Cisplatin, a platinum-containing antineoplastic drug: perspectives on analytical chemistry and prevention of ototoxicity

摘要

The platinum-containing drug cisplatin plays a key role in the curative andpalliative treatment of many solid malignancies. Unfortunately, the treatment canlead to sensorineural hearing loss, which limits the use of the drug. High singleand cumulative dose levels are risk factors, but there is a large interindividualvariability in the susceptibility to the ototoxic effects. The mechanisms behind theototoxicity have not been fully elucidated, but one hallmark is oxidative stress.Moreover, the ototoxicity is dependent on the exposure of cisplatin and/or itsbiotransformation product MHC in the perilymphatic compartment of thecochlea. The aim of the research presented in this thesis was to contribute to thedevelopment of treatment strategies against cisplatin-induced ototoxicity.Sulfur-containing nucleophiles are attractive candidate compounds against cisplatininducedhearing loss since they are prone to chemically interact with cisplatin andMHC and could potentially reduce the exposure of these platinum species in thecochlea. A second possible mechanism may be relief of oxidative stress. The aim of thein vitro study described in Paper I was to investigate how quickly the concentrations ofcisplatin and MHC can be reduced in the presence of five sulfur-containingnucleophiles. The results showed that thiosulfate was a promising candidate for futurestudies in vivo, since it reacted fast with cisplatin and, in particular, with MHC. Thisconclusion was further supported by the fact that thiosulfate is an endogenous ion, iswell tolerated, and has been used clinically for decades against e.g. cyanide poisoning.Systemic administration of thiosulfate has earlier been investigated in several in vitroand in vivo studies against cisplatin-induced ototoxicity. However, it has been unknownwhether thiosulfate at all reaches the cochlea. In the study described in Paper II, it wasdemonstrated that the distribution of thiosulfate to the perilymphatic compartment wasquick and extensive after an i.v. bolus injection in guinea pigs. Unfortunately, this wayof administration of thiosulfate in connection with systemic cisplatin delivery is risky,since it may lead to decreased antitumoral effects due to inactivation of cisplatin andMHC not only in the cochlea but also in tumor tissues. In the studies on which Paper IIIis based, it was found that the ototoxicity in cisplatin-treated guinea pigs was reducedby a local administration strategy employing a thiosulfate-containing hyaluronan geladministered into the middle ear cavity three hours prior to the systemic cisplatininjection.When quantifying cisplatin, unselective methods are almost always used, which mayconfound the results. In the final study, on which Paper IV is based, a sensitive, robust,and fast method using liquid chromatography and UV detection for the selectiveanalysis of cisplatin in blood was developed. This method will be a valuable instrumentin future studies exploring the role of pharmacokinetic parameters of cisplatin for theototoxic effects.