• Journal of Korean Biological Nursing Science
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• v.14 no.1
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• pp.49-56
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• 2012

Purpose: The purpose of this study was to compare the effects of anorexia induced by consecutive low-dose and high-dose of cisplatin (CDDP) on the hindlimb muscles of rats. Methods: Male Sprague-Dawley rats were assigned to three groups: Control group (C) received a saline (the same dose and duration as the low CDDP group), the high-dose cisplatin (High CDDP) group received a single 5 mg/kg dose of cisplatin, the consecutive low-dose cisplatin (Low CDDP) group had 1 mg/kg of cisplatin administered for five consecutive days. On the 8th day the soleus and gastrocnemius muscles were dissected. Body weight, food intake, activity, muscle weight, Type I, II fiber cross-sectional area (CSA) of the dissected muscles were measured. Results: Body weight, food intake, muscle weight and Type I, II fiber CSA of the High CDDP and Low CDDP groups were significantly less than the C group. The High CDDP group showed significant decreases, compared to the Low CDDP group, in body weight, food intake, activity score, muscle weight and Type I, II fiber CSA. Conclusion: Hindlimb muscle atrophy occurs due to anorexia induced by both consecutive low-dose and high-dose cisplatin. The muscle atrophy induced by consecutive low-dose cisplatin is less apparent than high-dose cisplatin.

• Toxicological Research
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• v.8 no.2
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• pp.235-253
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• 1992

A subacute toxicity study of cis-Malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II)(SKI 2053R) was carried out to obtain information on its toxicological profiles, and to determine the maximum tolerated dose in beagle dogs. Four groups of beagle dogs (2M and 2F per group, 0,0.5,1.0,2.0mg/kg/day)were given 15 i.v. injections of SKI 2053R. In order to compare the toxic effects of SKI 2053R with those of cisplatin, one group was treated with cisplatin(0.7mg/kg/day)according to the same treatment schedule. The dosing schedule was divided into 3 courses of 5 consecutive days with 23-day dose-free intervals between each course. After completion of the treatments, remaining dogs were necropsied under established guidelines. Three of four dogs in the high dose group and one of four dogs in the middle dose group treated with SKI 2053R died of hypovolemic shock secondary to hemorrhagic and ulcerative enterocolitis. No toxicity-related mortality occurred in the low dose group of SKI 2053R. No survivor was observed in the group of cisplatin. Clinical signs including vomiting, diarrhea, anorexia and loss body weight were apparent in dogs given either cisplatin or high and middle doses of SKI 2053R. Severe thrombocytopenia and leukocytopenia were observed in the high dose group of SKI 2053R and cisplatin-treatment group, while toxicities as bone marrow suppression were reversible. The significant elevation of serum ALP values in group of SKI 2053R(2.0 mg/kg/day and 1.0mg/kg/day) and cisplatin(0.7mg/kg/day)was observed. Slight proteinuria waa observed in high and middle dose level groups of SKI 2053R. In histopathological examinations, pathological alterations of liver, kidney and spleen were noted dose-dependantly in dogs treated with SKI 2053R, and there was no overt sign of toxicity in low dose group of SKI 2053R. Compared to SKI 2053R, more severe durg-related toxicities occurred in dogs treated with cisplatin. It waw estimated that maximum tolerated dose of SKI 2053R in this treatment schedule was 0.5~0.7mg/kg/day. In conclusion, overall toxic potential of SKI 2053R was approximately 3 times lower than that of cisplatin with respect of lethality.

