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ABSTRACT: To compare clinical data, sleep quality and health-related quality of life (HRQOL) with and without RLS in HD patients.
The international RLS study group diagnosis questionnaire was completed by 228 HD patients. The Pittsburg Sleep Quality Index (PSQI) for the evaluation of sleep quality and the Kidney Disease Quality of Life (KDQOL-SF) for the analysis of HRQOL were also used.
53 (23%) patients were diagnosed as RLS. Age and age at the initiation of HD were significantly younger in the RLS group. Serum calcium concentration (Ca) was significantly higher in the RLS group. Sleep quality evaluated by PSQI was significantly lower in the RLS group. In SF-36 domains of KDQOL-SF, bodily pain, general health perceptions, vitality, role functioning emotional, mental health and mental component score were significantly lower in the RLS group. In kidney targeted scales of KDQOL-SF, symptoms/problems, burden of kidney disease, cognitive function, quality of social interaction, sleep and patient satisfaction were significantly lower in the RLS group.
High Ca was possibly connected to the pathophysiology of RLS which impaired sleep quality as well as HRQOL including mental health and many kidney disease related scales.
Clinical nephrology 01/2007; 66(6):440-6. · 1.17 Impact Factor
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ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the pathway of uracil and thymine catabolism. DPD is also the principal enzyme involved in the degradation of 5-fluorouracil (5-FU), an anticancer chemotherapeutic agent that is used clinically to treat renal cell carcinoma (RCC). Little is known about the significance of DPD activity in human cancers. We investigated the activity of DPD in 68 RCC and the relationship between DPD activity and the sensitivity to 5-FU. The levels of DPD activity in RCC and normal kidney samples were determined by the 5-FU degradation assay. The sensitivity to 5-FU was assessed by the microculture tetrazolium dye assay. The activity of DPD was approximately 2-fold higher in normal kidney compared with RCC. DPD activity in Stage I/II RCC was approximately 2-fold higher than that in Stage III/IV RCC. The levels of DPD activity in Grade 1 and Grade 2 RCC were 3 and 2-fold higher, respectively, than that in the Grade 3 cancers. There was an inverse correlation between DPD activity in RCC cells and their sensitivity to 5-FU. Furthermore, 5-chloro-2,4-dihydroxypyridine (CDHP), a potent DPD inhibitor, enhanced the sensitivity to 5-FU. The current study is the first to demonstrate that the level of DPD activity was inversel correlated with both the progression of the disease and increased grade of RCC, and that DPD activity was inversely associated with the sensitivity of RCC to 5-FU, which was enhanced by a DPD inhibitor. These results suggest that a low DPD activity may be associated with the malignant potential of RCC. In addition, it may be possible to overcome 5-FU resistance by using DPD inhibitors in the treatment protocols of 5-FU-based chemotherapy for RCC.
European Journal of Cancer 04/2003; 39(4):541-7. · 5.54 Impact Factor
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H Nakanishi,
O Mazda,
E Satoh,
H Asada,
H Morioka,
T Kishida,
M Nakao, Y Mizutani,
A Kawauchi,
M Kita,
J Imanishi,
T Miki
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ABSTRACT: To accomplish efficient nonviral gene therapy against prostate cancer (PC), Epstein-Barr virus (EBV)-based plasmid vectors containing EBNA1 gene and oriP were employed and combined with a cationic polymer or cationic lipid. When EBV-plasmid/poly-amidoamine dendrimer complex was injected into PC-3-derived tumors established in severe combined immunodeficiency mice, a considerable expression of marker gene was obtained in the tumors, and the expression level was more than eight-fold higher than that achieved by conventional plasmid vector/dendrimer. Since most PC cells express the apoptotic signal molecule Fas (Apo-1/CD95) on their surface, Fas ligand (FasL) gene was transferred into PC cells to kill the tumor cells. In vitro transfection with pGEG.FasL (an EBV-plasmid with the FasL gene) significantly reduced the viability of PC cells, which subsequently underwent apoptosis. Intratumoral injections of pGEG.FasL into PC induced significant growth suppression of the xenograft tumors, in which typical characteristics of apoptosis were demonstrated by TUNEL staining and electron microscopic observations. When pGEG.FasL transfer was accompanied by systemic administrations of cisplatin, the tumors were inhibited even more remarkably, leading to prolonged survival of the animals. FasL gene transfection by means of EBV-based plasmid/cationic macromolecule complexes may provide a practical therapeutic strategy against PC.
