Relative lack of toxicity of transplatin compared with cisplatin in rodents

Blisard, Karen S.; Harrington, Deborah A.; Long, Debra A.; Jackson, Jack

doi:10.1016/s0021-9975(08)80106-5

Cited by 18 publications

(10 citation statements)

References 9 publications

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“…Trans-DDP, administered at the same total dose as cis-DDP, was essentially non-toxic by histological and biochemical assessments (Blisard et al 1991;Mello et al 1995;Sato et al 1996). Thus, Pt contents in the tissue did not correlate with organ damage, which suggest that a mechanism(s) involving steric interactions of Pt species, perhaps with cellular macromolecules such as DNA or RNA, might be important in the differential toxicity of these two compounds.…”

Section: Discussionmentioning

confidence: 94%

“…Zelazowski et al (1984) reported that about 2 mg/g wet weight of Pt was accumulated in the liver of rats administered 2 mg/kg of body weight of cis-DDP and 4 mg/kg of body weight of trans-DDP. Blisard et al (1991) reported that quantification of tissue Pt showed accumulation of large amounts of Pt in the kidney in animals with lower amounts in the liver. However, the amounts of tissue Pt measured in trans-DDPtreated animals were not lower than those measured in cis-DDP-treated animals; indeed, Pt concentrations in kidneys of trans-DDP-treated rats were more than 2.5 times larger than those in cis-DDP-treated rats.…”

Section: Discussionmentioning

confidence: 99%

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Protective Role of Metallothionein on DNA Damage in Rat Kidney Caused by Cis‐Diamminedichloroplatinum

Hosokawa

Okabe

Saito

et al. 2000

Pharmacology & Toxicology

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Cis-diamminedichloroplatinum (cis-DDP) has been used as an anticancer agent but it also causes nephrotoxicity. To study the cis-DDP metabolism and its effects, the induction of metallothioneins and DNA damage caused by cis-DDP were observed. Cis-DDP or trans-DDP was administered to seven-week-old Wistar male rats as three daily injections of 8.0 mg/kg body wt., intraperitoneally. Using the obtained kidneys, gel filtration assay, metal analysis, immunohistochemistry and terminal deoxy transferase-mediated deoxy uracil triphosphate nick end labeling (TUNEL) method were carried out to examine localization of metallothioneins and DNA damage caused by cis-DDP. Platinum (Pt) contents, 26.05∫12.01 mg/g body wt. and 51.29∫4.59 mg/g body wt. (average∫S.E.) were detected in the kidney of rats injected with both cis-and trans-DDP, respectively. Metallothionein was detected in the cortex of the kidney in rats administrated cis-DDP or trans-DDP. The mRNA was also detected in the same region. On the other hand cis-DDP showed induction of DNA damage on the cells in the outer stripe of the outer medulla but trans-DDP did not show any damage. The regioninduced DNA damage differed from that induced by metallothioneins. Cis-DDP is suggested to be mainly trapped at the proximal tubules by metallothioneins, and the rest of cis-DDP induces DNA damage at the outer stripe of the outer medulla. Metallothioneins are considered to contribute to the protection against cis-DDP in the rat cortex.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Protective Role of Metallothionein on DNA Damage in Rat Kidney Caused by Cis‐Diamminedichloroplatinum

Hosokawa

Okabe

Saito

et al. 2000

Pharmacology & Toxicology

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“…At 500 µM, the cells began to resemble those treated with cisplatin Fig. The trans isomer of cisplatin, trans-[PtCl 2 (NH 3 ) 2 ] (transplatin) is relatively non-toxic to cancer cells [84]. However, when treatment was accompanied by irradiation, dramatic changes were seen.…”

Section: Diazido-pt(iv) Complexesmentioning

confidence: 99%

Photoactivatable Platinum Complexes

Bednarski

Mackay²,

Sadler³

2007

ACAMC

224

217

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The development of photoactivatable prodrugs of platinum-based antitumor agents is aimed at increasing the selectivity and hence lowering toxicity of this important class of antitumor drugs. These drugs could find use in treating localized tumors accessible to laser-based fiber-optic devices. Pt(IV) complexes appeared attractive because these octahedral complexes are usually substitution inert and require reduction to the Pt(II) species to become cytotoxic. Based on the knowledge of Pt(IV) photochemistry, Pt(IV) analogs of cisplatin, [Pt(en)Cl(2)] and transplatin were designed, synthesized and investigated for their ability to be photoreduced to cytotoxic Pt(II) species. Two classes of photoactivatable Pt complexes have been looked at thus far: diiodo-Pt(IV) and diazido-Pt(IV) diam(m)ine complexes. The first generation, diiodo-Pt(IV) complexes, represented by cis, trans-[Pt(en)(I)(2)(OAc)(2)], react to visible light by binding irreversibly to DNA and forming adducts with 5'-GMP in the same manner as [Pt(en)Cl(2)]. Furthermore, the photolysis products are cytotoxic to human cancer cells in vitro. However, these complexes are too reactive towards biological thiols (i.e., glutathione), which rapidly reduced them to cytotoxic Pt(II) species, thus making them unsuitable as drugs. The second generation, diazido-Pt(IV) complexes, represented by cis, trans, cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] and cis, trans-[Pt(en)(N(3))(2)(OH)(2)], are also photosensitive, binding irreversibly to DNA and forming similar products with DNA and 5'-GMP in the presence of light as the respective Pt(II) complexes. However, they are stable to glutathione and thus show very low dark cytotoxicity. Light of lambda(irr) = 366 nm activates both complexes to cytotoxic species that effectively kill cancer cells by destroying their nuclei, leaving behind shrunken cell ghosts. Interestingly, the all-trans analog, trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] is non-toxic to HaCaT keratinocytes in the dark, but as active as cisplatin in the light. These studies show that photoactivatable Pt(IV) antitumor agents represent a promising area for new drug development.

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“…Although the trans isomer of cisplatin, trans-[PtCl 2 (NH 3 ) 2 ] (transplatin) is relatively nontoxic to cancer cells itself [53], it can be activated by light, whereupon it becomes as active as cisplatin. Recent studies show that light activates both chloride ligands of transplatin, and experiments on plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark) [54].…”

Section: Photoactivated Platinum Complexesmentioning

confidence: 99%