Biomedical subjects

O Yoshida

Publications and source records attributed to O Yoshida.

At least 199 records · Page 11Linked to original sources

PubMed1995

Inhibitory effect of dexamethasone and progesterone in vitro on proliferation of human renal cell carcinomas and effects on expression of interleukin-6 or interleukin-6 receptor.

Interleukin-6 (IL-6) has been suggested as an autocrine growth factor of human renal cell carcinomas. Since steroids are known to inhibit IL-6 gene expression, we investigated their effects on the growth of renal cell carcinoma. Dexamethasone inhibited proliferation of 2 of 4 renal cell carcinoma cell lines in a dose-dependent manner. In one of these 2 cell lines, IL-6 gene expression was also inhibited, but not in the other. The inhibitory effect of dexamethasone on cell proliferation was not reversed by the exogenous IL-6. In 1 of the 2 remaining cell lines, the inhibition of IL-6 gene expression was observed, although there was no inhibition of cell proliferation. Thus, inhibition of growth by dexamethasone did not correlate with an inhibitory action of dexamethasone on IL-6 mRNA expression. Progesterone inhibited the growth of 1 cell line without concomitant inhibition of IL-6 gene expression. Expression of IL-6 receptor mRNA was not altered. A dose-dependent increase in mRNA expression of gp130, the transducer of IL-6 signal, was induced by dexamethasone and progesterone in 2 and 1 of the 4 cell lines, respectively. These data suggest that, in some renal cell carcinomas, steroids may inhibit cell proliferation by a mechanism independent of their effects on mRNA expression of IL-6 and IL-6 receptors. Dexamethasone may be useful, not only for palliation of paraneoplastic syndrome caused by overproduction of IL-6, but also for inhibition of growth of renal cell carcinomas.

Antigens, CD↗

PubMed1995

Smaller ports result in shorter convalescence after laparoscopic varicocelectomy.

Minimal postoperative pain and a shorter convalescence after laparoscopic surgery are attributable to the small puncture wounds produced to accommodate trocars. We investigated the effects of trocar size on convalescence after 37 laparoscopic varicocelectomies. The initial 21 patients underwent the procedure with 2, 10 mm. ports and 1, 5 mm. port, while the last 16 underwent surgery with 3, 5 mm. ports. Postoperative convalescence was evaluated by a questionnaire. The patients who underwent the 5 mm. port technique achieved complete pain relief, returned to work and could resume work at preoperative levels significantly earlier than those who underwent the 10 mm. port technique (2.4 +/- 1.5 days versus 5.9 +/- 4.8 days, p < 0.03; 8.2 +/- 3.1 days versus 10.0 +/- 2.5 days, p < 0.03, and 10.2 +/- 4.4 days versus 14.3 +/- 6.5 days, p < 0.03, respectively). Our study showed that laparoscopic surgery with smaller ports resulted in less postoperative pain and a shorter convalescence than when larger 10 mm. ports were used.

Adolescent↗

PubMed1995

[Postoperative complications of self-catheterizable continent urinary diversions (Kock, Indiana, and appendiceal Mainz pouch) and patient care].

A self-catheterizable continent urinary reservoir has become one of the major options for urinary diversion in patients with invasive bladder cancer or other pelvic malignancies. We performed the Kock pouch, the Indiana pouch and the appendiceal Mainz pouch in 124, 51 and 4 patients with the mean followup periods of 50, 33, and 10 months, respectively. In the Kock pouch, the efferent and afferent nipple valve malfunction was seen in 16.7 and 21.3 percent each, requiring repair surgery, such as fixation of the efferent nipple to the pouch wall, reconstruction of an isoperistaltic nipple valve in the former, and removal of the Dacron fabric collar or re-anastomosis of the ureter to the pouch using LeDuc technique in the latter. In the Indiana pouch, stomal stenosis, an hourglass-like pouch deformity, difficult catheterization occurred in 3, 2 and 2 patients, respectively. Among the 4 patients with the appendiceal Mainz pouch, there were no major late postoperative complications except for mild stenosis of the conduit, handled with bougienage. As a whole, surgical revisions, related to urinary diversion, was done in 20.3, 10.6, 0 percent in the Kock, Indiana, Mainz pouch patients, respectively. Stone formation, mostly multiple and recurrent, occurred in 27.8, 6.4, 0 percent in the Kock, Indiana, Mainz pouch, respectively. Most of the stones were removed endoscopically via a stoma or by percutaneous approach. Acidosis was seen in 3 patients in both the Kock and Indiana pouch, and 3 patients with the Kock pouch suffered from symptomatic choleithiasis. At the time of the latest observation, continence was achieved in 90.2, 93.0, and 100 percent, whereas excretory urograms showed normal collecting systems in 64.5, 90.4, and 100 percent in the Kock, Indiana, and Mainz pouch, respectively. In conclusion, the Kock pouch, performed by an original method using unabsorbable polyester fabric collars and metallic staples, has an intolerably high rate of late complications, and either the modified Indiana pouch with ileal patch or the appendiceal Mainz pouch using the umbilicus as a stoma is recommended for a self-catheterization continent urinary diversion.

