Is DNA the Real Target of Antitumor Platinum Compounds?

Macquet, Jean‐Pierre; Butour, Jean‐Luc; Johnson, Neil P.; Razaka, H.; Salles, Bernard; Vieussens, Claude; Wright, Michel

doi:10.1007/978-1-4613-2837-7_4

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…This complex was incubated at 370C in the presence of acridine (input molar ratio acridine/nucleotide = 0. DISCUSSION The reaction of cis-Pt(NH3)2CI2 with nucleic acids proceeds through loss of chloride ions to form hydrolysis products and the limiting step is the extent of hydrolysis (1)(2)(3)(4)(5). In the in vitro reaction with nucleic acids the most frequent lesions are a cross-link between two bases and only a small proportion of monofunctional adducts has been detected, mainly for short incubation times (6)(7)(8)(9)(10)(11).…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism of action of cis-Pt(NH3)2Cl2 is not yet known, but it is often thought that its antitumor activity is related to its binding to DNA (2)(3)(4)(5). In the reaction of cis-Pt(NH3)2C12 and DNA, guanine residues are the preferred binding sites but adenine and cytosine residues also react, which leads to the formation of various types of adducts (6)(7)(8)(9)(10)(11).…”

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Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents.

Malinge¹,

Leng²

1986

Proc. Natl. Acad. Sci. U.S.A.

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The reaction of cis-diamminedichloroplatinum(II) and several synthetic or natural double-stranded polydeoxyribonudeotides has been carried out in the presence of such intercalating agents as ethidium bromide, proflavine, and acridine. After incubation of the reaction mixtures at 37C for 24 hr, some ethidium or proflavine, but no acridine, molecules are tightly bound to nucleic acids. Tight binding is defined by resistance to extraction with butanol, assayed by filtration at acid pH or by thin-layer chromatography at basic pH. In the ternary complexes, there is about one tightly bound ethidium (or proflavine) per platinum residue. At 370C, but not at 40C, tightly bound ethidium exchanges with free ethidium, whereas platinum residues do not exchange. The binding and the release of tightly bound ethidium are very slow (several hours). It is suggested that in the ternary complexes, nucleic acid-cis-Pt(NH3)2-intercalating agent, a bidentate adduct (guanine-ethidium or -proflavine)-cis-Pt(NH3)2, is formed. No tightly bound ethidium or proflavine is found when cis-diamminedichloroplatinum(II) is replaced by trans-diamminedichloroplatinum(II). Competition experiments between cis-diamminedichloroplatinum(II), poly(dG-dC), and poly(dG)--poly(dC) or poly(dA-dT) show that the presence of ethidium bromide, proflavine, or acridine interferes with the distribution of platinum between the polynucleotides. These results might help to explain the synergism for drugs used in combination with cis-diamminedichloroplatinum(ll) and in the design of new chemotherapeutic agents.Numerous works have been devoted to the study of the binding of the antitumor drug cis-diamminedichloroplatinum(II) [cis-Pt(NH3)2Cl2] to DNA. cis-Pt(NH3)2CI2 is clinically active against many different neoplasms and it is often used in combination with other anticancer drugs, such as doxorubicin (adriamycin) or bleomycin. Several studies have reported enhanced effects for combination drug therapy, including synergy (1).The mechanism of action of cis-Pt (NH3)2Cl2 is not yet known, but it is often thought that its antitumor activity is related to its binding to DNA (2-5). In the reaction of cis-Pt(NH3)2C12 and DNA, guanine residues are the preferred binding sites but adenine and cytosine residues also react, which leads to the formation of various types of adducts (6-11). On the other hand, for a given DNA, the nature of the adducts depends upon DNA conformation. In the reaction of cis-Pt(NH3)2CI2 and poly(dG-m5dC) in the Z conformation, a monodentate adduct is formed. In the reaction of cisPt(NH3)2CI2 and poly(dG-m5dC) in the B conformation, a bidentate adduct is formed (12).The conformations of B-DNA and Z-DNA are very different (13,14). To know whether smaller conformational changes of DNA could also play a role in the nature of the adducts, we have carried out the platination of nucleic acids in the presence of intercalating compounds. It has been already reported that new cis-Pt(NH3)2Cl2 binding sites were detected by means of exonuclease III when DNA ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents.

Malinge¹,

Leng²

1986

Proc. Natl. Acad. Sci. U.S.A.

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Platinum—Amine Complexes as Anticancer Agents

Farrell

1989

Transition Metal Complexes as Drugs and Chemotherapeutic Agents

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Quantitative subcellular distribution of platinum in rat tissues following i. v. bolus and i. v. infusion of cisplatin

Parti

Wolf

1990

Cancer Chemother Pharmacol

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An analysis of the subcellular localization of platinum was conducted in Sprague-Dawley (SD) rats following administration of an i.v. dose of 6 mg/kg cisplatin (bolus and infusion). Biodistribution studies were carried out in the liver and kidney of control animals, as well as in these same organs and in the tumor (Walker 256 adenocarcinoma) of SD rats. The results obtained illustrate that in addition to the platination of DNA in these tissues, significant amounts of Pt are also incorporated into the chromosomal protein (CP) and cytosolic fractions. The localization of Pt in the cytosolic fractions was highest in the kidney, followed by the tumor, and lowest in the liver when determined as the fractional percentage of the total amount of injected drug (%ID/g). The significance of such cytosolic and CP localization of Pt is not known at this time, but they may be involved in the cytotoxic effects of cisplatin, as this drug is cytotoxic to tumors and kidneys but not to the liver. The localization of cisplatin in the subcellular fractions of liver, kidney, and tumor showed a trend toward being higher after i.v. infusion than after i.v. bolus administration of the drug.

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Is DNA the Real Target of Antitumor Platinum Compounds?

Cited by 5 publications

References 20 publications

Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents.

Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents.

Platinum—Amine Complexes as Anticancer Agents

Quantitative subcellular distribution of platinum in rat tissues following i. v. bolus and i. v. infusion of cisplatin

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