Gene Therapy 04/2003; 10(5):434-42. · 3.71 Impact Factor
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Y Naya,
J Soh,
A Ochiai, Y Mizutani,
A Kawauchi,
A Fujito,
S Ushijima,
T Ono,
N Iwamoto,
T Aoki,
N Imada,
N Nakamura,
C Yabe-Nishimura,
T Miki
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ABSTRACT: Erectile dysfunction (ED) is a common complication of diabetes mellitus. Erythrocyte aldose reductase (AR) has been implicated in a variety of diabetic complications. The subjects were 62 diabetic patients, of whom 25 were treated with hemodialysis (chronic renal failure CRF group) and the remaining 37 did not have chronic renal failure (DM group). The controls were 20 healthy volunteers age-matched to the patients. The level of AR was measured by the quantitative determination kit for AR in all patients and controls. In this study, ED was diagnosed by 5-item version of the International Index of Erectile Function (IIEF-5). The average level of AR in the CRF group was significantly higher than that in the DM group and controls (P<0.001). The average level of AR in the DM group without ED was significantly lower than that in the DM group with ED and controls (P<0.005). These results suggest that the level of AR may be a useful modality for prediction of ED in diabetic patients.
International Journal of Impotence Research 08/2002; 14(4):213-6. · 1.71 Impact Factor
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Y Naya,
J Soh,
A Ochiai, Y Mizutani,
S Ushijima,
K Kamoi,
O Ukimura,
A Kawauchi,
A Fujito,
T Ono,
N Iwamoto,
T Aoki,
N Imada,
K Marumo,
M Murai,
T Miki
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ABSTRACT: In order to evaluate the erectile function in male renal failure patients treated with hemodialysis (HD), we investigated the International Index of Erectile Function (IIEF) in patients and healthy controls. The subjects were 174 male patients treated with HD, of whom 43 had diabetes mellitus (DM) and the remaining 131 patients did not have DM. The controls were 1133 healthy males. We evaluated the prevalence of erectile dysfunction (ED) using the erectile function (EF) score, which is one of the five domains of the IIEF, in each age group (upto 39 y old, 40-49 y old, 50-59 y old, 60-69 y old). The severity of ED was classified into five categories using EF in each age group. The univariate logistic regression analysis and multiple variate analysis of IIEF in HD patients were performed. The prevalence of ED in HD patients was significantly higher than that in the controls in each age group. The severity of ED in HD patients was also significantly higher than that in the controls in each age group. In the logistic regression analysis and multiple variate analysis of IIEF in HD patients, DM and age were significant risk factors on sexual dysfunction. ED was more prevalent in male renal failure patients treated with HD than in the controls. In the patient group, ED was more prevalent in older DM patients.
International Journal of Impotence Research 07/2002; 14(3):172-7. · 1.71 Impact Factor
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ABSTRACT: To investigate the differentiation of embryonal carcinoma (EC) by cisplatin, and the underlying mechanism, as untreated metastases of nonseminomatous germ cell tumours rarely consist of fully differentiated mature somatic tissues, but such mature metastases are more common after various treatments, including chemotherapy.
The TTSC-3 human testicular EC line heterotransplanted into nude mice was used as a target. After treating tumour-bearing mice with intraperitoneal injections of varying doses of cisplatin, the histopathology of the tumours was assessed and various gene expressions in the tumours determined by cDNA-array technology.
When cisplatin at 1 mg/kg/week was injected intraperitoneally into TTSC-3-bearing mice, there was no effect on tumour growth. However, injecting cisplatin at 5 mg/kg/week induced a marked regression of the tumour. In contrast, cisplatin at 3 mg/kg/week had a modest inhibitory effect on tumour growth and induced tumour dormancy. Histological examination showed that 5 weeks after injecting cisplatin (3 mg/kg/week), primitive mesenchymal-like cells increased, and 10 weeks afterward cartilage and well-developed glands (teratoma) were apparent; at > 15 weeks afterward there were no EC cells visible. cDNA probes from reverse-transcribed mRNAs of TTSC-3 treated with cisplatin or saline for 10 weeks were compared to identify genes differentially expressed in cisplatin-treated TTSC-3. Of 1176 different human cDNA transcripts in cisplatin-treated TTSC-3, three genes (tumour necrosis factor receptor 1, caspase 8 and Apaf1), which are associated with apoptosis, were expressed markedly more than after saline injection.
