Genotoxicity and cell cycle effects of platinum-based imaging agents in cisplatin-resistant human tumour cells.
A series of cis-dichloroplatinum(II) 2,3-diaminopropionamide complexes synthesised as potential imaging agents was tested for activity against a human ovarian tumour cell line (CI-80-13S) with high natural resistance to cisplatin and carboplatin as compared with other human cells. The most potent compound, the dimethyl ester of dichloro-[4-(methyleneiminodiacetic acid)phenyl (2',3'-diamino-propionamide)]platinum(II) (complex III), exhibited toxicity towards CI-80-13S cells similar to that observed in other cell lines, an effect that was not shown by the ligand alone or by cis-dichloroplatinum(II) 2,3-diaminopropionamide. However, complex III ester reproduced the genotoxic effects of cisplatin as judged by differential inactivation of two strains of adenovirus and by inhibition of cellular DNA and RNA synthesis; no major differences in these properties were observed between CI-80-13S and cisplatin-sensitive cells. Substantial inhibition of DNA and RNA synthesis was found within 2 h of treatment, much earlier than the effect of cisplatin. Complex III ester, which was 30- to 100-fold less potent than cisplatin, inhibited cell cycle progression in a similar way to equitoxic cisplatin, with cells accumulating in G2 at a dose of low toxicity and being arrested in all stages at higher levels. The latter in combination with colcemid caused extensive fragmentation of CI-80-13S cells. These results suggest that the mechanism of toxicity of such complexes involves factors, in addition to DNA damage, which rapidly inhibit nucleic acid synthesis and overcome natural resistance to cisplatin in the CI-80-13S cell line.
Lean
J
J
Queensland Institute of Medical Research, Herston, Australia.
Parsons
P G
PG
Awaluddin
A B
AB
Jacobs
J J
JJ
Maddalena
D J
DJ
Wilson
J G
JG
Khoo
S K
SK
Ward
C
C
D000256:Adenoviridae / Q000187:drug effects; D016190:Carboplatin; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004351:Drug Resistance / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D012334:RNA, Neoplasm; C063688:dichloro-(3-(methyleneiminodiacetic acid)phenyl-(2',3'-diaminopropionamide))platinum(II); C063689:dichloro-(4-methyleneiminodiacetic acid)phenyl-(2',3'-diaminopropionamide)platinum(II); C063687:dichloro-(4-hydroxy-3-(methyleneiminodiacetic acid)phenyl-(2',3'-diaminopropionamide))platinum(II); D016190:Carboplatin; D002945:Cisplatin