Cisplatin (CDDP) is a widely used anti-neoplastic drug presenting numerous side-effects such as: nausea and vomiting, neurotoxicity 1 2
, nephrotoxicity 3
, vestibulotoxicity 3
and ototoxicity 4–6
. The latter has been reported in many studies and is mainly characterized by an initial threshold shift at the higher frequencies (i.e., 4.0 and 8.0 kHz) 7
. Frequent and continuous CDDP administration can affect the lower frequencies resulting in a progressive hearing loss and difficulties in speech recognition in noisy environments.
The ototoxic effects of cisplatin have been primarily evaluated in various laboratory animals 8
. The first ototoxic impact seems to involve the cochlea, leading to anatomical changes on the organ of Corti and of the stria vascularis 9
. In such cases, it is possible to observe damage in the outer hair cells starting from the first row of the basal turn, alterations of the supporting cells and Reissner’s membrane 10
. These morphological alterations are considered as the direct effect of blocking the transduction channels of the outer hair cells 11 12
. The hearing loss caused by ototoxicity is progressive and irreversible and, with nephro-toxicity, is the main limiting factor of the CDDP dosage in current clinical therapeutic strategies.
Traditionally, in experimental animals, the overall alteration of the hearing threshold, due to cisplatin administration, has been studied by means of auditory brainstem responses (ABR) 4 5 7 13 14
. These measurements represent the integration (contribution) of individual responses from many neural fibres, therefore minute changes in cochlear micro-mechanics, caused by possibly transitory ototoxic effects, are not revealed. A detailed description of eventual dysfunction in cochlear micro-mechanics caused by cisplatin ototoxicity can be obtained via recordings of the otoacoustic emissions (OAEs) 8 15
. These are considered responses of cochlear origin, generated when the auditory periphery is stimulated by a click or a pure tone stimulus and their close relationship with the non-linear micro-mechanics of the outer hair cells has been well established. In this context, use of OAEs can establish not only the presence of an ototoxic effect, but also evidence regarding the progress of ototoxicity as seen from the perspective of the OHCs.
Species differences between Humans and experimental animals exist in the susceptibility of the inner ear. In general, doses inducing an ototoxic effect of cisplatin in experimental animals exceed the doses used in the treatment of patients. It has been demonstrated, in several species, that there is a significant individual variability of hearing loss related to cisplatin treatment 15
. Even though several parameters, such as the pharmacokinetic pattern and pre-treatment hearing status, have been taken into consideration 7
, no predictive factor for cisplatin-induced hearing loss has been identified.
The fact that a CDDP ototoxic insult results in the loss of outer hair cells due to apoptotic mechanisms has generated great clinical interest for substances: i. which might protect the inner ear from CDDP; and ii. which do not interfere with the activity of the anti-neoplastic agent. Animal studies 1 4 6 16
and clinical observations 1 17
have demonstrated that the family of thiosulphate compounds can protect from platinum ototoxicity including the drug carboplatin (a newer platinum compound). For the latter, Muldoon et al. 18
have shown that administration of sodium thiosulphate, following carboplatin treatment, significantly reduces ototoxicity in guinea pigs, times and doses being consistent with the anti-tumoural activity. In previous investigations 8 15
, we evaluated the toxic effects, induced by CDDP, in the Sprague-Dawley rat model, by means of electrophysiological and morphological studies of the cochlea. From these studies, it was concluded that hearing loss related to apoptosis of the outer hair cells can be reliably predicted by otoacoustic emission measurements. In the present study, we evaluated the protective efficacy of a systemic administration of D-methionine using, as measuring technique, otoacoustic emissions (OAEs) verified by auditory brainstem responses (used as gold standard) 19