The intermediate dose of cisplatin inhibited tumour growth of EC by inducing differentiation and enhancing apoptosis-related gene expression. These findings suggest that cisplatin may play a significant role in the differentiation of EC in vivo.
BJU International 04/2002; 89(4):454-8. · 2.84 Impact Factor
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ABSTRACT: Cytotoxic chemotherapy has shown little antitumour activity against renal cell carcinoma (RCC). Although immunotherapy is relatively effective against RCC, the response rate is approximately 20%. Therefore, there is an urgent need to increase this response rate. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) is one member of the tumour necrosis factor ligand family that selectively induces apoptosis of cancer cells. Since several cytotoxic anticancer drugs including 5-fluorouracil (5-FU) also mediate apoptosis, we reasoned that combined treatment of cancer cells with TRAIL and drugs might result in synergy and overcome the resistance of the cancer cell. This study has examined whether TRAIL can synergise with 5-FU in both cytotoxic and apoptotic assays against drug-resistant RCC cells. Cytotoxicity was determined by an 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. Treatment of Caki-1 cells with TRAIL in combination with 5-FU resulted in a synergistic cytotoxic effect. Synergy was also achieved in freshly derived RCC cells from 3 patients. The enhanced cytotoxicity was obtained irrespective of the sequence of the treatment, but the highest cytotoxicity was observed when Caki-1 cells were treated with TRAIL and 5-FU simultaneously. The synergy achieved in cytotoxicity with TRAIL and 5-FU was shown to be due to apoptosis. The mechanisms responsible for the synergistic cytotoxicity and apoptosis were examined. Treatment of Caki-1 cells with 5-FU enhanced the expression of p53 and bax, but had no effect on the expression of bcl-2. Incubation of Caki-1 cells with TRAIL enhanced the intracellular accumulation of 5-FU and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). Treatment of Caki-1 cells with TRAIL downregulated the expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) modestly, and upregulated the expression of orotate phosphoribosyltransferase (OPRT). However, the expression level of thymidine phosphorylase (TP) was not affected by TRAIL. This study demonstrates that combined treatment of RCC cells with TRAIL and 5-FU overcomes their resistance. The sensitisation obtained with freshly isolated RCC cells required low subtoxic concentrations of 5-FU. These findings support the potential application in vivo of a combination of TRAIL and 5-FU in the treatment of TRAIL/5-FU-resistant RCC.
European Journal of Cancer 02/2002; 38(1):167-76. · 5.54 Impact Factor
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ABSTRACT: To evaluate the relationship between bedwetting and development in infancy.
Questionnaires concerning micturition habits and development at 3 and 5 years of age were completed by the parents of 157 children who had had their health checked by pediatricians at a group checkup at 3 years of age.
The percentage of bedwetters in whom the frequency of bedwetting was at least once a month was 53% at 3 years of age and 21% at 5 years of age. The prevalent resolution period of bedwetting in infants was 2.5 to 3.5 years of age. The head circumference for boys at birth differed significantly between the bedwetters and nonbedwetters at both ages. Daytime symptoms were more frequent among bedwetters at both ages. Earlier toilet training had no influence on bedwetting at 5 years of age, although it led to earlier control at night at a younger age. Delays in speaking and walking might be factors connected to bedwetting. The prevalence of bedwetting in boys was higher than that in girls. Multiple logistic regression analysis revealed that daytime incontinence and sex were significant factors for bedwetting at 5 years of age.
Daytime incontinence and sex were the significant factors for bedwetting in infancy. Head circumference for boys and developmental delays in speaking and walking might also be important factors.
