Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions. Cisplatin (CDDP) elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion. Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis (NASH), however, associated changes to substrate toxicity is unknown. To test this, a methionine- and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics, transporter expression, and toxicity. NASH rats administered CDDP (6 mg/kg, i.p.) displayed 20% less nephrotoxicity than healthy rats. Likewise, CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min, renal secretion decreased from 6.23 to 2.80 mL/min, and renal CDDP accumulation decreased by 15%, relative to healthy rats. Renal copper transporter-1 expression decreased, and organic cation transporter-2 and ATPase copper transporting protein-7b increased slightly, reducing CDDP secretion. Hepatic CDDP accumulation increased 250% in NASH rats relative to healthy rats. Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats, although no drug-related toxicity was observed. These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance, which may alter nephrotoxicity.

Transformation of malignant biological behaviors and PD-L1 expression in esophageal squamous cell carcinomaYES-2 cell induced by CDDPresistance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the changes in malignant biological behaviors and expression of programmed cell death-ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) YES-2 cell line after cis-dichlorodiammine platinum (CDDP) induction (YES-2/CDDP-R). Methods: YES-2 cells were treated with CDDP from low concentration to high concentration (0.25-2.0 μg/ml) with intermittent impact (15-25 days per concentration) to establish ESCC CDDP-resistant cell line YES-2/CDDP-R. The morphological change of YES-2/CDDP-R cells was observed under the inverted microscope. Methyl thiazolyl tetrazolium (MTT) was used to detect cell sensitivity to CDDP. Wound healing assay was used to detect cell migration ability. qPCR and Western blotting were used to detect mRNA and protein expressions of PD-L1. Results: After CDDP gradien ttreatment for9 months,YES-2/CDDP-R cells were successfully established. The morphology of the YES-2/CDDP-R cells showed uneven size, intracellular vacuoles and significantly increased black particles along with the appearance of huge cells. The IC50 of CDDP for YES-2/CDDP-R cells was significantly higher than that for parental cells, indicating decreased sensitivity to CDDP (P<0.05). Compared to theYES-2 cells, the proliferation and migration of YES-2/CDDP-R cells were significantly increased (P<0.05 or P<0.01), and the mRNA and protein expressions of PD-L1 were significantly up-regulated (all P<0.001). Conclusion: YES-2 cells with CDDP resistance (YES-2/CDDP-R) were successfully established. The sensitivity of YES-2/CDDP-R cells to CDDP was significantly reduced while the abilities of cell proliferation and migration were enhanced. The up-regulation of PD-L1 in YES-2/CDDP-R cells suggests that CDDP-resistance could promote immune escape by inducing PD-L1 up-regulation.

Inactivation of TFEB and NF-B by marchantin M alleviates the chemotherapy-driven pro-tumorigenic senescent secretion

It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-B (NF-B) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy.

Genetic diversity analysis and germplasm identification of Paris species by CDDP markers / 中草药

Objective: To explore genetic diversity and phylogenic relationship among different types of Paris species and provide an effective method for the rapid identification of germplasm resources. Methods: CDDP marker was used to evaluate the genetic diversity and phylogenic relationship among 13 types of Paris species. And the coding of Paris genus plants was carried out based on method of CODE128 barcode. Results: Our results indicated that 73 polymorphic bands were amplified by 11 primers among 80 bands, and the ratio of polymorphic band was 91.25%. The observed number of alleles (Na), effective number of alleles (Ne), Nei’s gene diversity (H), and Shannon’s information index (I) was 1.912 5, 1.589 6, 0.342 3, and 0.507 0, respectively. The results of UPGMA analysis showed that there were great differences among 13 types of Paris species on genetic diversity. Based on CDDP markers, 13 barcode molecular identity cards were constructed for Paris species based on method of CODE128 barcode. Conclusion: There was abundant polymorphism among Paris species, and CDDP markers were effective to analyze the genetic diversity of Paris species, and the established barcode molecular identity for Paris species was sensitive and fast, which can be used for scientific research and industrial production of Paris genus.

