Nuclear and mitochondrial distribution of organoamidoplatinum(II) lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.
The DNA binding pattern of the organoamidoplatinum(II) compound 1a is of considerable interest because of its known activity against cisplatin-resistant cells. The activity of 1a appears to be due at least in part to a greater cellular uptake than cisplatin into cisplatin-resistant cells, but little is known of the DNA reactions of the organoamidoplatinum(II) compounds. In this study the level of DNA cross-linking and total DNA lesions formed by 1 a were measured by gene-specific Southern hybridization cross-linking assays and by quantitative PCR in cisplatin-sensitive (2008) and in cisplatin-resistant 2008/R human adenocarcinoma cell lines. The surprising result was that the major difference between cisplatin and 1a was that the number of interstrand cross-links induced by 1a were approximately 5-fold greater than that induced by cisplatin in the nuclear (but not mitochondrial) DNA of resistant cells, even though the total number of lesions were essentially the same in both sensitive and resistant cells. This result suggests that the extent of interstrand cross-linking is a critical determinant of the cellular response to 1a and that the enhanced uptake of 1a into resistant cells results in this elevated level of cross-linking, leading to good activity of 1a against cisplatin-resistant cells. It remains unclear as to why 1a exhibits such selective damage to nuclear DNA, and insight into the molecular aspects of this selectivity will provide new opportunities for the further development of new platinum-based agents with activity against cisplatin-resistant cells.
Talarico
T
T
Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Australia.
Cullinane
C M
CM
Gray
P J
PJ
Webster
L K
LK
Deacon
G B
GB
Phillips
D R
DR
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects* / Q000235:genetics / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D015342:DNA Probes; D004272:DNA, Mitochondrial / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000302:isolation & purification; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D015342:DNA Probes; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D013762:Tetrahydrofolate Dehydrogenase; D002945:Cisplatin