Urology 12/2001; 58(5):772-6. · 2.43 Impact Factor
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ABSTRACT: 5-fluorouracil (5-FU) is an anticancer agent clinically used against various cancers including bladder carcinoma. 5-FU inhibits thymidylate synthase (TS) and blocks DNA synthesis. TS is the key enzyme in the catalysis of the methylation from deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate. Little is known about the significance of TS in bladder carcinoma. The authors investigated the activity of TS in 82 bladder cancers and prognostic significance of the levels of TS and/or activities of dihydropyrimidine dehydrogenase (DPD), an important enzyme in the degradation of 5-FU.
The levels of TS and DPD activities in nonfixed, fresh, frozen, bladder carcinoma and normal bladder specimens were determined biochemically by the FdUMP binding assay and the 5-FU degradation assay, respectively.
The activity of TS was 10-fold higher in bladder carcinoma compared with normal bladder. TS activity in muscle-invasive bladder carcinoma was threefold higher than that in Ta and T1 cancer. In addition, the activity of TS in T1 bladder carcinoma was threefold higher than that in Ta cancer. The level of TS activity in Grade 3 bladder carcinoma was 4.5-fold and 3.5-fold higher than that in Grade 1 and Grade 2 cancers, respectively. Patients with Ta and T1 bladder carcinoma with low TS activity had a longer postoperative tumor-free period than those with high activity in the 2-year follow-up. Patients with Ta and T1 bladder carcinoma with high or low TS activity were divided into four subgroups: high or low DPD activity subgroups. Patients with low TS activity and high DPD activity had the longest postoperative disease-free period among the 4 subgroups during the 2-year follow-up.
To the authors' knowledge, the current study is the first study that demonstrated that the level of TS activity correlates with both the progression of the stage and the increase of the grade of bladder carcinoma and that elevated TS activity predicts early recurrence in Ta and T1 bladder carcinoma. These results suggested that elevated TS activity might have been associated with a higher chance of progression and recurrence of bladder carcinoma in the patients who participated in this study.
Cancer 09/2001; 92(3):510-8. · 4.77 Impact Factor
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ABSTRACT: The caspase family of proteases is speculated to have a crucial role in apoptosis. The effect of treatment with adriamycin (ADR), cisplatin (CDDP), 5-fluorouracil (5-FU), vinblastine (VLB), IFN-alpha, or IFN-gamma on the activation of caspase-3, -6, -8, and -9 in renal cell carcinoma (RCC) cells was investigated, to clarify the mechanisms of chemo- and immunotherapeutic agent-mediated apoptosis. Caspase activity was determined by a quantitative colorimetric assay. Apoptosis was monitored by acridine-orange staining assay. Treatment of ACHN cells with CDDP, VLB, IFN-alpha, or IFN-gamma did not activate caspase-3, but its activity was increased 7.2-fold (p = 0.0001) with ADR and 2.8-fold (p = 0.0385) with 5-FU in comparison with control. Furthermore, when the ADR treatment time was shortened from 24 to 8 or 2 h, the same caspase-3 activation occurred. Activation of caspase-3 was also observed in six freshly isolated human RCC cells after the treatment with ADR. Of the six freshly derived RCC cells treated with 5-FU, caspase-3 activity was increased 3.1-fold (p = 0.0051) and 2.4-fold (p = 0.0346) in two of them, respectively. Epirubicin and pirarubicin, compounds closely related to ADR, also respectively enhanced 4.2-fold (p = 0.0052) and 2.8-fold (p = 0.0147) caspase-3 activity in ACHN cells. The activation of caspase-3 observed with a colorimetric assay was confirmed with immunocytochemical analysis using the anti-active caspase-3 mAb, which specifically recognizes the active form of caspase-3. Furthermore, both active caspase-3 and apoptosis triggered by either ADR or 5-FU were inhibited significantly by the general caspase inhibitor Z-VAD-FMK, or a specific caspase-3 inhibitor DMQD-CHO. These findings provide a mechanistic explanation for anthracyclines and 5-FU induced-apoptosis.
International Journal of Oncology 08/2001; 19(1):19-24. · 2.40 Impact Factor
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ABSTRACT: The interaction of Fas and Fas ligand (FasL) plays an important role in cytotoxic T-lymphocyte-mediated and natural killer cell-mediated apoptosis against tumor cells. Circulating soluble FasL (sFasL) has been suggested to provide protection from Fas-mediated apoptosis. The current study examined this possibility in patients with bladder carcinoma.