Tragomycin A Enhances Chemosensitivity to Cisplatin in Ovarian Cancer Cell Lines by Down-regulating STAT3 / 华中科技大学学报(医学版)

Objective@#Our study aimed to investigate the effect of histone deacetylase inhibitor trichostatin A（TSA）on the cisplatin（CDDP） resistance of ovarian cancer cell lines and its molecular mechanism.@*Methods@#Cisplatin-resistant ovarian cancer cell line C13* and its parental line OV2008 were incubated with TSA（200 nmol/L） or/and CDDP（20 μmol/L），the inhibitory rate of tumor cells was determined by MTT assay. Flow cytometry and Western blotting were used to detect apoptosis of tumor cells. Western blotting was also used to detect STAT3 expression in C13* and OV2008 cells. After down-regulation of STAT3 by transfection of STAT3 siRNA in C13* cells，cisplatin-induced apoptosis was evaluated by flow cytometry.@*Results@#MTT assay showed that the proliferation inhibitory rates of the combination group after 48 or 72 h treatment were significantly higher than those of TSA and CDDP groups. The level of STAT3 protein was much higher in C13* cells than in OV2008 cells. Flow cytometry and Western blotting showed that TSA combined with CDDP significantly enhanced the apoptotic rate of C13* cells. STAT3 expression level was significantly higher in C13* cells than in OV2008. Downregulation of STAT3 can significantly improve CDDP-induced apoptosis of C13* cells. @*Conclusion@#Down-regulation of STAT3 by TSA endows cisplatin-resistant cells C13* with increased sensitivity to cisplatin.

Changes of Alternative Splice Variant of the SRSF12 by Cisplatin in Multiple Cells / 昆明医科大学学报

Objective To detect the changes of mRNA isoforms in multiple cancer cell lines with dose of cisplatin. Methods Total RNA of the cells treated by cisplatin were abstracted 24 h after the treatment. mRNA isoforms of SRSF12 gene were detected by semiquantitative RT-PCR. The ratios of mRNA isoforms were analyzed by gel image software and statistical analysis. Results Under the cisplatin treatment, 2 mRNA isoforms of SRSF12 were detected in five cells except Caski cells,their ratios and relative mRNA levels were changed. With the increase of dose of cisplatin, the ratio of isoform-a was slightly increased; but the ratio of isoform-b was different, the changes were not obvious in the A549 and 293FT cells, the weaker expression was expressed in the H1299 and C33A cells, and the two isoforms were gradually weakening in the Siha cells. Conclution Under the cisplatin treatment in multiple cancer cells, the expression of SRSF12 shows tissue-specific and cell type-specific patterns .

Effects of heme oxygenase-1 on cisplatin chemosensitivity in gastric cancer / 西安交通大学学报(医学版)

Objective To explore the roles of heme oxygenase-1 (HO-1 ) and protoporphyrin zinc IX (ZnPPIX ) , its inhibitor , in cisplatin chemotherapy for gastric cancer so as to provide potential targets for chemosensitivity in gastric cancer .Methods Gastric cancer cell line SGC7901 was used in vitro .MTT assay was carried out to determine the effects of ZnPPIX and CDDP on the proliferation in gastric cancer cells .The expression of HO-1 in gastric cancer cells was measured by Real-time PCR and Western blot ,respectively .The gastric cancer xenografts in nude mice were used to study the effects of ZnPPIX and CDDP in gastric cancer on tumor formation in vivo .Results The proliferation of cancer cells ,interfered by CDDP in combination with ZnPPIX ,could be significantly inhibited (P<0 .05) .Moreover ,CDDP could increase the expression of HO-1 in gastric cancer cells , which was reversed by ZnPPIX (P<0 .05) .The animal experiment showed that CDDP could inhibit gastric cancer growth in nude mice and reduce tumor volume and weight . Conclusion ZnPPIX could enhance the chemosensitivity of CDDP in gastric cancer ,which may be a potential sensitizer of cisplatin-based chemotherapy in gastric cancer .

Expression and significance of TMSG-1 in esophageal squamous carcinoma and EC109 cells / 西安交通大学学报(医学版)

