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On the discovery, biological effects, and use of Cisplatin and metallocenes in anticancer chemotherapy.

Gómez-Ruiz S, Maksimović-Ivanić D, Mijatović S, Kaluđerović GN - Bioinorg Chem Appl (2012)

Bottom Line: Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed.Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated.Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, 28933 Móstoles, Spain.

ABSTRACT
The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

No MeSH data available.


Related in: MedlinePlus

DNA adduct formation with cisplatin moiety.
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fig3: DNA adduct formation with cisplatin moiety.

Mentions: Although it is known that DNA is a major target for cisplatin, only 5–10% intracellular concentration of cisplatin is found in DNA fraction while 75–85% binds to nucleophilic sites of intracellular constituents like thiol containing peptides, proteins, replication enzymes, and RNA [6, 15–17]. This preferential binding to non-DNA targets offers the explanation for cisplatin resistance but also its high toxicity. Prerequisite of efficient formation of cisplatin DNA adducts is hydratization of cisplatin enabled by low chloride ions content inside the cells [18]. N7 of guanine and in less extend adenine nucleotide are targeted by platinum [19]. Binding of cisplatin to DNA is irreversible and structurally different adducts are formed. The adducts are classified as intrastrand crosslinking of two nucleobases of single DNA strand, interstrand crosslinking of two different strands of one DNA molecule, chelate formation through N- and O-atoms of one guanine, and DNA-protein crosslinks [20, 21]. Cisplatin forms about 65% pGpG-intrastrand crosslinks, 25% pApG-intrastrand crosslinks, 13% interstrand or intrastrand crosslinks on pGpXpG sequences, and less than 1% of monofunctional adducts (Figure 3) [22]. Crucial role of 1,2-intrastrand crosslinks in antitumor potential of the cisplatin is supported by two facts. First, high mobility group proteins (HMG) specifically recognize this type of cisplatin-DNA interaction and second, these adducts are less efficiently removed by repair enzymes [17]. In addition, important mediators of cisplatin toxicity are ternary DNA-platinum-protein crosslinks (DPCL) whose frequency is dependent from the cell type as well as the type of the treatment. DPCLs inhibited DNA polymerization or their own removal by nucleotide excision repair system more potently than other DNA adducts [17]. In fact, cisplatin DNA adducts can be repaired by nucleotide excision repair proteins (NER), mismatch repair (MMR), and DNA-dependent protein kinases protein [17].


On the discovery, biological effects, and use of Cisplatin and metallocenes in anticancer chemotherapy.

Gómez-Ruiz S, Maksimović-Ivanić D, Mijatović S, Kaluđerović GN - Bioinorg Chem Appl (2012)

DNA adduct formation with cisplatin moiety.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3401524&req=5

fig3: DNA adduct formation with cisplatin moiety.
Mentions: Although it is known that DNA is a major target for cisplatin, only 5–10% intracellular concentration of cisplatin is found in DNA fraction while 75–85% binds to nucleophilic sites of intracellular constituents like thiol containing peptides, proteins, replication enzymes, and RNA [6, 15–17]. This preferential binding to non-DNA targets offers the explanation for cisplatin resistance but also its high toxicity. Prerequisite of efficient formation of cisplatin DNA adducts is hydratization of cisplatin enabled by low chloride ions content inside the cells [18]. N7 of guanine and in less extend adenine nucleotide are targeted by platinum [19]. Binding of cisplatin to DNA is irreversible and structurally different adducts are formed. The adducts are classified as intrastrand crosslinking of two nucleobases of single DNA strand, interstrand crosslinking of two different strands of one DNA molecule, chelate formation through N- and O-atoms of one guanine, and DNA-protein crosslinks [20, 21]. Cisplatin forms about 65% pGpG-intrastrand crosslinks, 25% pApG-intrastrand crosslinks, 13% interstrand or intrastrand crosslinks on pGpXpG sequences, and less than 1% of monofunctional adducts (Figure 3) [22]. Crucial role of 1,2-intrastrand crosslinks in antitumor potential of the cisplatin is supported by two facts. First, high mobility group proteins (HMG) specifically recognize this type of cisplatin-DNA interaction and second, these adducts are less efficiently removed by repair enzymes [17]. In addition, important mediators of cisplatin toxicity are ternary DNA-platinum-protein crosslinks (DPCL) whose frequency is dependent from the cell type as well as the type of the treatment. DPCLs inhibited DNA polymerization or their own removal by nucleotide excision repair system more potently than other DNA adducts [17]. In fact, cisplatin DNA adducts can be repaired by nucleotide excision repair proteins (NER), mismatch repair (MMR), and DNA-dependent protein kinases protein [17].

Bottom Line: Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed.Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated.Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, 28933 Móstoles, Spain.

ABSTRACT
The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

No MeSH data available.


Related in: MedlinePlus