Toxic Effects Of Cisplatin Research Articles

Protective Effects of Increasing Vitamin E and A Doses on Cisplatin-Induced Oxidative Damage to Kidney Tissue in Rats

Objective: Cisplatin (DDP, cis-diamminedichloroplatinium II) is one of the most potent chemotherapeutic antitumor drugs, but is able to generate reactive oxygen species (ROS) and it also inhibits the activity of antioxidant enzymes in renal tissue. In the present study, we investigated the preventive effect of 100, 200 and 400 mg/kg b.w. doses of vitamin E (VE), and 25, 50, and 100 mg/kg b.w. doses of vitamin A (VA) combination on malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels and superoxide dismutase (SOD) activity in cisplatin-induced toxicity in rat kidneys. Our literature survey indicated a lack of any experimental study showing the beneficial effect of VA on cisplatin-induced MDA, NO, GSH and SOD changes. For this reason, we hoped that this study would provide a unique contribution in that respect. Materials and Methods: 59 Wistar rats (11 to replace prematurely lost animals) were used. 48 evaluable rats were divided into 8 groups (n = 6 in each group): control group, DDP alone (5 mg/kg b.w.) group, 3 VE combination treatment groups of VE100+DDP, VE200+DDP, and VE400+DDP, and 3 VA combination treatment groups of VA25+DDP, VA50+DDP, and VA100+DDP. Kidney MDA, GSH, NO levels and SOD activities were determined for the assessment of oxidant-antioxidant balance. Results: While in the DDP group the tissue levels of MDA and NO were found to be significantly higher than in the control group, GSH levels and SOD activities were significantly lower. MDA and NO levels were found to be significantly lower and GSH levels and SOD activities significantly higher in the VE200+DDP and VE400+ DDP groups when compared with the DDP alone group. MDA and NO levels were found to be significantly lower in the VA50+DDP and VA100+DDP groups when compared with the DDP alone group. However, identical comparisons with the DDP alone group showed significantly higher GSH levels and SOD activities in the VA25+DDP, VA50+DDP, and VA100+DDP groups. Among the VE100+ DDP, VE200+DDP, and VE400+DDP groups, and VA25+ DDP, VA50+DDP, and VA100+DDP groups, MDA and NO levels decreased and GSH levels and SOD activities increased steadily and significantly as the doses of VE and VA increased. Conclusion: These vitamins would be effective in protecting against cisplatin-induced tissue damage in rat kidneys. It is possible that the toxic effect of cisplatin is somehow minimized by a compensatory mechanism involving VE and VA via induction of antioxidant enzyme activities following intraperitoneal injection of DDP.

Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin

Cisplatin, a cancer chemotherapy agent, like many toxins, produces emesis and nausea. Abdominal vagotomy, or treatment with 5-HT 3 receptor antagonists, blocks cisplatin-induced emesis, which suggests that it produces (albeit indirectly) activation of 5-HT 3 receptors on vagal afferent fibers. Cisplatin induces a large release of intestinal 5-hydroxytryptamine (5-HT) that enters the hepatic portal vein, which may activate vagal afferent fibers in the portal vein or liver to induce emesis or other side effects of treatment (e.g., reduced food intake). This study was conducted to assess the effects of cisplatin on gastrointestinal and portal vein/liver vagal afferent fibers by recording the neurophysiological responses of the common hepatic branch (CHB) of the vagus in the rat. The CHB contains vagal afferent fibers that innervate the gastrointestinal (GI) tract, portal vein, and liver. Cisplatin (10 mg/kg; jugular vein, j.v.) produced an increase in multi-unit CHB activity and this effect was blocked by a 5-HT 3-receptor antagonist (Y-25130, 0.8 mg, j.v.). Cutting the gastroduodenal branch (GDB), a sub-branch of the CHB that contains GI afferent fibers, resulted in a complete suppression of the multi-unit CHB discharge produced by cisplatin treatment. Single units that were cisplatin sensitive had their activity reduced by either 5-HT 3 receptor antagonist treatment or cutting the GDB. Conversely, cisplatin insensitive units were not affected by 5-HT 3-antagonism or GDB ablation. The present results indicate that cisplatin activates GI vagal afferent fibers via 5-HT 3 receptors but does not affect portal vein/liver vagal afferent fibers, which indicates that intestinal but not hepatic afferent fibers are involved in the toxic effects of cisplatin.