Adult↗

PubMed1995

[Hemoptysis due to aortopulmonary fistula: a case report of successful surgical treatment].

A 76-year-old man was admitted for recurrent hemoptysis of 3 weeks' duration. Chest X-ray revealed lung emphysema, but no findings of thoracic aortic aneurysm. The patient's physician attributed to bronchoectasia, and he underwent angiography for the purpose of embolization of bronchial arteries. Angiography showed a small saccular thoracic descending aortic aneurysm and an aortopulmonary fistula. So aneurysmectomy and patch angioplasty was done under partial cardiopulmonary bypass. Lobectomy or wedge pulmonary resection was not necessary. His postoperative course was uneventful. In case of the patients with hemoptysis, the possibility of aortopulmonary fistula should be considered, and computed tomography or aortography should be done to rule out other pulmonary diseases.

Aged↗

PubMed1995

Immunohistochemical analysis of p53 and proliferating cell nuclear antigen (PCNA) in bladder cancer: positive immunostaining and radiosensitivity.

BACKGROUND: Preoperative radiation therapy followed by radical cystectomy for invasive bladder cancer has been considered beneficial for selected patients whose tumors display a pronounced initial response to radiotherapy. METHODS: In order to determine whether overexpression of p53 gene products or proliferating cell nuclear antigen (PCNA) can be used to predict the response of invasive bladder cancer to radiotherapy, an immunohistochemical study of bladder cancers with monoclonal antibodies to p53 or PCNA (PAb 1801 or PC10) was performed. The results of immunostaining of pretreatment biopsy specimens from 60 invasive bladder cancers were analyzed to determine the relationship between labeling for p53 or PCNA and radiosensitivity as determined by histopathological examination of cystectomy specimens obtained after preoperative radiation. RESULTS: The group with a good response to preoperative radiation therapy had better progression-free rates than did the group with a poor response (P < 0.05). There was no significant difference in radiosensitivity between patients with primary tumors with negative and positive immunostaining for p53. On the other hand, the PCNA labeling index (LI) differed significantly between tumors with poor and good histopathological responses to radiation therapy (P < 0.05). CONCLUSION: No correlation was found between immunohistochemically detectable alterations of p53 gene products and the radiosensitivity of invasive transitional cell carcinoma of the bladder. However, PCNA immunostaining may be useful for identifying patients for whom preoperative radiation might prove beneficial.

Adult↗

PubMed1995

Comparison of multidrug resistance gene expression levels with malignant potentials and influence of chemotherapy in urothelial cancers.

BACKGROUND: We sought to determine how often P-glycoprotein is involved in the drug-resistance of urothelial cancer, and whether MDR1 gene expression is correlated with tumor grade, invasiveness, or metastasis. METHODS: Forty-two tumor specimens and two normal bladder mucosal samples obtained from 34 urothelial cancer patients were analyzed. Reverse-transcription and polymerase chain reaction were conducted. MDR1 mRNA levels were determined by measuring the relative ratio of the MDR1 to beta-2-microglobulin (b2 m) mRNA specific PCR products. RESULTS: The MDR1/b2 m in two normal urothelial samples were 0.044 and 0.045. For untreated primary tumors, levels of MDR1 gene expression in 46% tumor samples were less than that of normal urothelium, while 27% showed expression levels with a MDR1/b2 m ratio more than 0.1. There was no statistical correlation between MDR1 mRNA level and tumor grade, stage, or metastatic status. There was higher MDR1 gene expression in two lymph node metastasis specimens and almost equal expressions in two more. There was no significant difference in the mean MDR1/b2 m ratio between postchemotherapy and untreated tumors. A remarkable elevation of the MDR1 mRNA level (15 times greater than prechemotherapy) was found in one tumor; mRNA levels of the multidrug resistance-associated protein (MRP) gene, glutathione S-transferase pi (GST-pi) gene or DNA topoisomerase II (topo II) gene did not increase. CONCLUSIONS: It is still unclear whether the MDR1 gene expression in urothelial tumor cells is inducible by the current combination chemotherapy regimens. RT-PCR quantitation is useful for determining the expression level of MDR1 gene in urothelial cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