• Tuberculosis and Respiratory Diseases
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• v.52 no.5
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• pp.463-474
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• 2002

Background : This study was designed to examine how glutathione, one of the nucleophilic sulfur compounds, effects the cisplatin cellular toxicity in the non-small cell lung cancer cell lines and normal lung epithelial cell line. Materials and Methods : Three cultured cell lines, the lung adenocarcinoma cell(NCL-H23), the lung squamous carcinoma cell(SK-MES-1) and the normal lung epithelial cell(L-132) line were exposed to various concentrations of cisplatin with or without glutathione. The relative viability was estimated as a means of measuring the cisplatin cellular toxicity using the MTT method. Results : In NCI-23, the response to cisplatin was sensitive but glutathione markedly increased the relative survival of the tumor cells by removing the antitumor effect of cisplatin. In both SK-MES-1 and L-132, the responses to cisplatin were less sensitive, and the chemoprotective effect of glutathione compared to and equal cisplatin dose was significantly higher in L-132 than in SK-MES-1(p<0.05). Conclusion : The protective effectes of of glutathione on cisplatin-induced cellular toxicity is more significant in normal lung epithelial cells than in squamous carcinoma cells.

• Tuberculosis and Respiratory Diseases
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• v.40 no.4
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• pp.367-377
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• 1993

Background: The benefits of combination chemotherapy in unresectable non-small cell lung cancer remain uncertain. But, according to the recent reports, the response rates of cisplatin-based polychemotherapy regimens are higher than those of single agent. Also, the response rates of high-dose cisplatin group are higher than those of low-dose cisplatin group. In attemp to answer the question whether treatments, combination chemotherapy (high VPP) and combination chemotherapy with radiation therapy, improve survival in advanced non-small cell lung cancer, we begin to study. Method: Thirty-five patients above stage III, diagnosed histologically as non-small cell lung cancer, were enrolled. Among them, nineteen received a combination chemotherapy consisting of VP-16 & high-dose cisplatin (100 $mg/m^2$) and/or radiation therapy. The other group (16 subjects) received no therapy. To investigate the differences of survival and response rates between two groups and the side effects related to therapy, we reviewed patients' records. Results: 1) The overall objective response rate was 47%(9/19) with one complete remission. 2) In patients who received polychemotherapy and radiation therapy, the response rate was 60%(6/10) with one complete remission and survival rates of 3 months, 6 months and 12 months were 100%, 70% and 40%. 3) In patients who received polychemotherapy, the response rate was 33% (3/9) with no complete remission and survival rates of 3 months, 6 months and 12 months were 78%, 67% and 33%. 4) Overall, treated patients survived significantly longer (p<0.05) than non-treated patients (median survival 307 days versus 95 days). 5) Analysis of the various prognostic factors disclosed that good performance status, stage III and squamous cell type showed the good response rates. 6) The toxicities were nausea and/or vomiting (100%), alopecia (90%), anemia (79%), leukopenia (69%), thrombocytopenia (2%), increased creatinine (16%) and neurotoxicity (5%). Conclusion: According to above results, there are relatively good results that high VPP combination chemotherapy in advanced non-small cell lung cancer improves survival in the treated group than in the non-treated group. Thus, it is considerd that we select the patients with proper indications and treat them with effective chemotherpy and radiation therapy. But, because improvement related to high VPP ploychemotherapy is not marked in this study, it is necessary that we should investigate follow-up studies in many cases.

• Toxicological Research
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• v.8 no.2
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• pp.217-233
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• 1992

This study was performed to determine the toxic effects of graded dose levels of SKI 2053R after repeated administration. Three groups of Sprague-Dawley rats(10M and 10F per group) were given a total of 25 i.v. injections of SKI 2053R (1.50,3.75,9.38mg/kg/day). In order to compare the toxic effects of SKI 2053R with those of cisplatin, one group of Sprague-Dawley rats (10M and 10F per group) were given a total of 25 i.v.injections of cisplatin (1.70mg/kg/day). The dosing schedule was divided into five courses of 5 consecutive days with 16-day dose-free intervals between each course. No drug-related toxicity occurred in low dose level group (1.50mg/kg/day) of SKI2053R. From the results of hematological examination, peripheral WBC counts, RBC counts and hemoglobin of high dose level group(9.38mg/kg/day)of SKI 2053R were significantly lower than those of no-treated group. Other toxicities including reduced final body weight, proteinuria and hematuria were observed in high dose level group of SKI 2053R. But, no change was detected in serum biochemical values of SKI 2053R treated groups. All of the rats in cisplatin treated group were died between 3 and 13 weeks, while rats treated with SKI2053R survived to the end except one rat of middle dose level group(3.75mg/kg/day). In histopathological examinations, rats that received cisplatin manifested severe tubular damage in kidney and hemosiderosis in spleen, but no critical pathological lesion was observed in rats of other groups. Considering the results of this study, it was concluded that non-toxic dose of SKI 2053R in this treatment schedule was estimated to be 3.75 mg/kg/day and the maximum tolerated dose was to be higher than 9.38mg/kg/day. The toxic profiles fo SKI 2053R were different from those of cisplatin, and its toxicity was considerably lower than that of cisplatin.