Copper(II) protects yeast against the toxicity of cisplatin independently of the induction of metallothionein and the inhibition of platinum uptake

We have made the unexpected discovery that copper sulfate protects Saccharomyces cerevisiae from the toxic effects of cisplatin. Addition of copper to the culture medium of yeast cells at concentrations above 0.1 μM significantly reduced the toxicity of cisplatin. Since a high-affinity copper transporter, Ctr1, has been reported to play a major role in the uptake of cisplatin, we examined the effects of copper on the cellular uptake of cisplatin. We found that the cellular concentration of platinum was not significantly affected by treatment of cells with 1 μM copper. It is known that mammalian metallothionein is induced by copper and is involved in acquired resistance to cisplatin. Copper significantly increased the level of mRNA for yeast metallothionein at a concentration that has effectively reduced the toxicity of cisplatin. However, the toxicity of cisplatin in cells with a disrupted gene for ACE1, a factor that regulates transcription of the yeast gene for metallothionein, was also significantly reduced by treatment with copper. These results suggest that copper protects yeast cells from cisplatin toxicity independently of induction of the synthesis of metallothionein and of the inhibition of platinum uptake. Since copper is one of the trace elements that are essential for cell function and since a relatively low concentration of copper (0.1 μM) significantly reduced cisplatin toxicity, it is possible that copper might play an important role in the expression of cisplatin toxicity.

Cisplatin ototoxicity in the guinea pig: vestibular and cochlear damage

The aim of the present study was to investigate both vestibular and cochlear cisplatin toxicity. Twelve albino guinea pigs were divided into an experimental ( n=8) and a control saline group ( n=4) and were treated with cisplatin at a daily dose of 2.5 mg/kg for 6 consecutive days. Vestibular dysfunction was evaluated by computing the gain of the vestibular ocular reflex (VOR) evoked by stimulation in the horizontal (HVOR) and vertical (VVOR) planes. Changes in cochlear function were characterised as compound action potential threshold shifts. After the functional testing, tympanic bullae were removed and processed for morphological examination of the sensorineural epithelium. The onset of vestibular functional impairment was observed on the third day, although the VOR gain decrease was not significant. The impairment of the vestibular function progressed until the sixth day becoming statistically significant particularly at VVOR mid frequencies of stimulation. At these frequencies both macula and crista ampullaris functions are involved. Concomitantly a progressive auditory threshold shift was observed at all stimulus frequencies. The decline of the auditory function was statistically significant from the third day of treatment and it was more evident at high frequencies. Morphological observations showed a massive loss of outer hair cells and a degeneration of the organ of Corti in the basal/middle turns and only a slight loss of hair cells of the cristae ampullares and maculae. In conclusion, functional and morphological data provide evidence that the toxic effect of cisplatin is more pronounced in the organ of Corti than in the vestibular epithelium.

D-Methionine and cisplatin ototoxicity in the guinea pig: D-methionine influences cisplatin pharmacokinetics

D-Methionine has recently been advocated as a protectant against cisplatin toxicity. The use of systemic D-methionine as a protector was studied in 58 guinea pigs. Kinetics and distribution of [ 11CH 3] D-methionine was analysed by positron emission tomography. Cisplatin and the monohydrated complex of cisplatin was quantified in blood ultrafiltrate using reversed-phase liquid chromatography with post-column derivatisation. Administration of 300 mg/kg of D-methionine caused a 30% decrease in the area under the concentration–time curve (AUC) of cisplatin. The toxic effect of cisplatin was studied after dose adjustment of cisplatin, i.e. with similar cisplatin AUC in the group receiving D-methionine and the saline control group. A significant ototoxic effect, measured as difference in pre- and 96 h post-treatment electrophysiological hearing threshold (auditory brainstem response), was observed at stimulus frequencies of 30 and 20 kHz. There was no difference between the groups in the extent of threshold shift. Quantitative outer hair cell counts showed a similar loss of cells in the two groups. All animals had a significant increase in plasma-creatinine but there was no difference between the groups. The results indicate that protection from cisplatin ototoxicity by systemic D-methionine can be explained by a lowered systemic exposure to the drug.