Shorter interval between cycles of cyclophosphamide, doxorubicin, cisplatin using recombinant human granulocyte colony-stimulating factor for urothelial cancer--phase I/II study.

BACKGROUND: Despite improvement in the response rate and protraction of the progression-free period of urothelial cancer produced by chemotherapy, severe bone marrow suppression often results in delays in the initiation of treatment cycles and/or decreases in drug dosages. Reduction of leukopenia during chemotherapy has been demonstrated by the combined administration of granulocyte colony-stimulating factor (G-CSF) in various malignancies. METHODS: A phase I/II study was conducted to assess whether the interval between cycles of CISCA (cyclophosphamide, doxorubicin, cisplatin) chemotherapy could be shortened under support of recombinant human granulocyte colony-stimulating factor (rhG-CSF) for urothelial cancer. Three or more patients with transitional cell carcinoma of the urinary tract were allocated to each of four different treatment intervals (step 1: 28 days, step 2: 21 days, step 3: 17 days, and step 4: 14 days) by reducing the interval in a step-wise manner. Two mg/kg/day of a rhG-CSF, lenograstim, was injected subcutaneously on days 3 to 16 (until day 14 for the 14-day interval group). RESULTS: Sixteen patients were enrolled, four patients were treated with the step 1 protocol, five with step 2, four with step 3, and three with step 4. Leukopenia/neutropenia was the most severe toxic reaction, but none of the patients at any step manifested neutropenia of WHO grade 4 for more than four days. There were no significant differences in the hematological and nonhematological toxicities among the 4 steps. Seven of eight patients with measurable diseases were treated with CISCA on shortened schedules (steps 2-4), and one complete remission (CR) and four partial responses (PR) were demonstrated. CONCLUSIONS: CISCA chemotherapy supported by rhG-CSF was safely shortened to a 14-day interval in the pilot study. The potential role of rhG-CSF in shortening the interval of CISCA, as well as the benefit of the intensified schedule, remains to be clarified.

Adolescent↗

PubMed1994

Enhancement of sensitivity of urinary bladder tumor cells to cisplatin by c-myc antisense oligonucleotide.

BACKGROUND: Tumor cells have different degrees of sensitivity and resistance to anticancer agents. The acquisition of drug resistance is a major concern in cancer treatment. Because the c-myc oncogene has been implicated in the poor prognosis of some human tumors including urinary bladder tumor (UBT), the resistance of such tumors to anticancer drugs may correlate with c-myc expression. The present study tested this hypothesis by examining the effect of c-myc antisense oligonucleotide treatment on the sensitivity of human UBT cells to anticancer chemotherapeutic agents. METHODS: Cytotoxicity determined by a 1-day microculture tetrazolium dye assay. C-myc mRNA was examined by Northern blot analysis. RESULTS: The T24 human UBT cell line constitutively expresses c-myc mRNA. Treatment of T24 cells with the c-myc antisense oligonucleotide resulted in a significant inhibition of the expression of c-myc mRNA. Treatment of T24 cells with the c-myc antisense oligonucleotide in combination with mitomycin C, Adriamycin, or 5-fluorouracil (5-FU) did not overcome their resistance to these anticancer chemotherapeutic agents. However, combination treatment with the c-myc antisense oligonucleotide and CDDP resulted in a synergistic cytotoxic effect on T24 cells and two freshly derived UBT cells. Further, treatment of CDDP-resistant T24 cells (T24/CDDP) with c-myc antisense oligonucleotide and CDDP reversed the resistance. Pretreatment of T24 cells with either agent and then treatment with the second agent resulted in the same cytotoxic activity as achieved in the presence of the two agents. The combination of c-myc antisense oligonucleotide and carboplatin also resulted in a synergistic cytotoxic effect on T24 cells, and the combination of c-myc antisense oligonucleotide and trans-diamminedichloro-platinum resulted in an additive cytotoxic effect. Incubation of T24 or T24/CDDP cells with the c-myc antisense oligonucleotide increased the intracellular accumulation of CDDP, but not the accumulation of 5-FU. CONCLUSIONS: This study demonstrates that combination treatment with c-myc antisense oligonucleotide and CDDP can overcome the CDDP-resistance of UBT cells and that the increased intracellular accumulation of CDDP by c-myc antisense oligonucleotide may play a role in the enhanced cytotoxicity obtained. The synergistic effect obtained with established UBT cells and freshly isolated UBT cells suggests that combination treatment with c-myc antisense oligonucleotide and CDDP may have clinical application in the therapy of CDDP-resistant UBT.

