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Cisplatin Ototoxicity

R3 !" 93-4-30 Introduction 1. Alkylating antineoplastic agent since 1970 for head and neck cancer ,metastatic testicular, ovarian, bladder, esophageal, cervical, bone, non-small lung cancer 2. Neutral, square-planar platinum coordination complex: Two carrier!#amine ligands influence antitumor activity(cis-configuration) Two leaving groups!---chloride groups affect water solubility,stability 3. Mechanism Formation of DNA adducts Production of reactive oxygen species(ROS) 4. Second-generation platinum analog,cis-diammine: less nephrotoxicity and ototoxicity but significant myelosupression,comparable antitumor spectrum to cisplatin Pharmacodynamics 1. 90 % of cisplatin bound to serum protein within 2 hrs (cisplatin-protein complex is inactive against tumor cells) 2. Two peaks of cisplatin half life: 25~50 mins(unbound), 53~73 hrs(total platinum) 3. Metabolism: liver,kidney Ototoxicity 1. S/S: otalgia, tinnitus(2~36 %, a few hour ~ a week after therapy), hearing loss (9~91%, 50 % in head and neck cancer patient, high freq-> low freq, may escape from PTA ,10% may recover spontaneously from1 ~18 months) 2. Risk factor of ototoxicity amount of single dose > cumulative dose level, bolus injection> infusion and dividing lose Advanced age impaired renal function,low serum albuin,anemia noise, amynoglycoside,diuretics Preexisting hearing loss? individual susceptibility 3. Plateau effect!#Kopelman(1988) 40-60 dB HL over 2-8 kHz <->Myers(1991) 75-90 dB at 6-8 kHz Inner ear pathology 1. The most severe damage in the third row of outer hair cell stereocilia bundles at basal turn.(tips links, disarrayed or fused, decreased in number) 2. Remaining rows of OHCs and IHCs damaged, shrink and disappear

3. Stria vascularis damagedthe entire organ of corti, Reissner $s membrane collapse 4. Lack of morphological change in the vestibular neuroepithelium in guinea pig Cellular action--Oxidative stress-induced apoptosis 1. Depletion of glutathione and antioxidant enzymes in cochlea(Ravi et al.,1995) 2. Administrate ROS into perilymphatic space causes decreased threshold sensitivity(Clarici and Yang ,1996) 3. Devarajan(2002) :Early but transient activation of caspase 8,and a subsequent but prolonged activation of caspase 9 after cisplatin treatment.

Cisplatin Chemoprotection 1. Free radical scavengers: systemic vs locally apply on R.W Alpha tocopherol(Vit E) (Masa-aki Teranishi 2001,2003) ABR response threshold , lipid perioxidation in cochlea, substantial loss of hair cell Thio-containing aminoacid (d- Methionine,L-Methionine) ,thiourea: bind cisplatin itself or reverse the binding od cisplatin to GSH Salicylate :scanvenger, or inhibit NFkB translocation to the nucleus L-N-Acetyl-cysteine: free radical scanvenger, precursor of free intracellular cysteine( be used to synthesize intracellular glutathione) 2. Iron chelator, calcium chelator 3. Neurotrophin-based gene therapy( HSVnt-3myc/SV40lac ) 4. pH manipulation: acidification of inner ear fluid result in more toxic complex of cisplatin Caspase inhibitor: short term protection Cisplatin gel :1~6 mg/m2 of tumor,20 %complete respose. Audiologic monitoring of ototoxicity 1.Baseline audiologic assessment, esp in patient receive high dose of cisplatin (100~120 mg/m2) 2.High-frequency audiometry (10K to 20K Hz) 3.TEOAE: for pediatric patient Reference: 1. Rybak, Leonard P.; Kelly, Thomas . Ototoxicity: bioprotective mechanisms Current Opinion in Otolaryngology & Head and Neck Surgery: Volume 11(5) October 2003 pp 328-333 2. Teranishi M, Nakashima T: Effects of trolox, locally applied on round windows, on cisplatin-induced ototoxicity in guinea pigs. Int J Pediatr Otorhinolaryngol 2003, 67:133%139. 3. Teranishi M, Nakashima T, Wakabayashi T: Effects of alpha-tocopherol on cisplatin-induced ototoxicity in guinea pigs. Hear Res 2001, 151:61%70. 4. Bowers WJ, Chen X, Guo H, et al.: Neurotrophin-3 transduction attenuates cisplatin spiral ganglion ototoxicity in the cochlea. Mol Ther 2002, 6:12%18. 5. Yuan J, Yankner BA: Apoptosis in the nervous system. Nature 2000, 407:802%809. 6. Huang T, Cheng AG Oxidative stress-induced apoptosis of cochlear sensory cells: otoprotective strategies. Int J Dev Neurosci. 2000 Apr-Jun;18(2-3):259-70. 7. Devarajan P, Savoca M Cisplatin-induced apoptosis in auditory cells: role of

death receptor and mitochondrial pathways Hear Res. 2002 Dec;174(1-2):45-54

8. Strasser A, O'Connor L, Dixit VM: Apoptosis signaling. Annu Rev Biochem 2000, 69:217%245. 9.Ballenger $s Otolaryngology Head and neck surgery 16th edition