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Tomohiko Ichikawa

Publications and source records attributed to Tomohiko Ichikawa.

53 records · Page 3Linked to original sources
PubMed2004

[Molecule based diagnosis].

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

Antineoplastic Agents↗
PubMed2003

Increased in situ gelatinolytic activity in renal cell tumor tissues correlates with tumor size, grade and vessel invasion.

Degradation of collagen, or gelatinolysis, by tumor cells is one of the most important events in tumorigenesis. We investigate the possible relationship between the in situ gelatinolytic activities exerted by matrix metalloproteinases (MMPs) and clinico-pathological factors in renal cell tumor (RCT) patients. Using the film in situ zymography (FIZ) method, we determined in situ localization of MMP-like gelatinolytic activities in cancerous and normal tissues in the kidney (n = 51). To clarify the MMP(s) responsible for the gelatinolytic activity in RCTs, we examined the expressions of MMP-2 and MMP-9 in the kidney tissues by means of gelatin zymography (GZG). MMP expression was also detected by RT-PCR and Western blotting analysis. We then investigated the associations of MMP expression, as detected by GZG, with the intensity of gelatinolytic activity, as determined by FIZ. We analyzed the possible relationship of FIZ findings to several clinico-pathological factors such as tumor size, grade, vessel invasion, histologic type, stage and metastasis. FIZ demonstrated that all tumor and normal kidney tissues showed in situ gelatinase activities, and that gelatinolytic activities in RCTs were much stronger than those of normal kidney tissues. There was a statistically significant correlation between the intensity of MMP-like gelatinolytic activity and tumor size, tumor grade and vessel invasion (p < 0.05), but not between it and histological type, tumor stage or metastatic status. FIZ showed that tumor tissues in 5 of the 6 patients with fatal outcome exhibited the intense gelatinolytic pattern. Stronger in situ gelatinolytic patterns were documented in cases with higher MMP-2 expression. The molecular species of MMPs detected by GZG were confirmed by RT-PCR and Western blotting analysis. The FIZ technique enables a direct assessment of in situ gelatinolytic activity in RCT tissues. The intensity of the activity seems to affect the biology of RCT tissues. Our results also indicate a major role for MMP-2 in in situ gelatinolysis in RCT tissues.

Adenocarcinoma↗
PubMed2003

Possible mechanism of dexamethasone therapy for prostate cancer: suppression of circulating level of interleukin-6.

BACKGROUND: Glucocorticoids may have favorable effects on prostate cancer patients showing clinical and/or biochemical failure after androgen ablation. The efficacy and mechanisms of dexamethasone therapy as possible alternative endocrine therapy were investigated. METHODS: Twenty five patients with prostate cancer treated by androgen ablation and showing a steady increase in serum prostate specific antigen (PSA) were treated with low-dose dexamethasone. RESULTS: Of 25 patients, 11 demonstrated 50% or more decline of serum PSA and 9 showed improvement of pain on dexamethasone therapy. Of 8 patients who responded to dexamethasone therapy, 5 had 80% or more decrease in serum interleukin-6 (IL-6). In contrast, none of 8 non-responders showed remarkable IL-6 suppression. Response of PSA was not correlated to the changes in serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, or androstendione. CONCLUSIONS: Significant suppression of serum IL-6, probably through inhibition of androgen-independent activation of androgen receptor, may be one of the mechanisms for the effect of dexamethasone therapy in prostate cancer patients with progressive disease.

Adenocarcinoma↗
PubMed2002

Loss of heterozygosity at 7q31.1 and 12p13-12 in advanced prostate cancer.

