L- and D- methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity

D. Reser, M. Rho, D. Dewan, L. Herbst, G. Li, H. Stupak, K. Zur, J. Romaine, D. Frenz, L. Goldbloom, R. Kopke, Joseph C. Arezzo, T. Van De Water

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Abstract

Treatment of metastatic tumors with ionic platinum compounds is hampered by the potent nephrotoxic, ototoxic and neurotoxic properties of these drugs. Recent studies have shown that sulfur-containing antioxidants relieve the dose limiting side effects of cisdiamminedichloroplatinum (CDDP), the most commonly used ionic platinum therapy. Here we report that both isomers of the sulfur-containing antioxidant methionine (MET) completely block the in vivo ototoxic and nephrotoxic effects of CDDP, and the duration of MET otoprotection is longer than has been previously reported. Rats treated with either L- or D-MET in addition to CDDP exhibited no signs of auditory system damage after 7 days, as evaluated by the auditory brainstem response and scanning electron microscopic examination of the organ of Corti, while CDDP- treated rats exhibited pronounced evidence of ototoxic damage after only 3 days. Microscopic examination of kidney tissue revealed moderate to severe nephrotoxic damage to CDDP-treated rats after 5 days, while rats co-treated with either MET isomer showed no evidence of kidney damage. Mortality among CDDP-treated subjects increased steadily over the period of the study, while all of the MET-protected rats survived. Finally, the efficacy of CDDP in the presence of L- or D-MET was evaluated in vitro using cultures of MTLN-3 breast tumor cell lines, and in vivo using implanted MTLN-3 tumors. Both L- and D-MET reduced the ability of CDDP to kill tumor cells in vitro and in vivo, however, our data suggest that a higher proportion of the antineoplastic activity of CDDP is retained in the presence of L- MET.

Original languageEnglish (US)
Pages (from-to)731-748
Number of pages18
JournalNeuroToxicology
Volume20
Issue number5
StatePublished - 1999

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Methionine
Antineoplastic Agents
Rats
Tumors
Sulfur
Isomers
Microscopic examination
Antioxidants
Cells
Platinum Compounds
Kidney
Organ of Corti
Neoplasms
Brain Stem Auditory Evoked Potentials
In Vitro Techniques
Platinum
Tumor Cell Line
Cell culture
Electrons
Tissue

Keywords

  • Auditory Brainstem Response
  • Cancer
  • Cisplatin
  • Evoked Potentials
  • Methionine
  • Otoprotection
  • Ototoxic Hearing Loss

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Toxicology

Cite this

L- and D- methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity. / Reser, D.; Rho, M.; Dewan, D.; Herbst, L.; Li, G.; Stupak, H.; Zur, K.; Romaine, J.; Frenz, D.; Goldbloom, L.; Kopke, R.; Arezzo, Joseph C.; Van De Water, T.

In: NeuroToxicology, Vol. 20, No. 5, 1999, p. 731-748.

Research output: Contribution to journalArticle

Reser, D, Rho, M, Dewan, D, Herbst, L, Li, G, Stupak, H, Zur, K, Romaine, J, Frenz, D, Goldbloom, L, Kopke, R, Arezzo, JC & Van De Water, T 1999, 'L- and D- methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity', NeuroToxicology, vol. 20, no. 5, pp. 731-748.
Reser, D. ; Rho, M. ; Dewan, D. ; Herbst, L. ; Li, G. ; Stupak, H. ; Zur, K. ; Romaine, J. ; Frenz, D. ; Goldbloom, L. ; Kopke, R. ; Arezzo, Joseph C. ; Van De Water, T. / L- and D- methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity. In: NeuroToxicology. 1999 ; Vol. 20, No. 5. pp. 731-748.
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abstract = "Treatment of metastatic tumors with ionic platinum compounds is hampered by the potent nephrotoxic, ototoxic and neurotoxic properties of these drugs. Recent studies have shown that sulfur-containing antioxidants relieve the dose limiting side effects of cisdiamminedichloroplatinum (CDDP), the most commonly used ionic platinum therapy. Here we report that both isomers of the sulfur-containing antioxidant methionine (MET) completely block the in vivo ototoxic and nephrotoxic effects of CDDP, and the duration of MET otoprotection is longer than has been previously reported. Rats treated with either L- or D-MET in addition to CDDP exhibited no signs of auditory system damage after 7 days, as evaluated by the auditory brainstem response and scanning electron microscopic examination of the organ of Corti, while CDDP- treated rats exhibited pronounced evidence of ototoxic damage after only 3 days. Microscopic examination of kidney tissue revealed moderate to severe nephrotoxic damage to CDDP-treated rats after 5 days, while rats co-treated with either MET isomer showed no evidence of kidney damage. Mortality among CDDP-treated subjects increased steadily over the period of the study, while all of the MET-protected rats survived. Finally, the efficacy of CDDP in the presence of L- or D-MET was evaluated in vitro using cultures of MTLN-3 breast tumor cell lines, and in vivo using implanted MTLN-3 tumors. Both L- and D-MET reduced the ability of CDDP to kill tumor cells in vitro and in vivo, however, our data suggest that a higher proportion of the antineoplastic activity of CDDP is retained in the presence of L- MET.",
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T1 - L- and D- methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity

AU - Reser, D.

AU - Rho, M.

AU - Dewan, D.

AU - Herbst, L.

AU - Li, G.

AU - Stupak, H.

AU - Zur, K.

AU - Romaine, J.

AU - Frenz, D.

AU - Goldbloom, L.

AU - Kopke, R.

AU - Arezzo, Joseph C.

AU - Van De Water, T.

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AB - Treatment of metastatic tumors with ionic platinum compounds is hampered by the potent nephrotoxic, ototoxic and neurotoxic properties of these drugs. Recent studies have shown that sulfur-containing antioxidants relieve the dose limiting side effects of cisdiamminedichloroplatinum (CDDP), the most commonly used ionic platinum therapy. Here we report that both isomers of the sulfur-containing antioxidant methionine (MET) completely block the in vivo ototoxic and nephrotoxic effects of CDDP, and the duration of MET otoprotection is longer than has been previously reported. Rats treated with either L- or D-MET in addition to CDDP exhibited no signs of auditory system damage after 7 days, as evaluated by the auditory brainstem response and scanning electron microscopic examination of the organ of Corti, while CDDP- treated rats exhibited pronounced evidence of ototoxic damage after only 3 days. Microscopic examination of kidney tissue revealed moderate to severe nephrotoxic damage to CDDP-treated rats after 5 days, while rats co-treated with either MET isomer showed no evidence of kidney damage. Mortality among CDDP-treated subjects increased steadily over the period of the study, while all of the MET-protected rats survived. Finally, the efficacy of CDDP in the presence of L- or D-MET was evaluated in vitro using cultures of MTLN-3 breast tumor cell lines, and in vivo using implanted MTLN-3 tumors. Both L- and D-MET reduced the ability of CDDP to kill tumor cells in vitro and in vivo, however, our data suggest that a higher proportion of the antineoplastic activity of CDDP is retained in the presence of L- MET.

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KW - Cancer

KW - Cisplatin

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KW - Otoprotection

KW - Ototoxic Hearing Loss

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