• Korean Journal of Clinical Pharmacy
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• v.20 no.1
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• pp.17-23
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• 2010

Aprepitant is a substance P/neurokinin-1 (NK1)-receptor antagonist that was approved in 2003 for prevention of CINV. In addition, updated anti-emetic guidelines that include the aprepitant regimen have been published by NCCN and ASCO. However there is scarce clinical data in Korea. The prospective study was performed to evaluate the prevention of high dose cisplatin induced nausea and vomiting in all patients who started high-dose cisplatin-based chemotherapy at our hospital. We checked the nausea severity and vomiting episodes by calling patients within 4 to 5 days after chemotherapy. The retrospective study was performed to compare the prevention of CINV in solid tumor patients who switched their anti-emesis regimen from the standard regimen to the aprepitant regimen. In aprepitant regimen, aprepitant was added to the same anti-emetic regimen used during previous cycles. We checked the nausea, vomiting grades and adverse events in electronic medical records (EMR). In prospective study, 195 patients were included in the analysis. 88.2% of patients achieved a complete response (no emesis and no rescue therapy). In retrospective study, 54 patients were reviewed. With aprepitant regimen, nausea and vomiting grades were improved in 22 patients (40.7%) and in 9 patients (16.7%), respectively. Compared with standard regimen, addition of aprepitant provided superior prevention against CINV in Korean patients receiving highly emetogenic cisplatin-based chemotherapy. Moreover, aprepitant significantly prevented CINV in patients who received the standard regimen to prevent CINV in previous chemotherapy cycles.

• Radiation Oncology Journal
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• v.17 no.2
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• pp.113-119
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• 1999