The levels of sFasL in the serum of 163 patients with bladder carcinoma were determined using an enzyme-linked immunoadsorbent assay. Antiautologous tumor cytotoxic activity was assessed by the 12-hour chromium isotope ((51)Cr) release assay.
The mean serum level of sFasL in patients with bladder carcinoma was 2.5-fold higher than that in healthy donors. The level of serum sFasL in patients with muscle-invasive bladder carcinoma was 2.5-fold higher than that in patients with superficial bladder carcinoma. In addition, serum sFasL levels in patients with T1 and Tis bladder carcinoma was 2-fold and 2.7-fold higher, respectively, than levels in patients with Ta bladder carcinoma. The serum level of patients with sFasL in Grade 3 bladder carcinoma were 2.4-fold and 1.7-fold higher than that in patients with Grade 1 and Grade 2 bladder carcinoma, respectively. Patients with Ta bladder carcinoma with a low level of serum sFasL (less than the median value) had a longer postoperative tumor-free interval than patients with a high sFasL level (greater than the median value) in the 5-year follow-up. There was an apparent inverse correlation between the level of serum sFasL and antiautologous tumor cytotoxic activity.
The results of the current study demonstrated that the level of serum sFasL is correlated with both disease progression and increase in the tumor grade, and that an elevated serum sFasL level predicted early recurrence in patients with Ta bladder carcinoma. These findings suggest that elevated serum sFasL levels might be associated with a greater risk of disease progression and recurrence in patients with bladder carcinoma.
Cancer 08/2001; 92(2):287-93. · 4.77 Impact Factor
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ABSTRACT: A 53-year-old female visited our hospital with a complaint of acute urinary retention. Transvaginal ultrasonography, computed tomography and magnetic resonance imaging showed extreme thickening of the urethral wall. Histopathological examination of the transvaginal needle biopsy suggested well-differentiated adenocarcinoma. She underwent total cysto-urethrectomy with partial vaginal wall resection and ileal conduit urinary diversion. Pathological diagnosis of the tumor was columnar adenocarcinoma invading into the vaginal wall and periurethral connective tissue. Fifty-eight cases of primary adenocarcinoma of the female urethra in the Japanease literature are briefly reviewed.
Hinyokika kiyo. Acta urologica Japonica 08/2001; 47(7):509-12.
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ABSTRACT: To investigate the effect of anti-Fas monoclonal antibody (mAb) on the intracellular concentration of doxorubicin in renal cell carcinoma (RCC) cells. Little is known about the influence of anti-Fas mAb on the intracellular concentration of chemotherapeutic agents.
The concentration of intracellular doxorubicin was determined by high-performance liquid chromatography. The mRNA and protein levels of multidrug resistance-associated protein gene were evaluated by reverse transcriptase-polymerase chain reaction and immunocytochemistry, respectively.
An increased concentration of doxorubicin inside the cells was found: 2.4-fold in ACHN cells (a human RCC cell line) after treatment with doxorubicin combined with anti-Fas mAb compared with doxorubicin alone. Of the five cases of freshly derived RCC cells treated with doxorubicin and anti-Fas mAb, the intracellular concentration of doxorubicin was increased 2.3 and 2.7-fold in two of them, respectively. Furthermore, both the mRNA and the protein levels of the multidrug resistance-associated protein gene were downregulated after treatment of ACHN cells with anti-Fas mAb. Treatment of ACHN cells with a combination of anti-Fas mAb and doxorubicin resulted in a potentiation of the doxorubicin-mediated cytotoxicity.
The increased intracellular concentration of doxorubicin by anti-Fas mAb might be one of the mechanisms responsible for the enhancement of doxorubicin-mediated cytotoxicity in RCC cells.
