Round window pH manipulation alters the ototoxicity of systemic cisplatin
Introduction
Cisplatin (cis-diamminedichloroplatinum) is an antineoplastic agent that is widely used against a variety of neoplasms. High dose cisplatin produces severe dose-limiting side effects, such as nephrotoxicity, gastrointestinal toxicity, peripheral neuropathy, myelosuppression and ototoxicity (Piel et al., 1974, Rybak, 1981, Fausti et al., 1999).
The antineoplastic efficacy of cisplatin is known to be affected by pH. Groos et al. (1986) reported increased cytotoxicity of cisplatin under acidic conditions, and decreased cytotoxicity under alkaline conditions in transitional carcinoma cells in vitro. Atema et al. (1993) reported the potentiation of cisplatin cytotoxicity in mouse leukemia cells in acidic conditions. Laurencot et al. (1995) also reported that acidic conditions potentiate the cytotoxicity of cisplatin in mouse mammary tumor cells. We previously reported that the ototoxicity of locally applied cisplatin is inhibited by the local application of basic phosphate-buffered saline (PBS) and potentiated by acidic PBS in the chinchilla (Tanaka et al., 2003). In the present study, we investigated the effects of locally applied PBS of variable pH on the ototoxicity of systemically applied cisplatin using the rat.
Section snippets
Animals
Twenty healthy male rats (207–342 g), free of external or middle ear pathology, were used in this study. At the time of application of solutions to the round window niche (RWN), no scar tissue or other pathology was noted. All animals had free access to commercial food and water and were maintained in an environment with controlled temperature and 12 h light–dark cycles. All procedures of this study were approved by the Southern Illinois University School of Medicine Laboratory Animal Care and
ABRs
In group 1, the animals received basic PBS on one RWN and neutral PBS on the opposite RWN and cisplatin intraperitoneally. The ABR threshold changes for the neutral PBS ears were 18.3±3.1, 20.0±5.8, 16.7±4.9, 18.3±6.5, 31.7±6.0 and 36.7±8.4 dB (mean±S.E.M.) for click, 2, 4, 8, 16 and 32 kHz, respectively. The threshold shifts for basic PBS ears were 5.0±5.0, 6.7±4.9, 3.3±2.1, 5.0±3.4, 13.3±5.6 and 15.0±6.7 dB for click, 2, 4, 8, 16 and 32 kHz, respectively (Fig. 1). There were significant
Discussion
We previously reported that locally applied basic PBS could protect against the ototoxicity of locally applied cisplatin and locally applied acidic PBS could potentiate the ototoxicity of cisplatin applied to the round window (Tanaka et al., 2003). Because cisplatin is a low molecular weight (MW) compound (300), we expected it to readily cross the round window membrane. Low MW compounds can freely cross the round window (Juhn et al., 1989, Okuno and Nomura, 1984), while the passage of higher MW
Acknowledgements
This research was supported by National Institutes of Health NIH (NIDCD) Grant RO1 DC02396.
References (30)
- et al.
Determination of the acid dissociation constant for cis-diammineaquachloroplatinum(II) ion. A hydrolysis product of cisplatin
J. Pharm. Sci.
(1994) - et al.
Cisplatin-induced hearing loss: Influence of the mode of drug administration in the guinea pig
Hear. Res.
(2000) - et al.
The preparation of acetic acid for use in otic drops and its effect on endocochlear potential and pH in inner ear fluid
Am. J. Otolaryngol.
(1989) - et al.
Effect of 4-methylthiobenzoic acid on cisplatin-induced ototoxicity in the rat
Hear. Res.
(1999) - et al.
Round window application of D-methionine provides complete cisplatin otoprotection
Otolaryngol. Head Neck Surg.
(2002) - et al.
Effects of gentamicin and pH on [Ca2+]i in apical and basal outer hair cells from guinea pigs
Hear. Res.
(2001) - et al.
Influence of pH on the ototoxicity of cisplatin: a round window application study
Hear. Res.
(2003) - et al.
The kinetics and cytotoxicity of cisplatin and its monohydrated complex
Cancer Lett.
(1998) - et al.
Potentiation of DNA-adduct formation and cytotoxicity of platinum-containing drugs by low pH
Int. J. Cancer
(1993) - et al.
A crystalline platinum blue: Its molecular structure, chemical reactivity and possible relevance to the mode of action of antitumor platinum drugs
Ann. NY Acad. Sci.
(1978)
Changes in renal handling of platinum in cisplatinum-treated rats following induction of met abolic acidosis or alkalosis
Res. Commun. Chem. Pathol. Pharmacol.
Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant
Cancer Chemother. Pharmacol.
Ototoxicity, nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig
Cancer Chemother. Pharmacol.
An individualized, sensitive frequency range for early detection of ototoxicity
Ear Hear.
Clinical aspects of round window membrane permeability under normal and pathological conditions
Acta Otolaryngol.
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