Objective To study the expression and significance of tumor metastasis suppressor gene-1(TMSG1) in esophageal squamous cell carcinoma (ESCC) and EC109 cells.Methods Immunohistochemistry S-P method was used to examine the expression of TMSG-1 protein in 136 cases of ESCC and 37 cases of normal esophageal mucosa.We analyzed the relationship between TMSG-1 and clinicopathological data of ESCC patients.EC109 cells were treated with 3 μg/mL of cisplatin (CDDP) in vitro for 24 h (the intervention group) and the control group was set up at the same time.The proliferation-inhibitory capability was analyzed with MTT assay.RT-PCR was used to examine the expression of TMSG-1 in the intervention group and the control group.Results The positive rate of TMSG-1 in ESCC and normal esophageal mucosa was 52.2％ (71/136) and 94.6％ (35/37),respectively.The expression of TMSG-1 in ESCC was significantly lower than that in normal esophageal mucosa (P＜0.05).The expression of TMSG-1 was related to TNM stage,differentiation degree and lymph node metastasis (P＜0.05).After EC 109 cells were treated with CDDP for 24 h,the proliferation inhibition rate was increased significantly compared with the control group (P＜0.01).RT-PCR results showed that the expression of TMSG-1 in the cells of the intervention group was significantly higher than that in the control group (P＜ 0.01).Conclusion The abnormal expression of TMSG-1 may play a role in the development and metastasis of ESCC.Examination of TMSG-1 may be useful for making diagnosis and guiding clinical therapy of ESCC.

Screening and diversity of resistance germplasm of Dendrobium officinale by CDDP markers / 中草药

Objective Conserved DNA-Derived Polymorphism (CDDP) markers were used in the study of the genetic diversity of 43 Dendrobium officinale and preliminary resistance screening, in order to provide a theoretical basis for the screening of D. officinale and the selection of fine varieties. Methods A total of 21 CDDP primers were used to amplify the genomic DNA of the test material with clear and polymorphic primers. Results Sixteen primers generated 151 bands, of which 144 (95.7%) were polymorphic. The results of data analysis on three population showed that the percentage of polymorphic locus (PPL) were between 65.56% and 82.12%, coefficient of genetic differentiation among natural populations (Gst) was 0.110 2, and the total gene flow (Nm) was 4.035 4. Indicating that anthropogenic factors may also promote the genetic diversity of D. officinale. Conclusion The genetic diversity of D. officinale was rich, and the results showed that there were eight plants with potentially good resistance among 43 materials.

Audiological profile of patients treated for childhood cancer / Perfil audiológico de pacientes tratados de câncer na infância

Abstract Objective: To characterize the hearing loss after cancer treatment, according to the type of treatment, with identification of predictive factors. Methods: Two hundred patients who had cancer in childhood were prospectively evaluated. The mean age at diagnosis was 6 years, and at the audiometric assessment, 21 years. The treatment of the participants included chemotherapy without using platinum derivatives or head and neck radiotherapy in 51 patients; chemotherapy using cisplatin without radiotherapy in 64 patients; head and neck radiotherapy without cisplatin in 75 patients; and a combined treatment of head and neck radiotherapy and chemotherapy with cisplatin in ten patients. Patients underwent audiological assessment, including pure tone audiometry, speech audiometry, and immittancemetry. Results: The treatment involving chemotherapy with cisplatin caused 41.9% and 47.3% hearing loss in the right and left ear, respectively, with a 11.7-fold higher risk of hearing loss in the right ear and 17.6-fold higher in the left ear versus patients not treated with cisplatin (p < 0.001 and p < 0.001, respectively). Children whose cancer diagnosis occurred after the age of 6 have shown an increased risk of hearing loss vs. children whose diagnosis occurred under 6 years of age (p = 0.02). Conclusion: The auditory feature found after the cancer treatment was a symmetrical bilateral sensorineural hearing loss. Chemotherapy with cisplatin proved to be a risk factor, while head and neck radiotherapy was not critical for the occurrence of hearing loss.

Resumo Objetivo: Caracterizar as alterações auditivas após o tratamento do câncer, segundo o tipo de tratamento identificando os fatores preditivos. Método: Foram avaliados prospectivamente duzentos pacientes que tiveram cancer na infância. A idade média ao diagnóstico foi de 6 anos e à avaliação audiométrica de 21 anos de idade. O tratamento incluiu quimioterapia sem uso de derivados de platina ou radioterapia em cabeça e pescoço em 51 pacientes; quimioterapia com uso de cisplatina sem radioterapia em 64 pacientes; radioterapia em cabeça e pescoço sem cisplatina em 75 pacientes; e 10 pacientes receberam o tratamento combinado de radioterapia em cabeça e pescoço e quimioterapia com cisplatina. Os pacientes foram submetidos à avaliação audiológica incluindo audiometria tonal, audiometria vocal e imitanciometria. Resultados: O tratamento envolvendo quimioterapia com cisplatina levou a 41,9% e 47,3% de perda auditiva na orelha direita e esquerda, respectivamente, apresentando risco 11,7 vezes maior de desenvolver perda auditiva na orelha direita e 17,6 vezes na orelha esquerda do que aqueles que não receberam cisplatina (p < 0,001 e p < 0,001; respectivamente). Crianças cujo diagnóstico do câncer ocorreu após os 6 anos de idade mostraram maior risco de apresentar perda auditiva do que crianças menores do que 6 anos de idade (p = 0,02). Conclusão: A característica audiológica encontrada após tratamento oncológico foi perda auditiva sensorioneural bilateral simétrica. A quimioterapia com cisplatina mostrou ser fator de risco, enquanto a radioterapia em cabeça e pescoço não foi determinante para aquisição da perda auditiva.

