Cisplatin by Ray Sahelian, M.D.

Cisplatin is a pharmaceutical chemotherapy drug that is used widely to treat different cancers including testicular, germ cell, head and neck, bladder and lung cancer. At the center of this drug is an atom of the metal platinum. It is this platinum that poisons the cancer cells. Cisplatin belongs to the group of medicines known as alkylating agents.

Cisplatin Side Effects
The most common problems experienced during cisplatin therapy and overdosage include nephrotoxicity, electrolyte disturbances, myelosuppression, neurotoxicity, anaphylactic reactions, and ototoxicity. Side effects with cisplatin include:

Fatigue - this is the most common cisplatin side effect and can last several weeks or months after cisplatin treatment is completed. Some people experience shortness of breath.
Nausea from cisplatin can be severe, however anti-nausea medicines can significantly reduce this cisplatin side effect.
Kidney damage can occur with cisplatin treatment
Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2.

Decrease in certain blood cells. Cisplatin can damage tissues and cells in the bone marrow. This can result in infections, anemia, or low platelet count leading to easy bruising.

Reducing cisplatin toxicity

There are several supplements that should be considered in an attempt to decrease cisplatin toxicity. It appears that antioxidants are helpful.

Acetyl-L-Cysteine may increase intracellualr glutathione levels and has been shown to reduce toxicity in rodents treated with cisplatin.

Vitamin E could be helpful as an antioxidant.
Alpha-lipoic acid may protect against cisplatin auditory toxicity in rats.

Ginko Biloba extract was also shown to protect against cisplatin auditory toxicity in rats.

Melatonin is a sleep hormone with potent antioxidant and anti-tumor activity

Quercetin could be helpful in reducing damage to the kidneys.

N Acetylcysteine and cisplatin ototoxicity

Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels.
J Pharmacol Exp Ther. 2005 Sep;314(3):1052-8. Epub 2005 Jun 10. Oregon Health & Science University, Department of Neurology, Portland, 97239, USA.
Cisplatin is a common, highly toxic chemotherapeutic agent. This study investigates chemoprotective effects of N-acetylcysteine (NAC) and sodium thiosulfate (STS) on in vitro and in vivo cisplatin toxicities. For ototoxicity studies, cisplatin (6 mg/kg) was administered to rats via a retrograde carotid artery infusion. Conclusion: the chemoprotection route and timing of administration can be manipulated to maintain cisplatin antitumor efficacy while protecting against toxicities.

Protection against cisplatin toxicity by administration of glutathione ester
The FASEB Journal, Vol 4, 3251-3255. ME Anderson, A Naganuma and A Meister. Department of Biochemistry, Cornell University Medical College, New York, New York.
The role of cellular glutathione in the prevention of toxicity due to the anti-cancer drug cisplatin was explored in mice treated with buthionine sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase (and therefore of glutathione synthesis), and with glutathione and glutathione monoisopropyl ester. Conclusion: The finding that glutathione ester is more effective than glutathione in protecting against the toxicity of cisplatin suggests that use of glutathione ester may be therapeutically advantageous.
     Dr. Sahelian comments: I wonder if acetylcysteine may have a similar effect to glutathione in reducing cisplatin induced toxicity since acetycysteine helps form intracellular glutathione.

Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model.
Hear Res. 2004 Jul;193(1-2):25-30. Department of Neurology, Oregon Health and Science University, Portland, OR 97201-3098, USA.
Cisplatin is a widely used chemotherapeutic agent that is highly ototoxic. Animal studies and clinical trials have shown that thiosulfates can protect against platinum-induced ototoxicity. This study investigated a new model for cisplatin ototoxicity in the rat, and tested the potential chemoprotective effect of administering N-acetylcysteine (NAC) before giving cisplatin. These data show that treatment with NAC can prevent cisplatin -induced ototoxicity in rats.

N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity.
Ren Fail. 2002 Jul;24(4):529-33. Nisar S, Feinfeld DA. Department of Medicine, Nassau University Medical Center, East Meadow, NY 11554, USA.
N-acetylcysteine (NAC) repletes intracellular stores of reduced glutathione and may be a scavenger of oxygen free radicals. We report a 52-year-old female who developed acute renal insufficiency after administration of one dose of 150 mg of cisplatin for treatment of squamous cell cancer of the esophagus. Her blood urea nitrogen and creatinine rose from 12 and 0.7 mg/dL, respectively, to 24 and 1.8 mg/dL on day 5 after cisplatin. On that day the patient was begun on NAC, starting with a loading dose of 140-mg/kg-body weight followed by 70mg/kg every 4h for 4 days. Two days after starting NAC her renal function began to improve, and although she failed to complete a full course of the drug, by day 10 her serum creatinine had fallen to 0.8 mg/dL. A previous report showed that N-acetylcysteine might reverse cisplatin -induced renal toxicity. Our case supports this hypothesis.

