研究者詳細 - 大家　基嗣

論文 - 大家　基嗣

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Application of conditionally replicating herpes vector for gene therapy treatment of urologic neoplasms

Oyama M., Uyemura K., Murai M., Yazaki T., Ohigashi T., Hoshi M., Horiguchi Y., Oya M., Asakura H., Nakashima J., Tachibana M.

Molecular Urology 4 （ 2 ） 83 - 87 2000年

ISSN 1091-5362

Herpes vector has been widely used for experimental gene therapy. We herein review the strategies of such therapy for the treatment of urologic neoplasms. Most experimental studies of genetically altered viruses have employed replication-incompetent vectors. However, such viruses are unable to infect additional cells subsequent to the initial infection event. Therefore, this strategy has relied heavily on the bystander effect because a large number of noninfected tumor cells remain. Conditionally replicating herpes vector G207 has been developed in order to overcome potential problems of safety and tumor specificity for human use. It has been used to treat malignant brain tumors because of its neural tropism. In the last few years, applications of G207 for non-neural tumors have been reported. Because G207 may be useful for the treatment of urologic malignant tumors, we evaluated the antitumor effect against several types of tumor cells both in vitro and in vivo. Our data suggest that G207 may be applicable for the treatment of urologic malignant tumors.

High frequency of inactivation of the imprinted H19 gene in sporadic hepatoblastoma

Fukuzawa R, Umezawa A, Ouchi K, Ikeda H, Hata J

International Journal of Cancer 82 （ 4 ） 490-497 1999年08月

研究論文（学術雑誌）, 共著

臨床病期C前立腺癌における放射線療法と内分泌療法

小山政史，中島淳，菊地栄次，斉藤史郎，大家基嗣，大東貴志，朝倉博孝，橘政昭，村井勝

泌尿器外科 12 （ 8 ） 962-965 1999年08月

研究論文（学術雑誌）, 共著

A Case of Solitary Contralateral Adrenal Metastasis of Renal Cell Carcinoma

Mizuno Ryuichi, Kikuchi Eiji, Ohya Mototsugu, Murai Masaru

Japanese Journal of Clinical Urology 53 （ 7 ） 517 - 519 1999年06月

ISSN 0385-2393

A 72-year-old male visited our out-patient clinic with right incidentally found renal tumor, which was discovered by computed tomography (CT) for the follow up study of chronic pancreatitis. CT also showed a left adrenal mass. Further evaluation suggested right renal cell carcinoma and left adrenal metastasis. Right nephrectomy and left adrenalectomy, saving the right adrenal gland, were performed on June 22, 1998. Histology confirmed renal cell carcinoma with contralateral adrenal metastasis.

Expression of G1→S transition regulatory molecules in human urothelial cancer

Oya Mototsugu, Schmidt Bettina, Schmitz-Dräger Bernd J., Schulz Wolfgang A.

Japanese Journal of Cancer Research 89 （ 7 ） 719 - 726 1998年07月

ISSN 0910-5050

Growth of cancer cells is characterized by accelerated passage through the cell cycle, which is often caused by deregulation of the G1→S transition. In this study the expression of G1→S transition regulatory molecules was analyzed in 32 transitional cell carcinoma specimens and fifteen normal tissues obtained by cystectomy or nephroureterectomy of mainly locally advanced tumors, as well as six bladder cancer cell lines. Expression of mRNAs for cyclins D1 and D2 and cyclin-dependent kinases (CDK) 2 and 4 was investigated by quantitative reverse transcription-polymerase chain reaction. Overexpression of cyclin D1 compared to normal mucosa was observed in 3 tumors (9.4%), but in neither of the cell lines. All tumors with overexpression were moderately differentiated (G2) pT1 or pT2 tumors, and thus among the less advanced specimens. Cyclin D2 was not expressed in normal bladder mucosa or in tumors. The expression of CDK4 mRNA varied within the same range in mucosa, tumors, and cell lines, CDK2 mRNA expression varied more strongly and was diminished in individual tumors and in four cell lines. It is concluded that cyclin D1 overexpression can play an important role in the early stage of urothelial tumorigenesis, driving cell proliferation. Ectopic expression of cyclin D2 or amplification of CDK4 does not occur at a significant frequency in urothelial carcinomas. Different expression patterns of cyclin D1 and CDK2 indicate heterogeneity in the mechanisms of G1→S transition deregulation in individual bladder tumors which may elicit differences in their biological and clinical behavior.

Control of cell cycle regulatory proteins and modulation of STATI proteins by INF-r in human prostatic JCA 1 cells

Oya Mototsugu, Konno S, Chen Y, Tazaki Hiroshi, Mallouch C, Wu JM

Int J Oncol 10 835-839 1997年12月

研究論文（学術雑誌）, 共著

Control of cell cycle regulatory proteins and modulation of STAT1 proteins by IFN-γ in human prostatic JCA-1 cells

Oya M., Konno S., Chen Y., Tazaki H., Mallouh C., Wu J. M.