Antineoplastic Agents↗

PubMed1994

Formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in human renal-cell carcinoma.

To study the possible involvement of reactive oxygen species (ROS) in the tumor biology of human renal-cell carcinoma (RCC), we analyzed 35 cases of RCC for 2 parameters of oxidative damage: 8-hydroxy-2'-deoxyguanosine (8-OHdG), a mutation-prone DNA-base-modified product, was measured by means of high-performance liquid chromatography (HPLC) with an electrochemical (EC) detector, and 4-hydroxy-2-nonenal (HNE)-modified proteins were measured with a polyclonal antibody against HNE-modified proteins. A 54% higher content of 8-OHdG was found in RCC than in the corresponding non-tumorous kidney, suggesting that the DNA of RCC is more exposed to ROS than is the DNA of non-tumorous kidneys. Immunohistochemistry for HNE-modified proteins showed a distinct staining pattern of fine to coarse granularity in the cytoplasm of RCC (n = 15), implying that lipid peroxidation products are located in cytoplasmic organelles. These results suggest that RCC constitutionally elaborates more ROS than is produced by the non-tumorous parts of kidneys. No correlation was found between clinical stage, histology, age or sex and the 2 parameters examined.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1994

Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification.

BACKGROUND: Previously, p53 (also known as TP53) gene mutations have been shown to be frequently detected in highly malignant urothelial cancers. Evidence has been accumulating that the disruption of the normal function of p53 may lead to genomic instability, including predisposition to gene amplification. Furthermore, the normal function of p53 may be abrogated by MDM2 (murine double minute-2) gene amplification in some human tumors. PURPOSE: Our purpose was to investigate the relationship between protooncogene amplification and p53 alteration in urothelial cancers by examining the existence of amplification of MDM2 and 14 other protooncogenes in 50 urothelial tumors in which p53 gene status was known. METHODS: We analyzed gene amplification by Southern-blot analysis in 50 urothelial cancer specimens. These tumors were previously examined for p53 mutations by polymerase chain reaction-single-strand conformation analysis, and 17 tumors contained p53 mutations. RESULTS: Two high-grade advanced tumors (4%) without p53 mutation harbored MDM2 amplification with concurrent int-2 gene amplification. As for other genes, amplification was detected for int-2 (also known as WNT2) (seven [14%] of 50), erbB-2 (also known as ERBB2) (three [6%] of 50), N-ras (also known as NRAS) (one [2%] of 50), L-myc (also known as MYCL1) (one [2%] of 50), and raf-1 (also known as RAF1) (one [2%] of 50). The amplification of at least one gene examined was observed in 11 (22%) of 50 tumors. The presence of p53 mutations was not significantly associated with the occurrence of gene amplification, since the amplification was detected in six (35%) of 17 tumors with p53 mutations and in five (15%) of 33 tumors without p53 mutations. However, eight (73%) of 11 tumors with proto-oncogene amplification harbored p53 mutations or MDM2 amplification. CONCLUSIONS AND IMPLICATIONS: A subset of advanced urothelial cancers without p53 mutations may harbor MDM2 amplification. This finding should be taken into account when adopting p53 alteration as a marker of aggressiveness in urothelial cancers. Although the abrogation of normal p53 function may be one of the key steps to protooncogene amplification, the data further indicate that the predisposition to gene amplification in urothelial cancers was not determined by the presence of p53 alteration alone.

