Cytotoxic activity and cellular processing in human ovarian carcinoma cell lines of a new platinum(II) compound containing a fluorescent substituted propylene diamine ligand.
A new fluorescent platinum(II) compound containing the N,N'-bis-(anthracen-9-ylmethyl)propane-1,3-diamine as a carrier ligand has been designed, synthesized and characterized. High cytotoxic activity of cis-[Pt(bapda)Cl2] is observed in A2780 and A2780R cells (human ovarian carcinoma sensitive and cisplatin-resistant, respectively). Nevertheless, cross-resistance to platinum from cis-[Pt(bapda)Cl2] in the A2780R cells was found. To study the role of GSH towards inactivation of cis-[Pt(bapda)Cl2], GSH-depleted and non-depleted A2780R cells were used in several in vitro studies. The results suggest that cis-[Pt(bapda)Cl2] is not susceptible to the inactivation by GSH. Cellular processing of bapda and cis-[Pt(bapda)Cl2] was followed using fluorescence microscopy in the A2780, the A2780R and GSH-depleted A2780R cells. Interestingly, differences in the cellular processing followed by fluorescence microscopy between normal and GSH-depleted A2780R cells have been observed for the carrier ligand. Sequestration of these compounds in acidic lysosomes is visible after incubation in most cases, and no fluorescence was observed in the nucleus. Interaction of cis-[Pt(bapda)Cl2] with calf thymus DNA strongly suggests that the this new platinum(II) compound intercalates between the DNA base pairs. Additionally, the reaction of cis-[Pt(bapda)Cl2] with 9-ethylguanine appears to be very slow, as studied by 1H and 195Pt NMR spectroscopy.
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Patricia
P
Marqués-Gallego
Hans
H
den Dulk
Jaap
J
Brouwer
Stefania
S
Tanase
Ilpo
I
Mutikainen
Urho
U
Turpeinen
Jan
J
Reedijk
D000475:Alkenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003959:Diamines / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005453:Fluorescence; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology*; D055668:Photochemical Processes; D010984:Platinum / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism*
D000475:Alkenes; D003959:Diamines; D010984:Platinum; C013658:propylene; D002945:Cisplatin