The cellular basis of the efficacy of the trinuclear platinum complex BBR 3464 against cisplatin-resistant cells.
Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional mononuclear platinum-based drugs. In this study we performed a comparative study of cisplatin and of the triplatinum complex BBR 3464 in a human osteosarcoma cell system (U2-OS) including an in vitro selected cisplatin-resistant subline (U2-OS/Pt). BBR 3464 was extremely potent in comparison with cisplatin in U2-OS cells and completely overcame resistance of U2-OS/Pt cells. In both cell lines, BBR 3464 accumulation and DNA-bound platinum were higher than those observed for cisplatin. On the contrary, a low frequency of interstrand cross-links after exposure to BBR 3464 was found. Differently from the increase of DNA lesions induced by cisplatin, kinetics studies indicated a low persistence of interstrand cross-link formation for BBR 3464. Western blot analysis of DNA mismatch repair proteins revealed a marked decrease of expression of PMS2 in U2-OS/Pt cells, which also exhibited microsatellite instability. Studies on DNA mismatch repair deficient and proficient colon carcinoma cells were consistent with a lack of influence of the DNA mismatch repair status on BBR 3464 cytotoxicity. In conclusion, the cytotoxic potency and the ability of the triplatinum complex to overcome cisplatin resistance appear to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared to conventional mononuclear complexes.
Perego
P
P
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. perego@istitutotumori.mi.it
Gatti
L
L
Caserini
C
C
Supino
R
R
Colangelo
D
D
Leone
R
R
Spinelli
S
S
Farrell
N
N
Zunino
F
F
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020137:Base Pair Mismatch / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019951:DNA Polymerase beta / Q000187:drug effects / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010984:Platinum / Q000493:pharmacokinetics; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D011506:Proteins; D011518:Proto-Oncogene Proteins; D010984:Platinum; D019951:DNA Polymerase beta; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes; C114062:BBR 3464; D002945:Cisplatin