Effect of the antitumor drug cis-diamminedichloroplatinum(II) and related platinum complexes on eukaryotic DNA replication

Abstract

An SV40-based in vitro replication system has been used to examine the effects of platinum compounds on eukaryotic DNA replication. Plasmid templates containing the SV40 origin of replication were modified with the anticancer drug cis-diamminedichloroplatinum(II) (cis-DDP, cisplatin) or the inactive analogues [Pt(dien)Cl]+ and trans-DDP. The platinated plasmids were used as templates for DNA synthesis by the DNA polymerases present in cytosolic extracts prepared from human cell lines HeLa and 293. Bifunctional adducts formed by cis- and trans-DDP inhibited DNA replication by 95% at a bound drug to nucleotide ratio [(D/N)b] of less than 9 x 10(-4), in contrast to the monofunctional [Pt(dien)Cl]+ analogues, which required a (D/N)b of 3.4 x 10(-3) for 62% inhibition of DNA replication. An average of two platinum adducts per genome was sufficient for inhibition of DNA replication by cisplatin. When trans-DDP-modified, but not cis-DDP-modified, SV40 origin containing plasmids [(D/N)b = 1.7 x 10(-3)] were allowed to incubate in the 293 cytosolic extracts for 1 h prior to addition of T-antigen to initiate replication, DNA synthesis was restored to 30% of control. This result suggested the presence of an activity in the extracts that reactivates trans-DDP-modified DNA templates for replication. This hypothesis was confirmed by an in vitro nucleotide excision repair assay that revealed activity in 293 and HeLa cell extracts selective for trans-DDP-modified plasmid DNAs. Such selective repair of trans-DDP-damaged DNA in human cells would contribute to its lack of antitumor activity.

Induction by Adozelesin and Hydroxyurea of Origin Recognition Complex-dependent DNA Damage and DNA Replication Checkpoints in Saccharomyces cerevisiae

“…The lethal effects of adozelesin in mammals occur in a cell cycle-specific and proliferation-dependent pattern that is essentially identical to that observed in orc2-1 and wild type S. cerevisiae cells treated with this drug: very sensitive in G 1 , less sensitive in S phase, and least sensitive in G 2 /M and G 0 (11,12). The G 0 resistance is particularly interesting, because a similar relationship between proliferative capacity and cytotoxic or apoptotic response has been observed with other DNA damaging agents and antitumor drugs (40,41), at least one of which, like adozelesin, has been shown to specifically inhibit initiation of DNA replication (42). In the context of the high degree of conservation of ORC proteins and other components of the origin licensing apparatus and the intra-S-phase DNA damage checkpoint, the G 1 -specific cytotoxic effects of adozelesin and other antitumor drugs in mammals may be caused by a similar ORC-dependent response that inactivates origin licensing.…”

A new anticancer platinum compound, (–)-(R)-2-aminomethyl-pyrrolidine(1,1-cyclobutanedicarboxylato) platinum(II): DNA interstrand crosslinking, repair and lethal effects in normal human, Fanconi's anaemia and xeroderma pigmentosum cells

“…Amounts of MC and Pt(II) interstrand crosslinks in the cell DNA are 2-10%, compared to 90% or more intrastrand crosslinks. Therefore, the XPA cells can tolerate a great amount of monoadducts and intrastrand crosslinks by the replication-dependent or postreplication repair pathway, even though the major d(GpG) intrastrand crosslinks effectively block replication in vitro (Ciccarelli et al, 1985;Heiger-Bernays et al, 1990;Lemaire et al, 1991;Iwata et al, 1991). In consequence, interstrand crosslinks are more potentially lethal than intrastrand adducts.…”

“…Thus, DWA2114R appears to be a promising new analog. Both Pt(II) intra-and interstrand crosslinks formed at the specific DNA sequences block DNA synthesis in vitro (Heiger-Bernays et al, 1990;Lemaire et al, 1991;Iwata et al, 1991) and in vivo (Roberts & Friedlos, 1987), and inhibit RNA transcription in vitro (Corda et al, 1991) at damaged sites. Some studies have indicated that the main cytotoxic lesions are abundant Pt(II) intrastrand crosslinks (HeigerBernays et al, 1990;Lepre & Lippard, 1990), while the others have indicated that the minor Pt(II) interstrand crosslinks are more lethal (Knox et al, 1986;Roberts & Friedlos, 1987).…”

“…Therefore, it remains to be determined which of intra-and interstrand crosslinks are more cytotoxic. Regarding excision repair, some fraction of CDDP-induced intrastrand cross-links is removed by nucleotide excision repair, but a substantial fraction is not in mammalian cells (Ciccarelli et al, 1985;Heiger-Bernays et al, 1990;Jones et al, 1991). Especially, the major d(GpG) intrastrand crosslink is poorly repaired (Bedford et al, 1988;Page et al, 1990) and not in vitro by extracts of normal human cells (Szymkowski et al, 1992).…”

Binding of the Escherichia coli UvrAB Proteins to the DNA Mono- and Diadducts of cis-[N-2-Amino-N-2-methylamino-2,2,1-bicycloheptane]dichloroplatinum(II) and Cisplatin

“…These observations suggest that their mechanism of action might be different from that of cis-DDP and might involve a biological processing of the monoadducts. Platinum mono and diadducts are repaired in prokaryotic and eukaryotic cells (2,(11)(12)(13)(14)(15)(16)(17)(18). Recent studies on trans-1,2-diaminocyclohexanedichloroplatinum(II), which is also characterized by a bulky nonexchangeable ligand, revealed that monoadducts were more efficiently repaired than diadducts by UvrABC excinuclease (14).…”