Blotting, Southern↗

PubMed1994

Overcoming tumor necrosis factor-alpha resistance of human renal and ovarian carcinoma cells by combination treatment with buthionine sulfoximine and tumor necrosis factor-alpha. Role of tumor necrosis factor-alpha mRNA down-regulation in tumor cell sensitization.

BACKGROUND: Previous studies have reported the glutathione plays a central role in a wide range of cellular functions, including protection, detoxification, transport, and metabolism. Buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamyl-cysteine synthetase, depletes intracellular glutathione. The study investigates the cytotoxic effect of BSO and tumor necrosis factor-alpha (TNF-alpha) used in combination on TNF-alpha-resistant human renal and ovarian cancer cells. METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. TNF-alpha mRNA was examined by Northern blot analysis. RESULTS: Combination treatment of TNF-alpha-resistant R4 and R11 human renal cell carcinoma cells with BSO and TNF-alpha overcame their resistance to TNF-alpha. In addition, the combination of BSO and TNF-alpha resulted in a synergistic cytotoxic effect on TNF-alpha-resistant OVC-8 and C30 human ovarian cancer cells. Treatment of R4, R11, and OVC-8 cells with TNF-alpha in combination with glutathione or N-acetyl-cysteine (NAC) showed an antagonistic cytotoxic effect. A possible mechanism of resistance to TNF-alpha in tumor cells is the expression of TNF-alpha mRNA or protein. R4 cells and OVC-8 cells constitutively expressed mRNA for TNF-alpha. Treatment of R4 cells or OVC-8 cells with BSO down-regulated the expression of TNF-alpha mRNA; however, treatment with TNF-alpha up-regulated the expression of TNF-alpha mRNA. When BSO was used in combination with TNF-alpha, the level of TNF-alpha mRNA enhanced by TNF-alpha was markedly reduced. Incubation of R4 cells with glutathione or NAC also down-regulated the expression of TNF-alpha mRNA. R11 and C30 cells did not constitutively express mRNA for TNF-alpha, and the BSO treatment had no effect on the TNF-alpha mRNA level. CONCLUSIONS: This study demonstrates that the combination of BSO and TNF-alpha can overcome the TNF-alpha resistance of tumor cells and that depletion of intracellular glutathione and down-regulation of TNF-alpha mRNA by BSO may play a role in the enhanced cytotoxicity seen with the combination of BSO and TNF-alpha. There may not be always a correlation between the expression of TNF-alpha mRNA in tumor cells and their resistance to TNF-alpha. The synergistic effect obtained with established renal cell carcinoma cells and ovarian cancer cells suggests that combination treatment with TNF-alpha and BSO could have clinical application in the therapy of TNF-alpha-resistant tumors.

Acetylcysteine↗

PubMed1994

Abnormal bone marrow B-cell differentiation in pre-B lymphoma-prone SL/Kh mice.

SL/Kh mice spontaneously develop pre-B lymphomas with surface phenotypes of B220+, BP-1+, Thy-1-, and surface immunoglobulin negative. The immunoglobulin heavy chain of lymphoma is clonally rearranged but the light chain gene remains in germline configuration. Studying prelymphoma stage SL/Kh bone marrow (BM), we found unusual multiclonal expansion of BP-1+ pre-B cells [34.8 +/- 5.8% (mean +/- SD)] by 4 weeks of age, whereas there were far fewer of such cells in most other laboratory strains (8 +/- 5%). The BP-1+ cells did not express surface immunoglobulin, Thy-1.1, or c-kit. Therefore, they seemed to belong to the pre-B II category. Increased numbers of BP-1+ cells were seen in F1 hybrids between SL/Kh and NFS/N; thus it was apparently a dominant heritable property of SL/Kh mice. Emergence of this population was independent of expression of endogenous ecotropic virus, since they were present in BMs of the F1 hybrid to C4W (Fv-4') and were not inhibited by neonatal injection of maternal resistance factor. In the radiation chimeras SL/Kh-->BALB/c, BP-1+ cells appeared abundantly (29.0 +/- 3.8%), whereas in the reciprocal chimeras BALB/c-->SL/Kh, for fewer (5.5 +/- 2.3%) appeared. Therefore, expansion of BP-1+ cells in prelymphomatous BM is a property of SL/Kh stem cells rather than BM microenvironments.

