WR-2721 (Amifostine) ameliorates cisplatin-induced hearing loss but causes neurotoxicity in hamsters: dose-dependent effects

Abstract

Chemoprotective agents reduce the toxic side effects of chemotherapy agents such as cisplatin. The conventional belief is that the chemoprotective agent WR-2721 (Amifostine), while protecting against most cisplatin-induced side effects, does not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in possibly protecting against cisplatin-induced ototoxicity. Thus, the dose-dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 18, 40, 80, or 400 mg/kg/injection of the rescue agent WR ( n = 5 or 10/group). Other groups received either 80 mg/kg/injection WR alone ( n = 5) or were untreated ( n = 14). Ototoxicity was assessed by auditory brain stem responses (ABR). WR provided dose-dependent rescue from cisplatin's ototoxicity with no protection at the low dose of 18 mg/kg, moderate protection at 40 mg/kg, and nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or higher caused neurotoxicity as evidenced by prolongations in the ABR's interpeak latencies. Thus, high doses of WR provided the beneficial effect of protecting against cisplatin-induced ototoxicity, but had the harmful side effect of neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced ototoxicity were likely due to the use of WR doses that were too small. The clinical implications of the beneficial and harmful effects of high doses of WR are discussed.

Figure 1

Serial ABRs evoked by 16,000 Hz tone pips. A. ABRs from a typical Control animal with an ABR clearly visible at 40 dB. B. ABRs from a typical CIS-treated animal with reduced amplitudes, prolonged latencies, and threshold elevated to about 80 dB. C. ABRs from a typical CIS + WR80 animal with preservation of amplitudes and threshold. The ABRs from the Control animal were adapted from a previous publication (Church et al. 1995).

Figure 2

Mean ABR threshold shifts as functions of treatment condition and tone pip frequency. The Control group’s data are represented by the normalized values of 0 dB. The pooled standard error (SE) values for the 2, 4, 8, 16, and 20 kHz conditions were 0.8, 0.9, 2.7, 3.8, and 3.3 dB, respectively; ^*signifies mean is significantly different from Control values; ** signifies mean is significantly different from corresponding Control and CIS + WR40 values.

Figure 3

ABR latency–intensity (L–I) profiles from typical animals in the CIS, CIS + WR40 and CIS + WR80 groups (stimulus = 16,000 Hz tone pips). The shaded region is the range of normalcy derived from Control data (means ± 2 SD). The thin dark lines show the L–I profiles of individual animals. A. Animals in the CIS group had L–I profiles suggestive of moderate to severe recruitment-type sensorineural hearing loss (SNHL). B, C. Animals in the CIS + WR40 and CIS + WR80 groups showed progressively greater protection from CIS-induced SNHL.

Figure 4

Mean P4–P1 interpeak latencies (IPLs) as functions of treatment condition and tone pip frequency (stimulus intensity = 100 dB). Treatment groups receiving WR doses of 40 mg/kg or higher had significantly longer P4–P1 IPLs than treatment groups receiving little or no WR treatment. P4–P1 IPL mean values of 2.62 ms or greater were significantly prolonged relative to the Control group (p < 0.05). Standard error (SE) values for the individual means ranged from 0.021 to 0.102 ms.