BACKGROUND: Allelic losses on chromosome arms 2q, 3p, 5q, 6q, 7q, 8p, 9p, 10p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 17q, 18q, and 21q are reportedly associated with progression and/or initiation of prostate cancer. In the present study, we performed a polymerase chain reaction (PCR) analysis of polymorphic microsatellite loci on the human chromosomes 7 and 12p13-12 in prostate cancer tissue to investigate the extent of involvement of these regions, which may contain putative tumor suppressor genes. METHODS: Tissue samples were obtained at autopsy from 17 men who died of hormone-refractory prostate cancer at Chiba University, Japan, and affiliated hospitals between June of 1992 and June of 1995. DNA from normal tumor or metastatic tissue was used as the template for PCR amplification of a set of 16 polymorphic microsatellite loci on human chromosome 7 and 6 loci on the human chromosome region 12p13-12. RESULTS: The frequencies of cases with loss of heterozygosity (LOH) at 7q31.1 were 8% in primary tumor tissue and 11% in metastatic tissue. The frequencies of cases with LOH at 12p13-12 were 12% in primary tumor tissue and 25% in metastatic tumor tissue. CONCLUSIONS: In the present study, the frequencies of LOH at 7q31.1 were lower than in Western patients, suggesting that LOH in this region is not related to progression of prostate cancer in Japanese patients. The frequency of LOH at 12p13-12 was similar to that reported in Western countries, indicating that 12p13-12 may contain a tumor suppressor gene of prostate cancer.

Autopsy↗
PubMed2002

CAG polymorphic repeat lengths in androgen receptor gene among Japanese prostate cancer patients: potential predictor of prognosis after endocrine therapy.

BACKGROUND: Several investigators have examined the clinical significance of the length of the CAG repeat at the N-terminal region of the androgen receptor in the pathogenesis of prostate cancer. Because the clinical significance of CAG repeat length during the course of prostate cancer in Japanese patients is unknown, the present study analyzed CAG repeat length in relation to several potential clinical factors. MATERIALS AND METHODS: A total of 88 Japanese patients with prostate cancer and a control group of 53 patients with benign prostatic disease were enrolled in this study. The length of the CAG repeat was determined by PCR sequencing and analyzed in relation to several clinical factors. RESULTS: The length of the CAG repeat did not significantly differ between prostate cancer and benign prostatic disease. Although not statistically different with regard to clinical stage and serum PSA level, the CAG repeat length was associated with histological grade and age at diagnosis. In addition, the CAG repeat length in CR and in non CR patients significantly differed at 22.1 +/- 2.4 and 24.4 +/- 3.0, respectively (P = 0.0264), suggesting that the CAG repeat length can act as a molecular marker with which to predict response to endocrine therapy in stage D prostate cancer patients. CONCLUSIONS: A shorter CAG repeat length appears to predict a response to endocrine therapy, showing a positive prognostic value and indicating good prognosis in the metastatic stage of prostate cancer patients.

Aged↗
PubMed2002

Functional evidence for a metastasis suppressor gene for rat prostate cancer within a 60-kilobase region on human chromosome 8p21-p12.

We recently demonstrated that the human chromosome 8p21-p12 region encodes a metastasis suppressor gene for rat prostate cancer. The presence of this region suppresses the metastatic ability of rat prostate cancer cells (N. Nihei et al., Genes Chromosomes Cancer, 17: 260-268, 1996). To define further the region harboring the metastasis suppressor gene, a truncated human chromosome 8 containing this region was transferred into highly metastatic AT6.3 rat prostate cancer cells by microcell-mediated chromosome transfer. The region of human chromosome 8 retained in each microcell hybrid was determined by a PCR analysis with sequence-tagged site markers, and this analysis placed the metastasis suppressor gene in the interval between D8S2249 and D8S2244 on human chromosome 8p21-p12. One of the metastasis-suppressed microcell hybrids was used for construction of representative yeast/bacterial artificial chromosome (YAC/BAC) library covering the candidate region using a transformation-associated recombination technology (N. Kouprina et al., Genomics, 53: 21-28, 1998). The final contig corresponding to the candidate region was assembled by four YAC/BAC clones. Each clone was transfected into the AT6.3 cells, and the resultant transfectants were tested for their metastatic ability in athymic nude mice. Introduction of a 60-kb YAC/BAC clone resulted in significant suppression of the metastatic ability without suppression of the tumorigenicity. In contrast, other YAC/BAC clones in the contig had neither metastasis nor tumor suppressor activity. This demonstrates that the 60-kb fragment from the human chromosome 8p21-p12 region contains the metastasis suppressor gene for the AT6.3 cells. Frequent loss of heterozygosity of this region is detected in human prostate cancer, which suggests that our target metastasis suppressor gene may also play an important role in the progression of human prostate cancer.

Animals↗
PubMed2002

Association of common missense changes in ELAC2 ( HPC2) with prostate cancer in a Japanese case-control series.