Purpose : To evaluate possible acute toxicity and early response of concurrent radiation therapy and low dose daily cisplatin as a radiosensitizer in patients with locally advanced uterine cervical carcinomas. Materials and Method : From December 1996 to January 1999, 38 previously untreated Patients with locally advanced squamous cell carcinoma of the uterine cervix (from stage IIB to stage IIIB) were treated at Inha University Hospital. All patients underwent standard pretreatment staging Procedures after the initial evaluation by gynecologists and radiation oncologists. Sixteen Patients with huge cervical mass (>4 cm) were submitted to the group treated with concurrent radiation therapy and low dose daily cisplatin while the remainder was treated with radiation therapy alone. Radiation therapy consisted of 4500 cGy external beam irradiation to whole pelvis (midline block after 3000 cGy), 900$\~$1000 cGy boost to involved parametrium, and high dose-rate intracavitary brachytherapy (a total dose of 3000$\~$3500 cGy/500 cGy per fraction to point A, twice per week). In the group treated with low dose cisplatin concurrently, 10 mg of daily intravenous cisplatin was given from the 1st day of radiation therapy to the 20th day of radiation therapy. Acute toxicity was measured according to expanded common toxicity criteria of the NCI (C) Clinical Trials. Early response data were analyzed at minimum 4 weeks' follow-up after completion of the treatment protocol. Results: Hematolgic toxici쇼 was more prominent in patients treated with radiation therapy and cisplatin. Six of 16 patients (37.5$\~$) treated with radiation therapy and cisplatin and one of 22 patients (4.5$\~$) treated with radiation therapy alone experienced grade 3 leukopenia. In Fisher's exact test, there was statistically significant difference between two groups regarding leukopenia (P=0.030). There was no apparent difference in the frequency of gastrointestinal and genitourinary toxicity between two groups (P=0.066). Three of 16 patients (18.7$\~$) treated with radiation therapy and cisplatin and two of 22 patients (9.1$\~$) treated with radiation therapy alone experienced more than 5 kg weight loss during the treatment. There was no statistically significant difference on weight loss between two groups (P=0.63). Two patients on each group were not evaluable for the early response because of incomplete treatment. The complete response rate at four weeks' follow-up was 80$\~$(16/20) for the radiation therapy alone group and 78$\~$ (11/14) for the radiation therapy and cisplatin group. There was no statistically significant difference in early response between two treatment groups (P=0.126). Conclusion : This study led to the conclusion that the hematologic toxicity from the treatment with concurrent radiation therapy and low dose daily cisplatin seems to be more prominent than that from the treatment of radiation therapy alone. There was no grade 4 hematologic toxicity or mortality in both groups. The hematologic toxicity in both treatment groups seems to be well managable modically. Since the risk factors were not balanced between two treatment groups, the direct comparison of early response of both groups was not possible. However, preliminary results regarding early response for patients with bulky cervical tumor mass treated with radiation therapy and low dose daily cisplatin was encouraging. Longer follow-up is necessary to evaluate the survival data. A phase III study is needed to evaluate the efficacy of concurrent daily low dose cisplatin with radiation therapy in bulky cervical cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6877-6882
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• 2015

Background: Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer. We investigated the effect of selenium (Se) with high dose vitamin E (VE) administration to prevent CDDP-induced nephrotoxicity in rats. Materials and Methods: In this study, 40 female Wistar rats were randomly divided into five equal groups. The first group, which served as the control, was administered physiological saline (2.5 cc/day, 5 days) intraperitoneally (IP), while group A was administered cisplatin (6 mg/kg BW/ single dose) plus physiological saline IP. Groups B, C, D received IP five doses of Se (1.5 mg/kg BW), and a high dose of VE (1000 mg/kg BW) (Se-VE) in combination before, simultaneously, and after CDDP, respectively. The rats were sacrificed five days after CDDP administration. Plasma malondialdehide (MDA), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), catalase, urea, creatinine levels, renal histopathological changes were measured. Results: The histopathological injury score, plasma levels of MDA, urea, creatinine were found to increase in group A compared to the control (p<0.05), while plasma levels of GSH-Px, GSH and catalase decreased (p<0.05). In contrast, plasma levels of MDA decreased (p<0.05) in groups B, C, D, which were treated with Se- VE, whereas levels of GSH-Px, GSH were found to increase only for group D (p<0.05). Plasma urea, creatinine levels improved in the treatment groups compared to group A (p<0.001). Histopathological changes caused by CDDP were also significantly improved after Se-VE treatment (p<0.05). Conclusions: Oxidative stress increases with CDDP-induced nephrotoxicity in rats. Se-VE supplementation might thus play a role in the prevention of CDDP-induced nephrotoxicity in patients.

• Journal of Chest Surgery
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• v.33 no.9
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• pp.697-706
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• 2000

