Chemical transformation of the anticancer drug oxaliplatin

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Oncology-Pathology

Sammanfattning: 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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