Vitamin E Protection from/ Potentiation of the Cytogenetic Toxicity of Cisplatin in Swiss Mice

Possible protection from or potentiation of the cytogenetic toxic effects of cisplatin (CP) 5 mg/kg b.w. in mouse bone marrow, spermatogonia by three different doses of ∞-tocopheryl acetate (vitamin E) 100, 200 and 300 mg/kg, and the transmission of such effects in the male germline, were assessed. CP-induced chromosomal aberrations (CAs) in bone marrow were decreased in vitamin E pretreated mice, but significantly (P ≤0.05) only with vitamin E 300 mg/kg. The percentages of dividing cells in bone marrow were increased in vitamin E-pretreated groups of mice, but not significantly. However, the frequency of CP-induced micronuclei (MN) in polychromatic erythrocytes (PCEs) declined significantly (P ≤0.01) in all the vitamin E-pretreated groups of mice. In spermatogonia the CP-induced CAs were also decreased significantly by vitamin E 200 mg/kg (P ≤0.01), and 100 and 300 mg/kg (P ≤0.05). However, transmission of CP-induced cytogenetic toxic effects from spermatogonia to spermatocyte, resulting in the formation of aberrant primary spermatocytes, was enhanced significantly in the mice pretreated with vitamin E 100 mg/kg (P ≤0.05) and 200 mg/kg (P ≤0.01). But the enhancement in the transmission of such effects was not significant in the mice pretreated with vitamin E 300 mg/kg. Besides, there was no significant change in vitamin E-pretreated groups of mice in the transmission of cytogenetic toxicity of CP from spermatogonia to sperm with the manifestation of abnormal sperm morphology. Thus, vitamin E protected bone marrow and spermatogonia from the cytogenetic toxic effects of CP, particularly efficiently at the highest tested dose (300 mg/kg), but it failed to protect from the transmission of such effects in the male germline of mouse and rather potentiated them to some extent. Treatment with vitamin E, an antioxidant, might be capable of protecting noncancerous cells from the oxidative damage caused by cisplatin but it might also reduce the effects of cisplatin on cancerous cells. Thus, the benefits of antioxidant treatment during cancer chemotherapy is yet to be demonstrated clearly.

Lack of correlation between cisplatin cytotoxic effect and potential Na, K-adenosine triphosphatase (Na, K-ATPase) activity or intracellular level of glutathione

The use of cisplatin as a cancer chemotherapeutic agent is limited by its dose dependent nephrotoxicity. It has been suggested that the differential toxic effects of cisplatin may be related to differences in Na+/K+ ATPase activity or levels of glutathione (GSH). The present study evaluated these possibilities by testing cells from different tissue origins for their sensitivities to cisplatin and the numbers of Na+/K+ ATPase, affinities to ouabain and intracellular glutathione levels. Our results have shown that the cytotoxic effect of cisplatin was in the order of Calu-1>U-138MG>HEK>SK-HEp1>AGS>TL cells. Dissociation contants (K-d) of the different cell lines to ouabain revealed that the U-138MG cells (29 pM) had the highest affinity while the SK-HEp1 cells (123 pM) had the lowest. In addition the most number of ouabain binding sites was detectable on the Calu-1 cells (2.388x10(5)/cell) with the lowest in the U-138MG (5.22x10(4)/cell) cells. Linear regression analysis of these data indicate that there is no correlation between toxicity of cisplatin to the density (p=0.6563) or affinity (p=0.5499) of the Na+/K+ ATPase to ouabain on the responding cells. Nor is there a direct correlation between cisplatin toxicity and the level of intercellular GSH. These results suggest that activity of Na+/K+ ATPase or level of GSH alone is not sufficient to account fbr the differential toxicity of cisplatin nor is it a necessary trait of cisplatin resistance.

Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomised trial

Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control--58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.