Enhanced activation of PERK-ATF4 pathway by Brefeldin A and cisplatin in human lung cancer GLC-82 ;cells / 实用医学杂志

Objective To investigate the molecular mechanisms of synergistic effects of BFA and CDDP on human lung cancer GLC-82 cells, and to test the levels of PERK-ATF4 pathway. Methods GLC-82 cells were incubated with 50 ng/mL of BFA or/and 2 μg/mL of CDDP for 24 or 48 hours. The levels of PERK, p-PERK and ATF4 in GLC-82 were analyzed by real-time PCRand/or Western Blot. Results The levels of PERK were lowest in CDDP group, but higher in BFA group (P < 0.05), the highest in group of BFA+CDDP (P < 0.05 or P < 0.01). The p-PERK level decreased in group of BFA+CDDP (P < 0.05 or P < 0.01). There was no significant change of ATF4 expression in CDDP group, but ATF4 expression increased slightly in BFA group, and increased further in group of BFA+CDDP (P < 0.05 or P < 0.01)which was also higher than that in BFA group or CDDP group (P < 0.05 or P < 0.01). Conclusions The upregulated levels of PERK and ATF4 by the combination of BFA and CDDP may be one of the mechanisms of synergistic anti-cancer effect of BFA and CDDP on GLC-82 cells.

Inhibition of Nrf2 by siRNA Regulates Chemosensitivity of Laryngeal Cancer to Cisplatin / 听力学及言语疾病杂志

Objective To determine the inhibitory effect of the synthetic Nrf 2 siRNA on the expression of Nrf2 gene in human laryngeal cancer cell lines Hep2 and to investigate the effects of Nrf2 siRNA on chemosensitivity of laryngeal carcinoma to cisplatin by detection growth and apoptosis in Hep2 cells .Methods The recombinant plas‐mid control siRNA and Nrf2 siRNA were transfected into Hep2 cells ,and western blot analysis of Nrf2 expression in Hep2 cells was performed 48 h after transfection .In order to determine whether Nrf2 siRNA can enhance the sensi‐tivity of Hep2 laryngeal cells to cisplatin ,we treated Hep2 cells with different concentrations of cisplatin after 24 h , and evaluated these cells for proliferation ,and apoptosis .CCK - 8 and flow cytometry assay were used for determi‐nation of cells proliferation and apoptosis in Hep2 cells .We calculated the inhibition rate and IC50 of the cell after treating with different concentrations of ciplatin .Results The laryngeal carcinoma cell stain Hep2 was transfected by Nrf2 siRNA and control siRNA respectively .The result of western blot showed the Nrf 2 expression was signifi‐cantly impeded at protein levels .CCK - 8 assay showed the proliferation of Hep2/Nrf2 siRNA and Hep2/ control siRNA was inhibited to 35 .55% to 46 .07% at 24 h respectively after treating with 4 μg/ml cisplatin .The chemo‐sensitivity to cisplatin in Hep2/Nrf2 siRNA was markly increased compared with Hep2/control siRNA .The IC50 in Hep2/Nrf2 siRNA was 5 .27 μg/ml contrast to 8 .107 μg /ml compared in Hep2/control siRNA .The result of flow cytometry analysis showed the apoptosis rate after Nrf 2 depletion was increased from 17 .1% to 26 .6% .Conclusion This study demonstrates that Nrf2 siRNA effectively inhibits Nrf2 gene expression in Hep2 cells leading to growth suppression and induction of apoptosis in Hep2 cells under cisplatin .The use of siRNA technique may pro‐vide a novel therapeutic approach to treat laryngeal cancer for enhance chemosensitivity .

RasGAP-derived peptide GAP159 enhances cisplatin-induced cytotoxicity and apoptosis in HCT116 cells

To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers.