International Journal of Oncology 10 （ 4 ） 835 - 839 1997年

ISSN 1019-6439

The addition of human recombinant IFN-γ (10² and 10³ IU/ml) inhibited human prostatic JCA-1 cell growth by 27% and 64%, respectively. Since the high dose of IFN-γ elicited an increase in G₁ concomitant with a decrease in G₂/M phases of the cell cycle, changes in the expression of cell cycle regulatory protein molecules were analyzed by Western blots. Results of these experiments show that IFN-γ down regulated the G₁/S transition molecules, e.g., cyclin D1, the cyclin-dependent protein kinase Cdk4, and the retinoblastoma gene product (pRB), but increased the G₂/M transition molecules, e.g., cyclin B1 and p34(cdc2) (Cdk1). Possible modulation of Cdk-inhibitors (CDKIs), e.g., p53 and p21(WAF1), which have checkpoint functions in the cell cycle, by IFN-γ, was also studied. The p53 was induced by both 10² and 10³ IU/ml IFN-γ. At 10³ IU/ml, IFN-γ inhibited p21(WAF1) increased the expression of STAT1α, and sustained the elevated STAT1α for up to 96 h. Thus several mechanisms may be involved in the antiproliferative effects of IFN-γ.

Application of the interferon minipellet to human renal cell carcinoma in nude mice

Marumo Ken, Oya Mototsugu, Murai Masaru

International Journal of Urology 4 （ 1 ） 55 - 61 1997年

ISSN 0919-8172

Background: The interferon (IFN) minipellet is a sustained-release formulation of human lymphoblastoid IFN, with atelocollagen used as the carrier material. We evaluated the antitumor effect of the IFN minipellet on an established human renal cell carcinoma cell line (KU-2) transplanted in nude mice. Methods: The treatment was started when tumor nodules had grown to 6 to 8 mm in diameter. The IFN minipellet, or an aqueous solution of IFN, was given by subcutaneous injection, or peritumor injection, on days 1 and 10. Antitumor effects were evaluated according to tumor weights calculated as (long diameter) x (short diameter)²/2 in 7 groups consisting of 6 mice each. Results: IFN levels remained detectable in both tumor tissue and serum up to in days after peritumor injection of the IFN minipellet. Administered by the peritumor route, the IFN minipellet inhibited growth of the tumor significantly as compared with tumor growth in the untreated mice. The IFN minipellet showed greater inhibition of tumor growth by peritumor injection compared to subcutaneous injection. The aqueous solution of IFN was not effective either by subcutaneous or by peritumoral injection. Conclusion: Results indicate that the IFN minipellet is useful in the treatment of renal cell carcinoma.

Biochemical modulation of 5-fluorouracil with murine interferon-α/β against murine renal cell carcinoma

Marumo Ken, Oya Mototsugu, Murai Masaru

International Journal of Urology 4 （ 2 ） 163 - 168 1997年

ISSN 0919-8172

Background: Conventional therapy for renal cell carcinoma using interferon (IFN) has shown limited antitumor action. The purpose of our study was to investigate synergistic antitumor effects of IFN and 5-fluorouracil (5-FU), and to elucidate the mechanisms of interaction between the 2 agents in mice. Methods: Antitumor effects and biochemical modulation of murine IFN-α/β and 5-FU were determined against the murine renal cell carcinoma cell line, Renca, in vivo. The activity of thymidylate synthetase and thymidine kinase was measured using cytosolic extract of the tumors. Results: Combination treatment with IFN-α/β and 5-FU produced a significant enhancement of growth inhibition against Renca tumor. Treatment with 5-FU resulted in a 2.7-fold increase in the total amount of thymidylate synthetase and an 11.6-fold increase in the thymidylate synthetase inhibition rate, while the administration of IFN-α/β did not significantly reduce the 5-FU-induced increase in thymidylate synthetase. The administration of IFN-α/β decreased thymidine kinase activity to 65.5% maximally, compared with that in the control mice or the mice treated with 5-FU. Conclusions: The reduction of thymidine kinase caused by treating the mice with IFN-α/β changes the utilization of exogenous thymidine for DNA synthesis, and may represent the mechanism of the additive antitumor effect of the 2 agents, through the suppression of the salvage pathway for deoxythymidine monophosphate induction.