Effects of S-CMC on the Cisplatin Toxicity in Rats

In the present study, some toxic effects of cisplatin are evaluated in rats. It was also investigated whether S-carboxymethylcysteine (S-CMC), a free radical scavenger, protects the experimental animals from the toxic effects of cisplatin. The 1st, 2nd, 4th and 5th groups received physiological saline, dimethyl sulphoxide, and S-CMC (100 and 500 mg/kg i.p.) for 3 days, respectively. The 3rd group received cisplatin (5 mg/kg i.p.) 12 h before sacrifice. The 6th and 7th groups received S-CMC (100 and 500 mg/kg i.p., respectively); additionally, these groups received cisplatin (5 mg/kg i.p.) 12 h before the rats were sacrificed. 5 mg/kg cisplatin decreased significantly serum creatinine and glutamic-oxaloacetic and glutamic-pyruvic transaminase levels as well as leucocyte counts. Although S-CMC did not change the effects of cisplatin on creatinine and liver enzyme levels, it eliminated the effect of cisplatin on leucocyte counts. Cisplatin increased significantly urinary creatinine level and creatinine clearance. Cisplatin caused some histological changes in kidney and liver.

Repair of cisplatin--DNA adducts by the mammalian excision nuclease.

Nucleotide excision repair is one of the many cellular defense mechanisms against the toxic effects of cisplatin. An in vitro excision repair assay employing mammalian cell-free extracts was used to determine that the 1,2-d(ApG) intrastrand cross-link, a prevalent cisplatin-DNA adduct, is excised by the excinuclease from a site-specifically modified oligonucleotide 156 base pairs in length. Repair of the minor interstrand d(G)/d(G) cross-link was not detected by using this system. Proteins containing the high mobility group (HMG) domain DNA-binding motif, in particular, rat HMG1 and a murine testis-specific HMG-domain protein, specifically inhibit excision repair of the intrastrand 1,2-d(GpG) and -d(ApG) cross-links. This effect was also exhibited by a single HMG domain from HMG1. Similar inhibition of repair of a site-specific 1,2-d(GpG) intrastrand cross-link by an HMG-domain protein also occurred in a reconstituted system containing highly purified repair factors. These results indicate that HMG-domain proteins can block excision repair of the major cisplatin-DNA adducts and suggest that such an activity could contribute to the unique sensitivity of certain tumors to the drug. The reconstituted excinuclease was more efficient at excising the 1,3-d(GpTpG) intrastrand adduct than either the 1,2-d(GpG) or d(ApG) intrastrand adducts, in agreement with previous experiments using whole cell extracts [Huang, J. -C., Zamble, D. B., Reardon, J. T., Lippard, S. J., Sancar, A. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 10394-10398]. This result suggests that structural differences among the platinated DNA substrates, and not the presence of unidentified cellular factors, determine the relative excision repair rates of cisplatin-DNA intrastrand cross-links in the whole cell extracts.

Leuprolide acetate prevents toxic effects of cisplatin on the kidneys and gastrointestinal tract.

We examined the protective effects of medical castration by means of gonadotropin-releasing hormone analogue (GnRHA) on the toxic effects of cisplatin in rats. Twelve days after a s.c. injection of a slowly-releasable form of leuprolide acetate (GnRHASR), rats were injected i.p. with cisplatin daily (3 mg/kg body weight (BW) for males and 4 mg/kg BW for females) for four days and sacrificed 24 h after the last injection. The doses caused acute tubular necrosis and gastrointestinal (GI) symptoms, i.e., diarrhea and fluid retention and bleeding in GI tract. GnRHASR pretreatment reduced serum urea nitrogen (SUN) and serum creatinine (SCre) increase and the incidence of GI symptoms. Histological analysis showed that rats pretreated with GnRHASR had noticeably less kidney damage. GnRHA thus demonstrated its ability to protect the kidneys and GI tract against cisplatin toxicity in both male and female rats. This finding suggests a potential clinical application of GnRHA in antineoplastic chemotherapy.

Cisplatin induced nephrotoxicity and the modulating effect of glutathione ester.