Urology 06/2001; 57(5):993-8. · 2.43 Impact Factor
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ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the pathway of uracil and thymine catabolism. DPD is also the principal enzyme involved in the degradation of 5-fluorouracil (5-FU), which is one of the anticancer chemotherapeutic agents currently used in the treatment of bladder cancer. Little is known about the significance of DPD activity in human cancers. We investigated the activity of DPD in 74 bladder cancers and the relationship between the DPD activity and the sensitivity to 5-FU. The levels of DPD activity in bladder cancer and normal bladder tissues were determined by the 5-FU degradation assay. The sensitivity to 5-FU was assessed by the microculture tetrazolium dye (dimethylthiazolyl-2-5-diphenyltetrazolium bromide; MTT) assay. The activity of DPD was approximately 2-fold higher in bladder cancer tissues compared with normal bladder tissues. DPD activity in invasive bladder cancers was approximately 2-fold higher than that in superficial cancers. In addition, the levels of DPD activity in grade 2 and grade 3 bladder cancers were approximately 3-fold and 4-fold higher than that in grade 1 cancers, respectively. Patients with superficial bladder cancer with a low DPD activity had a slightly longer postoperative tumour-free period than those with a high DPD activity over a 2-year follow-up period, but this was not significant. There was an inverse correlation between DPD activity in bladder cancer cells and their sensitivity to 5-FU. Furthermore, 5-chloro-2,4-dihydroxypyridine (CDHP), a potent DPD inhibitor, enhanced the sensitivity to 5-FU. The present study has demonstrated that the level of DPD activity correlated with the progression of the stage and an increase in the grade of the bladder cancer. These results suggest that an elevated DPD activity might be associated with the malignant potential of the bladder cancer. In addition, it might be possible to overcome 5-FU insensitivity by using DPD inhibitors in the treatment protocols of 5-FU-based chemotherapy for bladder cancers.
European Journal of Cancer 04/2001; 37(5):569-75. · 5.54 Impact Factor
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ABSTRACT: The development and acquisition of multiple drug resistance in cancer cells are a consequence of cancer chemotherapy and remain a major obstacle in treatment. Therefore, there is an obvious need for alternative approaches, such as immunotherapy and gene therapy. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is one of the tumor necrosis factor ligand families and it selectively induces apoptosis against cancer cells. Several cytotoxic anticancer drugs also mediate apoptosis and may share the common intracellular pathways leading to apoptosis. We reasoned that combination treatment of cancer cells with TRAIL and drugs may overcome this resistance. We evaluated whether bladder cancer cells are sensitive to TRAIL mediated cytotoxicity and whether TRAIL may synergize with anticancer agents in cytotoxicity and apoptosis against bladder cancer cells.
Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis.
Human T24 bladder cancer line was relatively resistant to TRAIL and TRAIL was not cytotoxic against normal bladder cells. Treatment of T24 cells with TRAIL in combination with 5-fluorouracil or mitomycin C did not overcome resistance to these agents. However, treatment of T24 cells with a combination of TRAIL and cisplatin resulted in a synergistic cytotoxic effect. Synergy was also achieved in the cisplatin resistant T24 line (T24/CDDP), 2 other bladder cancer lines and 3 freshly derived bladder cancer cells. The combination of TRAIL and carboplatin resulted in a synergistic cytotoxic effect on T24 cells. However, the combination of TRAIL and trans-diamminedichloroplatinum (II) resulted in an antagonistic cytotoxic effect. The synergy achieved in cytotoxicity with TRAIL and cisplatin was also achieved in apoptosis. Treating T24 cells with cisplatin enhanced the expression of bax but not bcl-2. Incubation of T24 cells with TRAIL increased the intracellular accumulation of cisplatin.
This study demonstrates that combination treatment of bladder cancer cells with TRAIL and cisplatin overcomes their resistance. The sensitization obtained with established cisplatin resistant and freshly isolated bladder cancer cells required low subtoxic concentrations of cisplatin, supporting the in vivo potential application of a combination of TRAIL and cisplatin for treating TRAIL resistant and cisplatin resistant bladder cancer.