Application of cytokine drug delivery systems to the immunotherapy of renal cell carcinoma in mice

Marumo Ken, Oya Mototsugu, Murai Masaru

Int J Urol 3 （ Supple 1 ） 24-27 1996年11月

研究論文（学術雑誌）, 共著

Pharmacokinetics and Antitumor Effects of an Interleukin-2 Immunocomplexing Agent in Murine Renal Cell Carcinoma

Oya Mototsugu, Marumo Ken, Murai Masaru, Tazaki Hiroshi

International Journal of Urology 3 （ 2 ） 141 - 144 1996年

ISSN 0919-8172

Background: Conventional therapy for renal cell carcinoma (RCC) using systemic administration of interleukin-2 (IL-2) has shown limited anti-tumor action. The purpose of this study was to investigate the anti-tumor effects of a newly developed immune complex of IL-2 (IC) against RCC. Methods: IC was prepared by mixing IL-2 and an anti-IL-2 monoclonal antibody at a molar ratio of 2:1. The pharmacokinetics and anti-tumor effects of IC were then studied in a murine RCC line, Renca. Results: Serum IL-2 levels were sustained longer in mice given IC than in mice given IL-2 alone after either subcutaneous or intratumoral injections. After an intratumoral injection of IC, the IL-2 concentration in the tumor nodules remained higher compared with mice given IL-2 alone. The anti-tumor effect was most pronounced in mice treated with intratumoral injections of IC. Conclusions: Results obtained here indicate that an immune complex of IL-2 provides a useful tool for the treatment of RCC by altering the pharmacokinetics of IL-2 in vivo.

Application of cytokine drug delivery systems to the immunotherapy of renal cell carcinoma in mice

Marumo K., Oya M., Murai M., Tazaki H.

International Journal of Urology 3 （ SUPPL. ） 1996年

ISSN 0919-8172

We have investigated the antitumor effects of human lymphoblastoid interferon (HLBI) mini-pellets, interleukin-2 (IL-2) entrapped in liposome (IL-2 liposome) and an immune complex of IL-2 and monoclonal antibody against IL-2 (IC-1). The HLBI mini-pellets were administered to nude mice bearing a human renal cancer cell line (KU-2). HLBI levels remained detectable both in the tumor tissue and the serum up to 10 days after peritumor injection. The HLBI mini-pellet significantly suppressed tumor growth by peritumor administration. The antitumor effect of IL-2 liposome on Renca, a murine renal cancer, resulted in the inhibition of tumor growth. An accumulation of Lyt-2^- and L3T4^- lymphocytes was seen in the tumor tissue which was treated with IL-2 liposomes. The IC-1 was prepared by mixing IL-2 and anti-IL-2 monoclonal antibody at a molar ratio of 2:1. Plasma IL-2 levels were sustained longer in mice given the IC-1 than in mice given IL-2 alone. The IC-1 complex exerted a more significant antitumor effect by local administration in Renca-bearing mice than the administration of IL-2 alone. We speculated that these effects were a result of sustained tumor IL-2 levels due to the increase in molecular weight. The results we obtained indicate that the cytokine drug delivery system has a long-acting cytotoxicity by administration to the tumor sites through efficient stimulation of the local immune response, and thus provides a useful tool for treatment of renal cell carcinoma.

Characteristics and prognostic factor in patients with advanced renal cell carcinoma (RCC) achieving complete response by treatment using biological response modifiers (BRM)

Marumo K., Huang Y., Oya M., Tachibana M., Murai M., Tazaki H.

Biotherapy 10 （ 3 ） 554 - 556 1996年

ISSN 0914-2223

One of 24 patients treated with human lymphoblastoid interferon (IFN), 2 of 20 patients treated by sequential administration of IFN and OK-432, and 3 of 18 patients treated with interleukin 2 achieved a complete response. All 6 patients had been nephrectomized, and had a common type of renal cell carcinoma. Metastatic sites were lung and mediastinum in one patient and lung alone in the other 5 patients. Five of 6 patients developed a recurrence between 11 months and 6 years of disease-free periods and did not respond to primarily effective therapy. The results demonstrated that careful observation is needed even after disappearance of a tumor by treatment with BRMs and establishment of a new modality for recurrent RCD was encouraged.

Intrarenal satellites of renal cell carcinoma ・ Histopathologic manifestation and clinical implication

Oya M, Nakamura K, Baba S, Hata J, Tazaki H

Urology 46 （ 2 ） 161-164 1995年07月

研究論文（学術雑誌）, 共著

Retroperitoneal Ewing's sarcoma

Oya M., Nakashima J., Ishii T., Nakamura K., Hata J. I., Tazaki H.

Urologia Internationalis 54 （ 2 ） 104 - 106 1995年

ISSN 0042-1138

We report a case of extraskeletal Ewing's sarcoma arising in the retroperitoneal cavity. The tumor was excised en bloc with the left kidney and infiltrated portion of the left ureter. Histological diagnosis was confirmed by both electron micrograph and immunohistochemical staining using a newly developed mouse monoclonal antibody 5C11, which specifically reacts with Ewing's sarcoma. An adjuvant chemotherapy T-11 regimen has been successfully preventing the recurrence.

