| 1. |
- Hellberg, Victoria, et al.
(författare)
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Cisplatin and oxaliplatin toxicity : importance of cochlear kinetics as a determinant for ototoxicity
- 2009
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Ingår i: Journal of the National Cancer Institute. - Cary : Oxford University Press. - 0027-8874 .- 1460-2105. ; 101:1, s. 37-47
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.METHODS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.RESULTS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.CONCLUSION: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.
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| 2. |
- Jerremalm, Elin
(författare)
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Biotransformation of the antineoplastic drug oxaliplatin : importance for effects and side effects
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oxaliplatin is a platinum-based cytostatic drug. It is used in combination with 5-fluorouracil and leucovorin for palliative and adjuvant treatment of metastatic colorectal cancer. The biotransformation of oxaliplatin is non-enzymatic and complexes with water, chloride, glutathione and methionine have been reported to be present in plasma ultrafiltrate from patients. Oxaliplatin gives rise to DNA adducts and, consequently, DNA damage. This is the predominant explanation for its antineoplastic effect. It is not known to what extent the parent drug and/or its biotransformation products contribute to the cytotoxic effect. Common side effects of oxaliplatin treatment are nausea, vomiting and neurotoxicity. To create a more solid ground for the understanding of the effects of oxaliplatin, we have elucidated the chemistry of the compound. Oxaliplatin contains a diaminocyclohexane and an oxalato ligand. In study I, hydrolysis of oxaliplatin was found to occur in two consecutive steps. In the first step, the oxalato ring was opened and in the second step it was lost, replaced by two water molecules. The ring-opening was reversible and the closing step was much faster than the opening step. In study II, the acid dissociation constant of the oxalato monodentate intermediate was determined to 7.23. At physiological pH less than 1 % of oxaliplatin will be present in the shape of the ring-opened intermediate. The reaction of oxaliplatin with chloride was investigated in study III. The oxalato ring was opened, replaced by one chloride and then it was lost, replaced by another chloride. The initial reaction was fast with a half-life of 5-10 minutes. The cytotoxicity of the ring-opened species, [Pt(dach)oxCl]-, was studied in vitro and was found not to exceed that of oxaliplatin. In study IV, the degradation of oxaliplatin in plasma ultrafiltrate was in good agreement with the degradation of oxaliplatin in the presence of a mixture of chloride, cysteine, methionine and glutathione at physiological concentrations. It has been proposed that the acute neurotoxic side effects of oxaliplatin treatment involve voltage-gated ion channels. Since charged molecules can affect ion channel function, we hypothesized in study V that [Pt(dach)oxCl]- could be involved. We studied the effects of oxaliplatin and [Pt(dach)oxCl]- on voltage-gated potassium channels, but concluded that we did not see any effects in our Xenopus oocyte experimental system. Apoptosis is commonly induced by DNA-damaging drugs. Apoptotic pathways induced by oxaliplatin and cisplatin were compared in study VI. While cisplatin-induced apoptosis was dependent on calcium and superoxide, oxaliplatin-induced apoptosis was not.
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| 3. |
- Jerremalm, Elin
(författare)
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Chemical transformation of the anticancer drug oxaliplatin
- 2005
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oxaliplatin is a new platinum based cytostatic drug. It is used in combination with 5-fluorouracil and leucovorin, both as palliative and adjuvant treatment of metastatic colorectal cancer. Various biotransformation products are formed non-enzymatically after oxaliplatin administration. Complexes with water, chloride, glutathione, and methionine have been found in plasma ultrafiltrate from patients. Oxaliplatin gives rise to DNA adducts, which are supposed to result in cell-killing. This is the predominant explanation of its anti-tumor effect. Weather it is oxaliplatin itself or some of its biotransformation products that are responsible for the cytotoxicity is unknown. The dose-limiting side effect after oxaliplatin treatment is a peripheral neuropathy. The mechanism of this toxicity is not fully understood. To create a more solid ground for the understanding of the effects of oxaliplatin, both in vitro and in vivo, we have tried to elucidate the chemistry of the compound. Oxaliplatin contains a diaminocyclohexane and an oxalato ligand. The scheme above shows the proposed mechanism of the hydrolysis of oxaliplatin, which was found to occur in two consecutive steps. First, the oxalato ring is opened and in the second step lost, replaced by two water molecules. The ring-opening step is reversible and at neutral pH, the closing step (k-1) is much faster than the opening step. This makes the oxaliplatin solution 'semi-stable' at pH around 7. The acid dissociation constant of the oxalato monodentate intermediate was determined to 7.23. This means that at physiological pH less than 1% of oxaliplatin will be in the shape of the monodentate intermediate. The reaction of oxaliplatin with chloride was also studied. It is similar to the hydrolysis reaction in that the oxalato ring is opened, replaced by one chloride, and then lost, replaced by another chloride. Interestingly, the first step has a fast initial rate with a half-life of only 5-10 minutes at 0.1 M chloride, while the replacement of the oxalato ligand with both chlorides has a half-life of about 17 hours. The cytotoxicity of the ringopened species, [Pt(dach)oxCl]-, was studied in vitro in a colon cancer cell line and found not to exceed that of oxaliplatin.
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