The Journal of Urology 02/2001; 165(1):263-70. · 3.75 Impact Factor
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ABSTRACT: Anti-Fas monoclonal antibody (mAb) kills Fas-expressing cells by apoptosis. Several anticancer agents also mediate apoptosis and may share common intracellular pathways leading to apoptosis with Fas. Thus, we reasoned that combination treatment of drug-resistant cells with anti-Fas mAb and drugs might overcome their resistance. We investigated whether anticancer agents enhance Fas-mediated apoptosis and cytotoxicity against renal cell carcinoma (RCC) cells. Treatment of ACHN RCC cells with anti-Fas mAb in combination with 5-fluorouracil, vinblastine, IFN-alpha, or IFN-gamma did not overcome resistance to these agents. However, combination treatment with anti-Fas mAb and Adriamycin (ADR) resulted in a synergistic cytotoxic effect. Furthermore, synergy was also obtained even when the exposure time was shortened from 24 h to 8 or 2 h. Synergy was also achieved in four other RCC cell lines and five freshly derived human RCC cells. Treatment with anti-Fas mAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on ACHN cells. Similar results were achieved with a combination of humanized anti-Fas mAb and ADR. Incubation of ACHN cells with ADR augmented the expression of Fas and p53, but not Bcl-2, Bax, or caspase-3. However, the activity of caspase-3 itself was apparently enhanced after treatment with ADR alone or combined treatment with anti-Fas mAb. The synergy obtained in cytotoxicity with anti-Fas mAb and ADR was also achieved in apoptosis. Exposure of ACHN cells and freshly derived RCC cells to ADR enhanced their susceptibility to lysis by peripheral blood lymphocytes and tumor-infiltrating lymphocytes. This study demonstrates that combination treatment of RCC cells with anti-Fas mAb and ADR might overcome their resistance. The sensitization required a low concentration of ADR and a short exposure time, thus supporting the potential in vivo application of a combination of ADR and anti-Fas mAb or immunotherapy in the treatment of ADR- and/or immunotherapy-resistant RCC.
Cancer Research 07/2000; 60(11):2912-8. · 7.86 Impact Factor
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ABSTRACT: Previous studies indicated that cancer patients lack functional anti-tumor cytotoxic lymphocytes. However, anti-tumor cytotoxic lymphocytes may coexist with immunoresistant tumor cells. We reasoned that anti-tumor cytotoxic activity of lymphocytes may be revealed if the tumor cells are sensitized to killing. It has been reported that adriamycin (ADR) exhibits various immunomodulating activities. In the present study, we investigate the effect of ADR on the susceptibility of freshly isolated bladder cancer cells to lysis by autologous non-activated peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL).
Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay.
Treatment of ADR-resistant fresh bladder cancer cells with ADR at 0.1 microg./ml. or more for 3 hours or more enhanced their susceptibility to lysis by autologous PBL. This ADR-induced enhancement of susceptibility of fresh bladder cancer cells to lysis by PBL was also observed when lymphokine activated killer cells, purified natural killer cells and T lymphocytes were used as effector cells. Furthermore, while cytotoxicity of freshly derived TIL against autologous bladder cancer cells was minimal, significant cytotoxicity was observed with ADR-treated bladder cancer cells. The ADR analogs, epirubicin and pirarubicin, also enhanced the susceptibility of bladder cancer cells to lysis by autologous PBL. Treatment of bladder cancer cells with ADR had no effect on the expression of MHC class I on the cancer cells or the frequency of bladder cancer target cell conjugates to autologous PBL. Treatment of bladder cancer cells with ADR augmented their sensitivity to anti-Fas monoclonal antibody and tumor necrosis factor-a. Pretreatment of effector cells with ADR had no effect on their cytotoxic function.
These findings demonstrate that PBL and TIL in patients with bladder cancer exhibit anti-tumor cytotoxic function, but their function is not manifested due to development or acquisition of tumor cell resistance to killing. However, the resistance of bladder cancer cells to killing by cytotoxic lymphocytes is overcome if cancer cells are sensitized by subtoxic concentrations of ADR. These findings suggest that treatment of bladder cancer patients with low doses of ADR may sensitize the cancer cells to killing by autologous circulating and tumor infiltrating lymphocytes and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/or immune-resistant bladder cancer.