n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity.
Laryngoscope. 2001 Jul;111(7):1147-55. Department of Otolaryngology, Albert Einstein College of Medicine, New York, New York, USA.
The aim of this study is to determine the efficacy of L-N-acetyl-cysteine (L-NAC) as a protectant for inner ear auditory sensory cells against the toxic effects of cisplatin. Conclusions: Our in vitro studies have demonstrated that L-NAC protected both auditory neurons and hair cells from the toxic effects of cisplatin. Because it protects both of these inner ear structures, L-NAC may be potentially useful in protecting hearing, in general, from cisplatin-induced damage. In addition, L-NAC has low systemic and mucosal toxicity. It also has a low molecular weight that may allow it to readily cross the round window membrane. All these characteristics make it potentially suitable for transtympanic application for the prevention of the ototoxicity of cisplatin in vivo.

Vitamin E for cisplantin induced hearing loss

Protective effects of alpha-tocopherol and tiopronin against cisplatin-induced ototoxicity.
Acta Otolaryngol. 2004 May;124(4):421-6. Institute of Otolaryngology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
To investigate the possible protective effects of alpha-tocopherol and tiopronin against cisplatin-induced cochlear damage. Cisplatin ototoxicity and nephrotoxicity seem to result from the inhibition of cochlear antioxidant defences, causing an increase in the amount of reactive oxygen species. Antioxidants, such as alpha-tocopherol and tiopronin, are able to suppress lipid peroxidation, thus attenuating tissue damage. CONCLUSION: This study supports the hypothesis that alpha-tocopherol and tiopronin interfere with cisplatin-induced damage, and suggests that concurrent treatment with the two drugs can be useful in protecting against hearing loss.

Vitamin E reduces cisplatin ototoxicity.
Laryngoscope. 2004 Mar;114(3):538-42. Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois
Cisplatin ototoxicity is a major dose-limiting factor in the treatment of several neoplasms. Vitamin E, a slow-acting free radical scavenger, has been shown to ameliorate nephrotoxicity and endothelial cell damage in animals receiving cisplatin. The purpose of the study was to determine the effectiveness of vitamin E as an otoprotectant. itamin E appears to have a protective effect against cisplatin ototoxicity.

Melatonin for cisplantin induced hearing loss
Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.
J Pineal Res. 2000 Mar;28(2):73-80. Unit of Pediatric Otorhinolaryngology, Virgen del Rocio University Infantile Hospital, Sevilla, Spain.
The mechanism of the ototoxicity caused by cisplatin is based in the generation of reactive oxygen species, which interferes with the antioxidant protection of the organ of Corti. Conversely, the protection of the cochlea with antioxidants ameliorates the ototoxicity by cisplatin. The ototoxicity produced by cisplatin can be reversible or persistent, depending on the age of the patient, cumulative doses, number of chemotherapy cycles, history of noise exposure, and deteriorating renal function. We have obtained in rats an ototoxic chart utilizing cisplatin (10 mg/kg body weight injected intraperitoneally, once only). Together with this treatment, the animals were treated with melatonin in the drinking water (10 mg/L) or injected subcutaneously (250 microg), and with an antioxidant mixture, injected subcutaneously, composed of 0.25 mg alpha-tocopherol acid succinate, 3 mg ascorbic acid, 1 mg glutathione, and 60 mg N-acetylcysteine. The ototoxicity produced by cisplatin was maximal from days 7 to 10 post-treatment, returning to normal values in a month. When melatonin and the antioxidant mixture were present, the recovery was between days 10 and 15 post-treatment, independent of the means of administration of the pineal product. We conclude that the ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.