The objective of this study was to assess the therapeutic advantage of glutathione ester along with cisplatin. Comparisons were made with renal reduced glutathione, enzymatic antioxidants, and lipid peroxidation levels. Cisplatin caused differential toxic effects on renal antioxidants and lipid peroxidation. However administration of glutathione ester modulates the toxic effects of cisplatin observed in renal antioxidants and lipid peroxidation. The finding that glutathione ester co-administration along with cisplatin is more effective and advantageous in protecting against the nephrotoxicity of cisplatin when it was given alone.

Protection by an ACTH4-9 analogue against the toxic effects of cisplatin and taxol on sensory neurons and glial cells in vitro.

Sensory neuropathy is a serious side effect of anti-tumour drugs such as cisplatin and taxol. There are indications that an analogue of the adrenocorticotrophic hormone 4-9 fragment (ACTH4-9: Met(O2)-Glu-His-Phe-D-Lys-Phe) can prevent these neurotoxic effects. We studied the potential protective effects of this analogue in cultures of chick dorsal root ganglia and rat Schwann cells treated with cisplatin or taxol to gain insight into the mode of action and characteristics of this neuroprotection. Neurite outgrowth of sensory neurons in vitro was dose-dependently inhibited by cisplatin and taxol; after 48 hr, 10 micrograms/ml cisplatin reduced outgrowth from 431 +/- 17 microns to 220 +/- 6 microns and 0.01 micrograms/ml taxol from 344 +/- 3 microns to 200 +/- 43 microns. Co-treatment of 10 micrograms/ml cisplatin with the ACTH4-9 analogue (0.1 nM-1 nM) resulted in about 35% more outgrowth than cisplatin alone. In contrast, the analogue could not prevent taxol neurotoxicity. Migration of neurons and satellite cells from the DRG-body is completely inhibited by 10 micrograms/ml cisplatin. Taxol had no effect on the migration of these cells. In addition, cisplatin was more toxic to Schwann cells than taxol; 3-10 micrograms/ml cisplatin significantly reduced their laminin content, total protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase activity, and cell division. The ACTH4-9 analogue (0.01 nM-100 nM) had no effect on the migration of cells out of the DRGs and could not prevent the toxic effect on the Schwann cells. These data support our hypothesis that the neuroprotective effect of ACTH4-9 analogue is brought about by a direct action on neurons, possibly by replacing a Schwann-/satellite-cell derived trophic factor.

Amelioration of cisplatin toxicity in rat renal cortical slices by dithiothreitol in vitro.

1. The protective effects of dithiothreitol (DTT) on cisplatin-induced nephrotoxicity were investigated with rat renal cortical slices. 2. The nephrotoxic effects of cisplatin (2 mmol l-1) were manifested in several ways: the Na+ and water content were increased while K+ was decreased. The malondialdehyde (MDA) concentration in the slices and the lactate dehydrogenase (LDH) released into the medium were increased. The uptake of p-aminohippurate (PAH), the synthesis of glucose and the glutathione (GSH) concentration in the slices were all decreased. 3. Despite a DTT-related increase in platinum (Pt) uptake by the slices, DTT (0.5-2 mmol l-1) ameliorated all these toxic effects of cisplatin in a concentration related manner. 4. The results suggest that the protective mechanism of DTT is its antioxidative action. DTT is also a metal chelator, however, and so a protective effect via chelation of Pt by DTT cannot be excluded.

Alpha-melanocyte-stimulating hormone has protective properties against the toxic effect of cisplatin on cultured dorsal root ganglia.

Alpha-melanocyte-stimulating hormone has protective properties against the toxic effect of cisplatin on cultured dorsal root ganglia.

Toxic effects of cisplatin alone and in combination with gentamicin in stria vascularis of guinea pigs

The toxic effects on the stria vascularis of treatment with cisplatin alone and combined with the aminoglycoside antibiotic, gentamicin, were studied in guinea pigs. The toxicity induced in albino and pigmented guinea pigs was investigated morphologically with light and transmission electron microscopy, and functionally by brainstem-evoked response audiometry. The results of hearing thresholds were variable, ranging from no change in one ear in some of the animals to a hearing loss of 20 dB in one or both ears when treated with low-dose cisplatin alone or in combination with gentamicin. Bilateral deafness resulted from high-dose cisplatin combined with gentamicin. The combined treatment produced prominent structural damage in the stria vascularis. The results should be considered when aminoglycoside therapy is required in conjunction with cisplatin.