Background: Isolated lung perfusion(ILP) was developed as a new treatment approach to non-resectable primary or metastatic lung cancer, because of its ability to reduce systemic toxicity while delivering high-dose chemotherapeutic agents to the target organs. This research was planned to evaluate the direct toxic effect of high-dose cisplatin to the lung tissue during isolated lung perfusion. Material and Method: Fifteen mongrel dogs were divided in the perfusate for 40 minutes. The second group was composed of 5 mongrel dogs which underwent ILP with cisplatin 2.5 mg/Kg added to the perfusate for 30 minutes and 10 minutes with washing solution without cisplatin. The third group underwent the same procedure as the second group except cisplatin 5.0 mg/Kg in the perfusate. Activities of serum angiotensin converting enzyme(ACE), tumor necrosis factor-$\alpha$(TNF-$\alpha$), and concentration of serum lactate dehydrogenase(LDH) and blood urea nitrogen/creatinine (BUN/Cr) were analyzed in each groups at the time of pre-perfusion, 1 hour, 1 day, 1 week, and 2 weeks after ILP. Result: Serum ACE activities before and 1 hour, 1 day, 1 week, and 2 weeks after ILP in control group were 45.1$\pm$6.3, 44.6$\pm$9.3, 46.7$\pm$9.5, 50.8$\pm$9.1, 46.1$\pm$4.3 U/L. Those in cisplatin 2.5 and 5.0 mg/Kg groups were 49.4$\pm$12.6, 39.0$\pm$8.6, 42.3$\pm$15.9, 50.0$\pm$2.6, 53.8$\pm$8.3 and 55.5$\pm$12.3, 47.0$\pm$6.3, 45.1$\pm$6.9, 74.8$\pm$19.5, 60.2$\pm$12.0 U/L, respectively. Serum TNF-$\alpha$ activities in each group before and after ILP were 5.0$\pm$1.5 / 7.7$\pm$2.2 / 6.6$\pm$2.5 / 4.3$\pm$1.3 / 5.2$\pm$1.1(control), 8.7$\pm$1.6 / 9.9$\pm$2.2 / 7.9$\pm$1.5 / 6.3$\pm$2.2 / 7.4$\pm$2.4 (cisplatin 2.5 mg/Kg), and 6.9$\pm$0.7 / 8.9$\pm$3.4 / 7.9$\pm$4.0 / 3.3$\pm$0.9 / 5.8$\pm$1.3 pg/ml(cisplatin 5.0 mg/Kg). Mean LDH levels of each group were 225.7 / 271.3 / 328.9 / 350.8 / 255.7(control), 235.7 / 265.7 / 336.0 / 379.5 / 299.2 (cisplatin 2.5 mg/Kg), and 259.6 / 285.2 / 340.6 / 433.4 / 292.4 IU/L(cisplatin 5.0 mg/Kg). So there was no significant difference in serum ACE, TNF-$\alpha$, and LDH activity changes after ILP between the 3 groups. And, there was no significant changes in BUN/Cr in each groups, which was independent of ILP and perfused concentration of cisplatin. In addition, all dogs survived the ILP and there was no significant evidence of pulmonary vascular injury after 2 weeks of ILP with cisplatin. Conclusion: There was no harmful effect of cisplatin to the lund tissue of the mongrel dog up to 5.0 mg/Kg in perfusate. Therefore, it is perceived to be safe and effective to deliver high-dose cisplatin to the lung without pulmonary toxicity and renal damage with ILP.

• Molecules and Cells
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• v.19 no.1
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• pp.143-148
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• 2005

Heptaplatin, cis-malonato [(4R,5R)-4,5-bis (amino-methyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI-2053R, Sunpla) is a new platinum derivative with antitumor activity comparable to cisplatin on various cancer cell lines. Preclinical studies suggest that it is less nephrotoxic than cisplatin. This study was undertaken to examine the combined effect of heptaplatin and ionizing radiation on two established human squamous carcinoma cell lines (NCI-H520, SQ20B). The cytotoxic activity of heptaplatin was concentration-dependent in both cell lines. When low dose heptaplatin was combined with high dose ionizing radiation, there was an additive cytotoxic effect on NCI-H520 cells (P < 0.05), while a moderate dose of heptaplatin and a low dose of ionizing radiation had an additive cytotoxic effect on the growth of SQ20B cells (P < 0.05). FACS analysis and DAPI staining showed that their additive cytotoxic effects were correlated with the induction of apoptosis. Further studies are warranted using heptaplatin and ionizing radiation in squamous cell carcinoma as a substitute for cisplatin.