Does the Antitumoral Activity of Platinum(IV) Derivatives Result from their in Vivo Reduction?

Rotondo, E.; Fimiani, Vincenzo; Cavallaro, Antonia; Ainis, Tommaso

doi:10.1177/030089168306900105

Cited by 22 publications

(6 citation statements)

References 21 publications

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“…Despite studies reporting in vitro binding of platinum(IV) species to nucleobase models in the absence of reductants [101-107], evidence that platinum(IV) species can enter cells [108], and that they can bind to DNA more slowly but at similar sites as their platinum(II) counterparts [109-111], it is believed that Pt IV is likely to be reduced before undergoing substitution [112]. Reduction to platinum(II) is probably essential for activation and effective antitumour activity of platinum(IV) complexes [113-118]. Platinum(IV) complexes would not be expected interact with nucleic acids in vivo due to the slow substitution kinetics compared to their reduction rates since substitution is slow.…”

Section: Photoactivatable Platinum(iv) Complexesmentioning

confidence: 99%

Unusual DNA binding modes for metal anticancer complexes

2009

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DNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes.

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Section: Photoactivatable Platinum(iv) Complexesmentioning

confidence: 99%

Unusual DNA binding modes for metal anticancer complexes

2009

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“…Pt(IV) complexes, compared to their Pt(II) counterparts, are extremely inert to substitution reactions, and increasing evidence suggests that for Pt(IV) diamines to be active, they must first be reduced by biological reductants [e.g., ascorbate or glutathione (GSH)] to the corresponding Pt(II) antitumor agent. 7c,d, Thus, Pt(IV) complexes may be regarded as inactive prodrugs. The covalent binding of Pt(II) to DNA is widely consider responsible for the therapeutic activity of these drugs (for recent reviews see ref ).…”

Section: Introductionmentioning

confidence: 99%

“…We reasoned that if the rate of reduction of Pt(IV) to Pt(II) could be increased in and around the tumor relative to normal tissue, then a more effective, less toxic therapy would be achieved. Along these lines, Kido et al8f showed recently that the combination of GSH with tetraplatin, a tetrachloroplatinum(IV) diamine, in a short-term (i.e., 2 h) in vitro treatment of L1210 cells leads to an increase in antiproliferative activity approaching that of the dichloroplatinum(II) diamine; that is the IC 50 value of tetraplatin decreases from 1.2 to 0.75 μM when 10 μM GSH is present.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and X-ray Crystal Structure of trans,cis-[Pt(OAc)₂I₂(en)]: A Novel Type of Cisplatin Analog That Can Be Photolyzed by Visible Light to DNA-Binding and Cytotoxic Species in Vitro

et al. 1996

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An original approach intended to facilitate the intratumoral activation of Pt(IV) diamines by illumination with visible light to form photolysis products that irreversibly bind to DNA and are cytotoxic to human cancer cells is reported. The novel Pt(IV) complex trans,cis-[Pt(OAc)2I2-(en)] was prepared by the acetylation of trans,cis-[Pt(OH)2I2(en)] with acetic anhydride in CH2-Cl2; trans,cis-[Pt(OH)2I2(en)] was synthesized by oxidation of [PtI2(en)] with 30% aqueous H2O2. trans,cis-[Pt(OAc)2I2(en)] crystallized from methanol as deep-red needles with a = 9.029(4) A, b = 11.443(2) A, c = 12.822(2) A, beta = 95.48(3) degrees, monoclinic space group Cc, and Z = 4. The conformation of the acetato groups around the O-Pt-O axis deviated significantly from the conformation of the acetato groups in the X-ray crystal structure reported for the cis-dichloro analog, which may explain the very different aqueous solubilities of the two compounds. trans,-cis-[Pt(OAc)2I2(en)] and trans,cis-[Pt(OH)2I2(en)] displayed broad ligand-to-metal charge-transfer bands centered at lambda = 389 and 384 nm, respectively (epsilon = 1372 and 1425 M-1 cm-1, respectively), with tailing out to ca. 550 nm. When trans,cis-[Pt(OAc)2I2(en)] was incubated with calf thymus DNA in the absence of light, no covalent binding of Pt to DNA was measurable after 6 h; however, irradiation with light of wavelengths > 375 nm resulted in 63 +/- 13% of the platinum being covalently bound to DNA after 6 h, suggesting that a photoreduction to Pt(II) species took place. Although trans,cis-[Pt(OH)2I2(en)] was also labile to visible light, only 10 +/- 2% DNA platination was observed after 6 h of illumination; however, covalent binding of Pt to DNA took place quantitatively when a reducing agent such as glutathione was added to the photolyzed incubations. These results provide evidence that the photolysis of the trans-dihydroxo analog resulted predominately in the substitution of the iodide ligands for water rather than a reduction of Pt(IV) to Pt(II). When protected from light, trans,cis-[Pt(OAc)2I2-(en)] and trans,cis-[Pt(OH)2I2(en)], both at a concentration of 10 microM, had half-lives of 6.6 +/- 0.5 and 46.8 +/- 8.8 h, respectively, at 37 degrees C in Eagle's minimum essential medium (EMEM) containing 5% fetal calf serum. When irradiated with light lambda(irr) > 375 nm, the half-lives were decreased by 24- and 53-fold for the diacetato- and dihydroxoplatinum(IV) complexes, respectively. Compared to the "dark" control, the in vitro treatment of TCCSUP human bladder cancer cells with trans,cis-[Pt(OAc)2I2(en)] resulted in 35% greater growth inhibitory activity when during the first 1.5 h of drug exposure the cells were irradiated with light lambda irr > 375 nm. The photolysis of trans,cis-[Pt(OH)2I2(en)] with visible light resulted in a 22% enhancement of antiproliferative activity.