Animals↗

PubMed1994

Urinary excretion of mutagens and covalent DNA damage induced in the bladder and kidney after passive smoking in rats.

Using 32P-postlabeling assay, we studied the effect of sidestream smoke of cigarettes, so-called passive smoking, on the covalent DNA adduct formation in an animal model. Urine samples of 18 rats, 9 male and 9 female, before smoking resulted in an average of 2.4 adducts per 1 x 10(7) nucleotides per 24-h urine of a rat in the target plasmid DNA after incubation for 2 h in vitro. Urine samples of 4 out of 6 rats after exposure to sidestream smoke induced additional adducts in the target DNA. The incidence increased to 17.5 adducts per 1 x 10(7) nucleotides per 24-h urine of a rat. Without exposure to smoke, no increase in the adduct formation was observed. Adduct formations similar to those induced in vitro were detected in the bladder and kidney DNA, but not in the testicular DNA, of the four rats exposed to sidestream smoke. These observations suggest that passive smoking causes covalent DNA damage of the cells in the bladder and kidney by excreting chemicals in urine. Passive smoking as well as active smoking might contribute to the bladder and renal carcinogenic process.

Animals↗

PubMed1994

Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines.

Treatment of renal cell carcinoma (RCC) by conventional chemotherapy and immunotherapy has resulted in minimal remissions. Alternative forms of therapy are therefore being sought. The present study investigated the sensitivity of RCC cell lines to several toxins used alone and in combination with other agents. RCC lines were relatively sensitive to the direct cytotoxic effect of diphtheria toxin (DTX), Pseudomonas aeruginosa exotoxin A (PEA) and ricin. Furthermore, DTX in combination with tumor necrosis factor-alpha (TNF-alpha) resulted in synergistic cytotoxic activity. The mechanism of synergy was examined. A possible mechanism of resistance to TNF-alpha in tumor cells is the expression of TNF-alpha mRNA or protein. R11 cells did not constitutively express mRNA for TNF-alpha, however, treatment of R11 cells with TNF-alpha induced the expression of TNF-alpha mRNA. When DTX was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was markedly reduced. These studies suggest that DTX in combination with TNF-alpha can overcome the resistance of RCC lines and that the marked downregulation of TNF-alpha mRNA by DTX may play a role in the enhanced cytotoxicity seen with the combination of DTX and TNF-alpha. Furthermore, the combination treatment might also potentiate the antitumor host responses. The implications of these findings in clinical therapy are discussed.

ADP Ribose Transferases↗

PubMed1994

Effects of shock waves on the mouse fetus.

Extracorporeal shock wave lithotripsy is contraindicated during pregnancy because its effects on the fetus remain to be ascertained. The purpose of this study was to elucidate the effects of shock waves on fetuses at various stages of pregnancy. Pregnant mice received 100, 250, or 500 shock waves on 8, 10, 12, 14, and 16 days postcoitum. The effect on fetal survival rate and weight was minimal in the early stages of pregnancy. In the later stages of pregnancy, however, the number of viable fetuses decreased in proportion to an increasing number of shock waves, and almost no viable fetuses were found in the group treated with 500 shock waves. Fusion and necrosis were found in many dead fetuses. Histological examination of the fetuses, which was obtained immediately after the shock wave treatment, revealed hemorrhages in the brain, lungs and subcutaneous tissue. This study indicated that shock waves lead to fetal damage and death in the late stage of pregnancy in mice.

Animals↗

PubMed1994

Enhanced antitumor effect of Bacillus Calmette-Guérin in combination with fibrinogen on urinary bladder tumor.