Protection against cisplatin toxicity by administration of glutathione ester 1

The role of cellular glutathione in the prevention of toxicity due to the anti-cancer drug cisplatin (cis-diamminedichloroplatinum) 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. Pretreatment of mice with BSO enhanced the lethal toxicity of cisplatin by about twofold. Administration of glutathione ester (dose, 2.5-7.5 mmol/kg) protected against lethal cisplatin toxicity; glutathione was also effective, but much less so. Glutathione ester, in contrast to glutathione, is effectively transported into cells and split to glutathione intracellularly. The previous findings that administered glutathione does not protect against lethal toxicity due to cadmium ions and mercuric ions, whereas glutathione ester does, suggest that intracellular glutathione is required for protection against these heavy metal ions. That administration of glutathione has a protective effect on cisplatin toxicity suggests that the toxic effects of cisplatin may be exerted both intracellularly and extracellularly, and that extracellular glutathione (or its degradation products) may form a complex with cisplatin extracellularly. 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.

Phase I clinical and pharmacokinetic study of diethyldithiocarbamate as a chemoprotector from toxic effects of cisplatin.

Diethyldithiocarbamate (DDTC) has been shown to provide protection against most clinically significant toxic effects from cisplatin (DDP) without inhibiting tumor response in a variety of murine animal models. We conducted a phase I clinical and pharmacokinetic study of DDTC in combination with DDP to establish the types and severity of toxic effects and to determine whether protection of normal tissues and tumors occurs. Twenty-two courses of DDP plus DDTC were given to 10 patients. No nephrotoxic effects were seen at DDP doses of 50-120 mg/m2, and three patients had amelioration of nausea and vomiting. Objective antitumor responses were observed. Dose-limiting toxic effects from DDTC occurred at 150 mg/kg; these consisted of numbness in the infusion arm often accompanied by severe diaphoresis, chest discomfort, and agitation during DDTC infusion. These toxic effects resolved spontaneously, however, after termination of the infusion. The preliminary results suggest that plasma levels of DDTC that provide excellent protection in rodents were exceeded at the doses used in our clinical study without compromising antitumor response.

High-dose carboplatin with diethyldithiocarbamate chemoprotection in treatment of women with relapsed ovarian cancer.

Diethyldithiocarbamate (DDTC) has been found to protect the bone marrow, kidneys, and gastrointestinal tract from the toxic effects of cisplatin and carboplatin (CBDCA) in animal models. In an attempt to minimize the toxic effects of high-dose CBDCA (800 mg/m2), a pilot study was undertaken in which women with relapsed or refractory epithelial ovarian cancer were treated with high-dose CBDCA, which was followed 3 hours later with DDTC (4 g/m2). There were four partial responses and no complete response in 21 patients who could be evaluated (overall response rate, 19%). Significant toxic effects, including three treatment-related deaths, were associated with the regimen. This study suggests that while high-dose CBDCA plus DDTC may be active in relapsed or refractory ovarian cancer, it is associated with clinically significant hematologic and autonomic toxic effects.

Cisplatin ototoxicity in guinea pigs with special reference to toxic effects in the stria vascularis.

The toxic effects of cisplatin (cis-diamminedichloroplatinum [II]) on the organ of Corti are well established. Few and conflicting data on this drug's effects on the stria vascularis exist. The present study presents animal experiments on the toxic effects of cisplatin in the stria vascularis and in the organ of Corti. Cisplatin-induced toxicity in albino and pigmented guinea pigs was evaluated morphologically and functionally, using light and transmission electron microscopy as well as auditory brainstem-evoked potentials on the organ of Corti and the stria vascularis. The results showed variability in hearing thresholds, ranging from no change to hearing loss of 30 dB, and prominent damage in the organ of Corti and in the stria vascularis. The toxic effects to both the organ of Corti and the stria vascularis should be considered when cisplatin is used in chemotherapy.