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“…The antitumor activity of platinum(1V) compounds has been suggested to require in vivo reduction to the kinetically more labile, and therefore reactive, platinum(I1) derivatives (Rotondo et al, 1983;Blatter et al, 1984;Eastman, 1987a;Pendyala et al, 1990). They have been considered as the compounds which are unable to react directly with DNA.…”

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confidence: 99%

DNA Interactions of Antitumor Platinum(IV) Complexes

et al. 1995

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Modifications of natural DNA and synthetic double‐stranded oligodeoxyribonucleotides by cis ‐diam‐minedichloro‐trans ‐dihydroxyplatinum(IV) (oxoplatin) were studied by means of ELISA, Maxam‐Gilbert footprinting techniques, HPLC of enzymically digested DNA, and transcription assay. It was found that oxoplatin can bind DNA directly without addition of a reducing agent. In addition, the antibodies elicited against DNA modified by cisplatin were not competitively inhibited by DNA modified by oxoplatin. However, DNA containing the adducts of oxoplatin became a strong inhibitor of these antibodies, if it was subsequently treated with ascorbic acid, which is a reducing agent. These results were interpreted to mean that oxoplatin can form DNA adducts containing the platinum moiety in the quadrivalent state. The direct irreversible binding of the platinum(IV) drug is, however, slow as compared to the reaction of its platinum(II) counterpart. It was also found that oxoplatin preferentially binds to guanine residues and can form DNA intrastrand and interstrand cross‐links containing platinum(IV). The DNA adducts containing platinum(IV) can inhibit in vitro transcription by a prokaryotic DNA‐dependent RNA polymerase. We find that the platinum(IV) complex binds to DNA at similar sites as its platinum(II) counterpart. On the other hand, the DNA adducts containing the platinum(II) or platinum(IV) analogues differ in the number of ligands and the formal charge on their platinum center. We suggest that these dififerences could be responsible for distinct conformational features and stability of DNA modified by platinum(II) or platinum(IV) complexes.

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Does the Antitumoral Activity of Platinum(IV) Derivatives Result from their in Vivo Reduction?

Cited by 22 publications

References 21 publications

Unusual DNA binding modes for metal anticancer complexes

Unusual DNA binding modes for metal anticancer complexes

Synthesis and X-ray Crystal Structure of trans,cis-[Pt(OAc)₂I₂(en)]: A Novel Type of Cisplatin Analog That Can Be Photolyzed by Visible Light to DNA-Binding and Cytotoxic Species in Vitro

DNA Interactions of Antitumor Platinum(IV) Complexes

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Does the Antitumoral Activity of Platinum(IV) Derivatives Result from their in Vivo Reduction?

Cited by 22 publications

References 21 publications

Unusual DNA binding modes for metal anticancer complexes

Unusual DNA binding modes for metal anticancer complexes

Synthesis and X-ray Crystal Structure of trans,cis-[Pt(OAc)2I2(en)]: A Novel Type of Cisplatin Analog That Can Be Photolyzed by Visible Light to DNA-Binding and Cytotoxic Species in Vitro

DNA Interactions of Antitumor Platinum(IV) Complexes

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Synthesis and X-ray Crystal Structure of trans,cis-[Pt(OAc)₂I₂(en)]: A Novel Type of Cisplatin Analog That Can Be Photolyzed by Visible Light to DNA-Binding and Cytotoxic Species in Vitro