Although intravesical instillation of Bacillus Calmette-Guérin (BCG) is an established and effective therapy for superficial urinary bladder tumor (UBT), the current major problems are BCG-resistant UBT and recurrence after BCG therapy. The injection of BCG and fibrinogen could be expected to induce the formation of a fibrin mesh, which would trap BCG and and prolong its antitumor action. The present study has been designed to investigate whether fibrinogen has the ability to augment antitumor activity of BCG against UBT. A single injection of BCG/fibrinogen solution into the subcutaneous tissue of C3H/He mice was performed. Histopathological examination revealed prolonged accumulation of BCG and marked infiltration of inflammatory cells at the injected site, as compared with the injection of BCG or fibrinogen alone. When BCG was used in combination with gelatin sponge, prolonged BCG accumulation was also observed, but not many inflammatory cells were induced, as compared with injection of BCG/fibrinogen combination. When BCG/fibrinogen solution was injected into MBT-2 murine UBT transplanted into C3H/He mice, the formation of fibrin fibers, which trap BCG, was induced, and many inflammatory cells around the tumor were seen. A pronounced inhibitory effect on tumor growth and prolonged survival of tumor-bearing mice were achieved, as compared with the injection of BCG alone. Dead BCG/fibrinogen solution had a modest inhibitory effect on the tumor growth. This study suggests that combination treatment with BCG and exogenous fibrinogen may prolong accumulation of BCG by BCG by trapping BCG in fibrin meshwork, and may induce marked infiltration of inflammatory cells into tumor stroma, causing marked regression of the tumor. The possible clinical implications of the combined use of BCG and fibrinogen are discussed.

Administration, Intravesical↗

PubMed1994

Obstructive azoospermia of unknown origin: sites of obstruction and surgical outcomes.

Although the majority of patients with obstructive azoospermia have medical histories or signs related to seminal tract obstruction, the pathogenesis of the obstruction is unknown in some patients. Of 38 patients with obstructive azoospermia treated at our hospital preoperative data did not indicate causes or sites of obstruction in 6. Operative and pathological findings showed obstruction at the proximal convoluted vas deferens or between the most distal portion of the cauda epididymis and the vas deferens in 8 of 11 blocked seminal tracts. Microsurgical epididymovasostomy resulted in a patent anastomosis in all 6 patients and pregnancy in 2. In patients with obstructive azoospermia of obscure preoperative causes, it is highly probable that the obstruction sites are in the convoluted vas deferens or the transitional region between the cauda epididymis and vas deferens, and that fertility may be restored by microsurgical epididymovasostomy.

Adult↗

PubMed1994

Overcoming TNF-alpha and drug resistance of human renal cell carcinoma cells by treatment with pentoxifylline in combination with TNF-alpha or drugs: the role of TNF-alpha mRNA downregulation in tumor cell sensitization.

Previous studies have demonstrated that one of the possible mechanisms responsible for the resistance of tumor cells to tumor necrosis factor-alpha (TNF-alpha) is the expression of TNF-alpha mRNA and/or protein. Pentoxifylline (PTX) suppressed TNF-alpha gene transcription and downregulates the expression of TNF-alpha mRNA and the secretion of TNF-alpha protein in macrophages and monocytes. This study investigates whether PTX downregulates the expression of TNF-alpha mRNA and/or protein in renal cell carcinoma (RCC) cells and whether PTX enhances the sensitivity of TNF-alpha-resistant RCC cells to TNF-alpha. Further, we explored whether PTX enhances the sensitivity of RCC cells to agents other than TNF-alpha by downregulation of the expression of TNF-alpha mRNA and protein. The R4 human RCC cell line constitutively expressed TNF-alpha mRNA and protein and was resistant to TNF-alpha. When R4 cells were incubated with PTX, the level of TNF-alpha mRNA and protein was markedly reduced. Pentoxifylline and TNF-alpha together overcame the resistance of R4 cells to TNF-alpha. The R11 human RCC cell line did not constitutively express TNF-alpha mRNA or protein, and was resistant to TNF-alpha. The expression of TNF-alpha mRNA in R11 cells, but not the production of TNF-alpha protein, was induced by TNF-alpha. When PTX was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was markedly reduced. The combination of PTX and TNF-alpha overcame the resistance of R11 cells to TNF-alpha. Pentoxifylline also enhanced the sensitivity of R4 cells to interferon-alpha. Pentoxifylline and anti-TNF-alpha monoclonal antibody augmented the sensitivity of R4 cells to cis-diamminedichloroplatinum (II) (CDDP). This study demonstrated that PTX, in combination with TNF-alpha, IFN-alpha or CDDP, overcame the drug resistance to RCC cells and that downregulation of TNF-alpha mRNA by PTX may be related to the cytotoxicity enhanced by the combination. The implications of these findings for clinical therapy are discussed.

Carcinoma, Renal Cell↗