Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy.
Our aim was 2-fold: to investigate the role of alpha-tocopherol supplementation on the antitumor activity of DDP and to evaluate the effect of alpha-tocopherol on the survival and neurotoxicity of DDP-treated mice. Experiments performed on the M14 human melanoma line demonstrated that alpha-tocopherol supplementation did not influence the efficacy of DDP; the inhibition of cell survival and of the in vivo tumor growth after treatment with alpha-tocopherol and DDP combination was similar to that observed after DDP alone. Conversely, alpha-tocopherol was also able to increase survival of mice treated with a high dose of DDP. While DDP alone produced death in about 70% of mice, the combination reduced deaths to about 30%. Analysis of oxidative stress markers and peroxidative damage in organs indicated that the protective effect of alpha-tocopherol was mainly related to its antioxidant activity. A significant increase in the concentration of TBARS and decreased PUFAs and catalase activity were observed after DDP treatment, while with alpha-tocopherol the levels of these markers were comparable to those observed in untreated mice. Histologic analysis performed on peripheral nerve revealed that alpha-tocopherol also protected mice from severe neurologic damage induced by DDP treatment. In conclusion, our results demonstrate that alpha-tocopherol protects against the systemic toxicity and neurotoxicity induced by DDP without interfering with its antitumor activity and suggest that this combination is a promising strategy to improve the therapeutic index of DDP-based chemotherapy.
Leonetti
Carlo
C
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy. leonetti@ifo.it
Biroccio
Annamaria
A
Gabellini
Chiara
C
Scarsella
Marco
M
Maresca
Vittoria
V
Flori
Enrica
E
Bove
Loredana
L
Pace
Andrea
A
Stoppacciaro
Antonella
A
Zupi
Gabriella
G
Cognetti
Francesco
F
Picardo
Mauro
M
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009420:Nervous System / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D015996:Survival Rate; D013997:Time Factors; D014407:Tumor Cells, Cultured; D024502:alpha-Tocopherol / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D024502:alpha-Tocopherol; D002945:Cisplatin