腎細胞癌のインターロイキン2治療に与える宿主免疫能の影響

丸茂健，大家基嗣，上野宗久，中村薫，村井勝，田崎寛

Biotherapy 9 （ 7 ） 905-910 1995年

研究論文（学術雑誌）, 共著

Laparoscopy assisted orchiopexy-Technical feasibility and indications

Baba S, Asanuma H, Oya M

Jpn J Endourol ESWL 8 （ 2 ） 144-147 1995年

研究論文（学術雑誌）, 共著

Antitumor effects of interleukin 2 against advanced renal cell carcinoma and prognosis of the patients by long term follow-up

Oya M., Marumo K., Tazaki H.

Biotherapy 9 （ 3 ） 348 - 349 1995年

ISSN 0914-2223

Eighteen patients with advanced renal cell carcinoma (RCC) were treated by systemic administration of interleukin-2 (IL-2) from March 1986 to October 1988. All of the patients received 1 x 10⁶ units of IL-2 twice a day for at least 4 weeks. Three patients achieved complete response (CR), 10 no change (NC) and 5 progressive disease (PD). Therefore, the response rate was 16.7%. Survival rate was compared with historical control group of 27 patients with advanced RCC in our institution. One, three and five year survival rate of the patients treated with IL-2 was 78%, 44% and 33%, although the historical group was 57%, 19% and 19%. We conclude that IL-2 can improve prognosis of patients with advanced RCC.

Host immune reactivity as a prognostic factor in interleukin-2 therapy of renal cell carcinoma

Marumo K., Oya M., Ueno M., Nakamura K., Murai M., Tazaki H.

Biotherapy 9 （ 7 ） 905 - 910 1995年

ISSN 0914-2223

Eighteen patients with advanced renal cell carcinoma (RCC) were treated with interleukin-2 (IL-2). Seven patients were compared in terms of immunological aspects. They had survived for 55 months or more, and included three patients whose metastatic lesions had disappeared (group A) and 11 patients (group B) who had survived for 1.5 to 39 months. ECOG performance status (PS) was 0 or 1 in six of seven patients in group A, whereas no patient had a PS of 0, three patients had a PS of 1, two patients a PS of 2, and six of the 11 patients in group B had a PS of 3 or 4. Mean natural killer (NK) activity (% ⁵¹Cr release) before initiation of the therapy was 50 in group A and 26 in group B patients. However, at 2 weeks and 4 weeks, respectively, after initiation of the therapy, there was no marked difference between the two groups. Lymphokine-activated killer (LAK) activity and the number of peripheral blood lymphocytes before and after initiation of the therapy tended to be higher in group A patients. These results indicated that those patients who had achieved an objective response to IL-2 therapy or survived relatively longer exhibited a better immune status before the initiation of therapy. However, this tendency was not in evidence in some individual patients. Moreover, tumor response to IL-2 therapy was suggested to depend on the sensitivity to killer cells and other biological characteristics of each tumor cell as well as on the immune status of the patients.

Intrarenal satellites of renal cell carcinoma

Oya Mototsugu, Nakamura Kaoru, Baba Shiro, Hata Jun Ichi, Tazaki Hiroshi

Urology 46 （ 2 ） 161 - 164 1995年

ISSN 0090-4295

Objectives: This study was designed to gain more insight into the incidence of satellites of renal cell carcinoma related to the pathologic stage and grade of the primary tumor. Methods: One hundred eight nephrectomized kidneys with renal cell carcinoma were sectioned at 3-mm intervals and inspected microscopically for satellite carcinomas. The number, site, size, and distance of satellite carcinomas found were recorded in relation to the primary carcinoma. Results: The overall incidence of satellite carcinoma was 6.5% (7 of 108). The incidence of satellite carcinoma in relation to the pathologic staging of the primary tumor was 7.1 % (1 of 14) in pT1, 3.0% (2 of 66) in pT2, and 14.3% (4 of 28) in pT3. The incidence was higher in patients with N1 disease (25%) than in those with NO (5.0%), and higher in M1 disease (25%) than in those in MO (5.77%). There was no relationship between the grade and multicentricity. Conclusions: The incidence of satellite carcinoma was higher in cases with high-stage primary carcinoma. However, even in localized diseases (pT1, pT2), satellite carcinomas were found at a 3.75% incidence. When nephron-sparing surgery is indicated in low-stage cases, precise clinical staging using a combination of various imaging modalities is mandatory, with intraoperative ultrasonography being one possible modality for detecting a concomitant satellite carcinoma.

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