Inhibition of the JNK pathway downregulates lung-resistance pro-tein and enhances the chemosensitivity of A549 cells to cisplatin / 中国肿瘤临床

Objective: To investigate the relationship between the c-Jun N-terminal kinase (JNK) pathway and lung-resistance protein (LRP). Methods:A549 cells were treated with various concentrations of CDDP for 72 h. The LRP mRNA expression was then analyzed using reverse transcription PCR (RT-PCR). LRP, JNK, and P-JNK were analyzed by Western blotting. The A549 cells were then pretreated with SP600125 (2 μg/ml to 4 μg/ml ) for 1 h. Afterward, CDDP (16 μg/ml) was added into the culture for 72 h. A Cell Counting Kit-8 was used to investigate the sensitivity of CDDP to the A549 cells. Flow cytometry was used to detect the apoptosis rate. The LRP mRNA expression was analyzed using RT-PCR. LRP, JNK, and P-JNK were analyzed by Western blotting. Results:CDDP in-duced the mRNA and protein expression of both LRP and P-JNK in a dose-dependent manner. Pretreatment with SP600125 enhanced the sensitivity of CDDP to the A549 cells and increased the apoptosis rate. However, the LRP mRNA and LRP expression in the pre-treated cells was lower than that in the presence of CDDP alone. Conclusion:In A549 cells, CDDP induces the LRP expression via the JNK pathway. This result suggests that lung cancer therapy can be improved by the addition of CDDP to inhibit the JNK signaling path-way.

Clinical Study: Phase II Study of Continuous ACNU (nimustine) and CDDP (cisplatin) Infusion Followed by Conventional Radiotherapy in Patients with High Grade Astrocytomas

OBJECTIVE: This study is aimed at evaluating the efficacy and the toxicity of a 72-hour continuous intravenous infusion of ACNU and CDDP before radiotherapy in adult patients with newly diagnosed anaplastic astrocytoma and glioblastoma. METHODS: Forty-three adult patients with a postoperative Karnofsky performance status greater than 60 were entered into this protocol without any prior treatment. Two cycles of preradiation chemotherapy were performed at 6-week intervals. Conventional radiotherapy was begun 6 weeks later. Magnetic resonance (MR) imaging studies were conducted pre- and postoperatively, and follow-up MR images at the beginning of each treatment and every three months after radiotherapy completion. Response rate, survival rate, prognostic factors and complications were evaluated. RESULTS: Among 43 patients mentioned above, twenty-one patients completed two cycles of chemotherapy. One patient showed complete remission, ten partial response, seven stable disease and three progressive disease. The median survival time was 15.9 months. Overall response rate was 22.3%. Twenty-seven showed pancytopenia, including two bleeding tendencies, one intracerebral hemorrhage resulting to death, and another two infections. Considering the prognostic factors, only a mutated p53 level of under 20%(% of tumor cells containing mutated p53) was correlated with survival prolongation. Prognostic factor of age under 45 was the only significant factor of extending the time to progression. CONCLUSION: This treatment protocol shows favorable results of preradiation chemotherapy using ACNU and CDDP.

Roles of reactive oxygen species in HepG_2 cell apoptosis induced by CDDP / 第三军医大学学报

Objective To investigate the effects of acivicin on HepG 2 cell apoptosis and the effects of acivcin with cis diaminedichloroplatinum (CDDP) on HepG 2 cell apoptosis and on production of intracellular ROS. Methods HepG 2 cells were treated with acivcin, CDDP, and acivicin combined with CDDP. The cytotoxicity was measured by MTT assay. Flow cytometry was used to detect the intracellular ROS, and the rate of apoptosis was determined by TUNEL assay. Results The concentration of acivicin to cause HepG 2 IC 50 was 1.4 mmol/L, and CDDP was 67 ?mol/L. Significant increases in intracellular ROS content were observed in HepG 2 cells 24 h after treatment with acivicin (1.4 mmol/L), CDDP (67 ?mol/L), or acivicin (1 4 mmol/L) plus CDDP (67 ?mol/L), especially with acivicin (1 4 mmol/L) plus CDDP (67 ?mol/L). HepG 2 cell apoptotic rates induced by acivicin (1 4 mmol/L) at 24, 48, and 72 h were (16 3?3 5), (27 9?4 3), (47 2?3 0), respectively, and a significant difference was observed compared to that of control group ( P

Relationships between induction of apoptosis by CDDP in Scaber cell and apoptosis-related proteins / 中国药理学通报

