2013
DOI: 10.1016/j.taap.2013.09.018
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A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors

Abstract: In human trials certain heat shock protein 90 (Hsp90) inhibitors, including 17-DMAG and NVP-AUY922, have caused visual disorders indicative of retinal dysfunction; others such as 17-AAG and ganetespib have not. To understand these safety profile differences we evaluated histopathological changes and exposure profiles of four Hsp90 inhibitors, with or without clinical reports of adverse ocular effects, using a rat retinal model. Retinal morphology, Hsp70 expression (a surrogate marker of Hsp90 inhibition), apop… Show more

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Cited by 59 publications
(61 citation statements)
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“…In the present study, TAS-116 was distributed less in retina than in plasma in rats; consequently, TAS-116 did not produce any detectable photoreceptor injury. It has been proposed that the retina/plasma drug-exposure ratio and retinal elimination profile might be useful indicators of the ocular toxic potential of HSP90 inhibitors (33). Indeed, our results are consistent with previous results showing that ganetespib does not cause the same degree of visual symptoms and is eliminated from retina more rapidly than other HSP90 inhibitors (33).…”
Section: Discussionsupporting
confidence: 92%
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“…In the present study, TAS-116 was distributed less in retina than in plasma in rats; consequently, TAS-116 did not produce any detectable photoreceptor injury. It has been proposed that the retina/plasma drug-exposure ratio and retinal elimination profile might be useful indicators of the ocular toxic potential of HSP90 inhibitors (33). Indeed, our results are consistent with previous results showing that ganetespib does not cause the same degree of visual symptoms and is eliminated from retina more rapidly than other HSP90 inhibitors (33).…”
Section: Discussionsupporting
confidence: 92%
“…It has been proposed that the retina/plasma drug-exposure ratio and retinal elimination profile might be useful indicators of the ocular toxic potential of HSP90 inhibitors (33). Indeed, our results are consistent with previous results showing that ganetespib does not cause the same degree of visual symptoms and is eliminated from retina more rapidly than other HSP90 inhibitors (33). However, there is the possibility that the lower retinal distribution of some HSP90 inhibitors is merely correlated with lower tissue penetration of the compounds.…”
Section: Discussionmentioning
confidence: 99%
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“…Thirstrup and coworkers noted that HSP90 inhibition in both their study and Chen's 17-AAG study alleviated synaptic impairments well within 24 h and suggested that HSP90 inhibition may work independent of tau clearance (Thirstrup et al 2015). Unfortunately, the toxicity of conventional HSP90 inhibitors limits their role in the clinical setting (Zhou et al 2013).…”
Section: Background: Synapse Formation and Maturationmentioning
confidence: 97%