The Journal of Urology 01/2000; 162(6):2170-5. · 3.75 Impact Factor
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ABSTRACT: Resistance to conventional anticancer chemotherapeutic agents remains one of the major problems in the treatment of bladder cancer. Hence, new therapeutic modalities are necessary to treat the drug-resistant cancers. Apo-2 ligand (Apo-2L) is member of the tumor necrosis factor ligand family, and it induces apoptosis in cancer cells. Several cytotoxic anticancer drugs, including Adriamycin (ADR), also mediate apoptosis and may share the common intracellular pathways leading to cell death. We reasoned that combination treatment of the drug-resistant cancer cells with Apo-2L and drugs might overcome their resistance. Here, we examined whether bladder cancer cells are sensitive to Apo-2L-mediated cytotoxicity and whether Apo-2L can synergize with ADR in cytotoxicity and apoptosis against bladder cancer cells. Recombinant human soluble Apo-2L (sApo-2L), which carries the extracellular domain of Apo-2L, was used as a ligand. Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. Human T24 bladder cancer line was relatively resistant to sApo-2L. Treatment of T24 line with combination of sApo-2L and ADR resulted in a synergistic cytotoxic effect. Synergy was also achieved in the ADR-resistant T24 line (T24/ADR), two other bladder cancer lines, and three freshly derived human bladder cancer cell samples. In addition, T24 cells were sensitive to treatment with sApo-2L combined with epirubicin or pirarubicin. The synergy achieved in cytotoxicity with sApo-2L and ADR was also achieved in apoptosis. Intracellular accumulation of ADR was not affected by sApo-2L. Incubation of T24 cells with sApo-2L down-regulated the expression of glutathione S-transferase-pi mRNA. This study demonstrates that combination treatment of bladder cancer cells with sApo-2L and ADR overcomes their resistance. The sensitization obtained with established ADR-resistant bladder cancer cells and freshly isolated bladder cancer cells required low subtoxic concentrations of ADR, thus supporting the in vivo potential application of combination of sApo-2L and ADR in the treatment of ADR-resistant bladder cancer.
Clinical Cancer Research 10/1999; 5(9):2605-12. · 7.74 Impact Factor
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ABSTRACT: Fas and Fas ligand play an important role in cytotoxic T lymphocyte-mediated cytotoxicity. Like Fas ligand, anti-Fas monoclonal antibody (mAb) induces apoptosis of cells expressing Fas and mimics tumor necrosis factor-alpha (TNF-alpha) in its cytotoxic activity, but not in regard to other TNF-alpha-mediated activities. Since combination treatment with TNF-alpha and some anticancer chemotherapeutic agents results in synergistic cytotoxicity against various cancer cells, anti-Fas mAb may also synergize with anticancer agents in exerting cytotoxicity. The present study examined this hypothesis using bladder cancer cells. Cytotoxicity was examined by a 1-day microculture tetrazolium dye assay. Treatment of T24 cells with anti-Fas mAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, combination treatment with anti-Fas mAb and adriamycin (ADR) resulted in a synergistic cytotoxic effect on T24 cells, three other bladder cancer lines, and fresh bladder cancer cells derived from four patients. Treatment with ADR enhanced the expression of Fas on T24 cells. The expression of P-glycoprotein was not affected by the antibody-mediated sensitization. This study showed that combination treatment of bladder cancer cells with anti-Fas mAb and ADR can overcome their resistance and that the upregulation of Fas expression by ADR may play a role in the enhanced cytotoxicity.
Journal of Infection and Chemotherapy 10/1999; 5(3):139-143. · 1.80 Impact Factor
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ABSTRACT: Nephrogenic adenoma is a rare, benign tumor of the urinary tract. The origin of this tumor is supposed to be a metaplastic transformation of urothelium in response to stimulation such as recurrent urinary tract infections or surgical trauma. We experienced three cases of nephrogenic adenoma originating in the bladder. The first patient was a 29-year-old man with right vesicoureteral reflux (VUR). When Teflon injection for VUR was performed, a papillary tumor was found on the right wall of the bladder. Transurethral resection of the bladder tumor (TUR-Bt) was performed. The second patient was a 72-year-old woman who was suffering from chronic cystitis. Although she was treated with antibiotics for one year, the symptoms were not improved. Cystoscopy showed multiple papillary tumors at the retrotrigonum of the bladder and TUR-Bt was performed. The third patient was a 75-year-old man who had a history of the left pelvic and bilateral ureteral tumors. Left radical nephroureterectomy and right radical ureterectomy with an ileal graft replacement was performed. Three years later, cystoscopy demonstrated a papillary tumor at the retrotrigonum, which was resected transurethrally. Our cases are the 20th to 22nd cases of the nephrogenic adenoma of the bladder reported in the Japanese literature.
Hinyokika kiyo. Acta urologica Japonica 10/1998; 44(9):667-70.