AIM To investigate the effect of cisplatin on apoptosis in Scaber cell. METHODS The apoptotic cells were detected by TUNEL,HE,eletronic micrpscopy. RESULTS Treatment of Scaber cells with CDDP resulted in characteristics typical of apoptosis. CDDP induced apoptosis of Scaber cells in time and concentration dependent manner. To further investigate the mechanism of apoptosis induced by CDDP, the expressions and activity of apoptosis associated proteins such as bcl 2, bax and caspase 3 were examined using S P method.The results showed: CDDP caused time and concentration dependent decreases in bcl 2 and increased in bax proteins.CDDP bcl 2 and its translocation to perinuclei and nuclei. The expression of caspase 3 in Scaber cell were determined during apoptosis induced by CDDP. CONCLUSION Our investigetion showed that the apoptosis induced by CDDP is related to the increase of bax protein, and the decrease of bcl 2 protein. and its translocation to perinuclei and nuclei.

Study on the Apoptosis in Human Prostate and Breast Cancer Cells / 대한암학회지

PURPOSE: Apoptosis is a form of cell death characterized by specific morphological changes in the dying cell including contraction of cytoplasm, chromatin condensation, and cellular fragmentation into membrane-bound bodies. A common biological marker of apoptosis is the degradation of nuclear DNA resulting in a ladder of nucleosome-sized DNA fragments when resolved by electrophoresis. The potential therapeutic implications of simultaneous activation of apoptosis in androgen-dependent and androgen-independent prostatic cells are clearly very important in the development of cancer treatment modalities for advanced prostate cancer. The efficacy of chemotherapeutic agents correlates with their ability to induce apoptosis, Therefore, quantification of experimentally induced apoptosis in cancer cell lines is likely to be a predictor of the outcome of treatment. The main objective of this study was to examine the induction of apoptosis as a new strategy for cancer therapy by cis-diamminedichloroplatinum (CDDP) or 12-0-tetradecanoyl phorbol 13-acetate (TPA) in human prostate (androgen-dependent LNCaP and androgen-independent DU-145), and breast cancer cells (MCF-7). MATERIALS AND METHODS: DNA gel electrophoresis, flow cytometry and transmission electron microscopy for morphological analysis were used to further characterize drug response in human prostate and breast cancer cells. RESULTS: Treatment of the LNCaP and DU-145 cells with CDDP or TPA resulted in dose-dependent growth inhibition and accumulation of cells in Ao (apoptotic region), and caused significant degradation of the genomic DNA into intemucleosomal-sized DNA fragments, indicating apoptosis. In contrast, MCF-7 cells showed little or no DNA fragmentation. CONCLUSION: These studies suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to the efficacy of chemotherapeutic .agents. CDDP and TPA may have clinical implication in the treatment of prostate cancer. In particular, cytotoxic effects of TPA may well lead to new possibilities for improved strategy.

Study of the Antagonist Effects of Sodium Salicylate on the Cisplatin Induced Hearing Impairment in Guinea Pigs / 听力学及言语疾病杂志

Objective To investigate the antagonist effects of sodium salicylate(NaSA) on the cisplatin(CDDP) induced hearing impairment in guinea pigs.Methods 60 guinea pigs were randomly divided into four groups: ①CDDP +NaSA(50 mg/kg) group,②CDDP +NaSA(100 mg/kg) group,③CDDP +NaSA(150 mg/kg) group and ④CDDP +NS(normal saline) control group.Auditory brainstem response(ABR) and distortion product otoacoustic emission(DPOAE) were used to evaluate their effects on hearing threshold and DPOAE amplitudes.Results The ABR responses of groupsⅠ,Ⅱ and Ⅲ were significantly lower than in the control group(P0.05).The ABR responses for group Ⅰ were significantly higher than group Ⅲ(P

BCNU-CDDP Continuous Infusion Chemotherapy in Recurrent Oligodendroglioma

Eight patients with recurrent oligodendroglioma were treated with 1.3-bis(2-chloroethyl) nitrosourea(BCNU) and CDD continuous infusion chemotherapy. They were 5 with benign oligodendrogliomas and 3 with anaplastic oligodendrogliomas. All the recurrent tumors had been treated with surgery and radiotherapy. Four patients had already received chemotherapy with ACNU. Seven of them showed response to continuous infusion chemotherapy. The time from the response to progression was 15 to 67 weeks. No severe complication of the chemotherapy was found. In conclusion, BCNU-CDDP continuous infusion chemotherapy is an effective treatment modality in recurrent oligodendrogliomas.