1 to DNA adducts blocks the repair of damaged DNA. In order to further evaluate such a mechanism, several cis-platinum complexes with known antitumor activity have been used to treat DNA and the affinity of HMG1 to the DNA adduct induced by each drug was determined. The dissociation constants for the complexes of HMG1 with the platinated probe were obtained by gel mobility shift assays. The antitumor activity of the tested platinum compounds was found to correlate with the binding affinity of HMG1 to the respective drug-DNA adduct. These findings support the view that HMG1 contributes to cytotoxicity of cis-platin by shielding damaged DNA from repair. In addition, they offer a fast test for screening new platinum compounds for antitumor activity.
Pasheva
Evdokia A
EA
Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
Ugrinova
Iva
I
Spassovska
Nadejda C
NC
Pashev
Iliya G
IG
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D002945:Cisplatin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004354:Drug Screening Assays, Antitumor; D024243:HMGB1 Protein / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D011485:Protein Binding
D000970:Antineoplastic Agents; D018736:DNA Adducts; D024243:HMGB1 Protein; C057270:cisplatin-DNA adduct; D002945:Cisplatin