Quercetin for cisplatin induced kidney damage
Comparative study of multiple dosage of quercetin against cisplatin-induced nephrotoxicity and oxidative stress in rat kidneys.
Pharmacol Rep. 2006 Jul-Aug;58(4):526-32. Departamento de Alimentos e Nutricao, Faculdade de Ciencias Farmaceuticas de Araraquara, UNESP, Rod. Araraquara/Jau, km 01, 14801-902, Araraquara, SP, Brazil.
Quercetin, a typical bioflavonoid ubiquitously present in fruits and vegetables, is considered to be helpful for human health. Cisplatin is one of the most active cytotoxic agents in the treatment of a wide range of solid tumors. The aim of this study was to investigate the possible effect of quercetin, a bioflavonoid with antioxidant potential, on cisplatin -induced nephrotoxicity and lipid peroxidation in rats. Gavage administrations of water, propylene glycol and quercetin (50 mg/kg) were made 24 and 1 h before saline or cisplatin (5 mg/kg) ip injections and were repeated daily for 2, 5 or 20 subsequent days. The kidneys were removed to determine the levels of thiobarbituric acid-reactive substances (TBARS) and for histological studies. Cisplatin increased lipid peroxidation, urine volume and plasma creatinine levels and decreased urine osmolality. Treatment with quercetin attenuated these alterations. These results demonstrate the role of oxidative stress and suggest a protective effect of quercetin on cisplatin -induced nephrotoxicity in adult Wistar rats.

Rehmannia  is an option
Protective effect of Rehmannia glutinosa on the cisplatin -induced damage of HEI-OC1 auditory cells through scavenging free radicals.
J Ethnopharmacol. 2006 Oct 11;107(3):383-8. Epub 2006 Apr 6. Department of Food and Nutrition, Kunsan National University, Kunsan, South Korea.
The steamed root of Rehmannia glutinosa has been used in traditional Oriental Medicine for treatment of inner ear diseases, such as tinnitus and hearing loss. In the present study, we showed that the ethanol extract of steamed roots of rehmannia glutinosa protected HEI-OC1 auditory cells from cisplatin cytotoxicity in a dose-dependent fashion. These results indicate that rehmannia glutinosa protects cisplatin -induced HEI-OC1 cell damage through inhibition of lipid peroxidation and scavenging activities of free radials.

How does cisplatin work?
Cisplatin interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells is also be affected by cisplatin, side effects will occur.

How is cisplatin administered?
Cisplatin is given by an injection into the vein over at least 1 hour. Cycles are repeated weekly or more often depending on the type of cancer treated and the spread of the cancer.

Brand names for cisplatin

Cisplatyl, Cytoplatino, Neoplatin, Placis, Platiblastin, Platinex, Platinol, Platistil, Platistin, Platosin.

Cisplatin for anal cancer
Treating anal cancer patients with cisplatin to try to shrink tumors before beginning standard therapy does not boost survival rates.

Cisplatin for lung cancer

Cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, and carboplatin (Paraplatin; Bristol-Myers Squibb), together with newer chemotherapies, such as docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, paclitaxel (Taxol; Bristol-Myers Squibb), vinorelbine (Navelbine; GlaxoSmith-Kline, Philadelphia, (Alimta; Eli Lilly and Company, Indianapolis, and gemcitabine (Gemzar; Eli Lilly and Company), have improved treatment outcomes in advanced non-small cell lung cancer (NSCLC).

Cisplatin and aspirin
Aspirin therapy may help combat some of the toxic effects of the cancer drug cisplatin. In a study reported in the May, 2006 issue of Laboratory Investigation, scientists found that treatment with the aspirin conversion product salicylate reduced hearing and kidney damage in animals given cisplatin. Cisplatin is well known for its nephrotoxic and ototoxic side effects.

Cisplatin emails
Q. I was wondering if any clinical study has been done in role of NAC in cisplatin induced ototoxicity. have read about the n-acetylcysteine experiments on rats but didn't come across any article on any research on human beings.
   A. We have not come across any human studies with cisplatin and acetylcysteine except for one case study.

Q. I read through you article on cisplatin and hearing loss with some of the studies listed. I was wondering if there is anything available to help reverse high frequency hearing loss caused by cisplatin? My 3 year old daughter has sustained severe hearing loss due to cisplatin in treating hepatoblastoma. She is wearing hearing aids, but at an appointment today we were told she had further loss. We are now 4 months post chemo and did not expect more loss. Any information would be appreciated.
   A. The antioxidants discussed on this page, acetylcysteine, vitamin E, etc., are the ones we are familiar with, and we don't know if using them in children would have benefits, but if your doctor approves, they are worth a try. The dosage would be a portion of the adult dosage. We wish her full recovery.

Q. My husband experienced Cisplatin-induced nephrotoxicity after 1 treatment. He has regained some of his kidney function, but the Doctors will not give him contrast on his CT scans now. do you know if there is anything that can be given to protect the kidneys after cisplatin damage. Or any herb or juice that would increase kidney function.
   A. Perhaps you can discuss with your doctor some of the herbs and nutrients discussed above.