The recently identified prostate cancer susceptibility gene ELAC2 ( HPC2) harbors two common missense variants, a serine to leucine substitution at residue 217 (Leu217) and an alanine to threonine substitution at residue 541 (Thr541). We genotyped the two variants in a Japanese cohort consisting of 350 prostate cancer patients 242 male population controls, and 114 male low-risk controls. Both missense alleles, Leu217 and Thr541, were carried at higher frequency in Japanese patients than in the controls (Leu217, P= 0.0012; Thr541, P = 0.0145), and the odds ratios associated with carrying these sequence variants were higher in Japanese than in Caucasians. Although the Leu217 and Thr541 variants of ELAC2 are less common in Japanese than in Caucasians, both variants confer significantly increased risk of prostate cancer in Japanese. Carriage of these variants was not associated with age at diagnosis, tumor stage, or tumor grade in these Japanese prostate cancer patients. The allele-specific pattern of risk observed in Japanese and familial Caucasian patients was qualitatively similar; however, the magnitude of that risk was considerably greater in Japanese than in Caucasians.

Case-Control Studies↗
PubMed2002

Distinct patterns of chromosomal losses in clinically synchronous and asynchronous bilateral renal cell carcinoma.

PURPOSE: Bilateral renal cell carcinoma has been reported to occur in 1% to 4% of patients with renal cancer. However, whether bilateral renal cell carcinoma involves metastatic lesions of the contralateral kidney or develops as simultaneous primary tumors remains unclear to date. Thus, we investigated chromosomal losses and von Hippel-Lindau (VHL) gene abnormalities in bilateral tumors from patients with nonfamilial bilateral renal cell carcinoma. MATERIALS AND METHODS: Genomic DNA was exacted from 2 tumors in 8 patients each with nonfamilial bilateral renal cell carcinoma, including clinically asynchronous and synchronous disease in 5 and 3, respectively. The DNA was then subjected to microsatellite analysis on 13 chromosomal loci. In addition, polymerase chain reaction-single nucleotide specific conformation polymorphism analysis and direct sequencing of 3 exons of the VHL gene were performed. RESULTS: All 5 asynchronous cases showed loss of the same allele in bilateral tumors, indicating a common clonal origin. In contrast, 2 of the 3 synchronous cases showed different patterns of chromosomal loss in the right and left renal tumors, suggesting bilateral primary origins. The other synchronous case with loss of the same allele in each tumor involved right stage T3b and left stage T1a neoplasms. No VHL gene mutations were detected in any case. CONCLUSIONS: Except for a small number of cases synchronous and asynchronous bilateral renal cell carcinoma may represent the simultaneous appearance of separate primary tumors and metastatic progression from the contralateral kidney, respectively.

Adult↗
PubMed2002

Clinical characteristics of prostate cancer in elderly Japanese patients 80 years of age or older.

OBJECTIVE: Prostate adenocarcinoma is predominantly a disease of elderly men. This study retrospectively examined prostate adenocarcinoma in Japanese patients 80 years of age or older to determine the natural history and prognosis of this malignancy in the elderly population. METHODS: The medical records of 593 patients were reviewed, with respect to age, histologic grade, clinical and pathological stage, treatment modality and clinical outcome. A variety of possible clinical factors were compared between patient groups > or = 80 and < 80 years old. RESULTS: No significant difference in clinical stage, tumor grade, and performance status (PS) was found between two age groups of patients with prostate cancer. A significant stage migration between pre-PSA era and PSA era was found only in the group < 80 years old. In the series of stage D2 cancer patients, while there was no significant difference in cause-specific and progression-free survival rates between the two groups, the younger group < 80 years old had a better marker response at 3 months from the start of endocrine therapy compared with the older group (P = 0.0048, chi2 analysis). CONCLUSION: These data suggest that patients > or = 80 years with prostate cancer present with similar histologic grade and disease stage as younger patients, although the younger group with stage D2 had a better marker response to endocrine therapy.

Adenocarcinoma↗
PubMed2002

Expression of thymidine phosphorylase in primary human renal cell carcinoma by ELISA method.

Thymidine phosphorylase (TP) expression in 100 paired samples of renal cell carcinoma (RCC) and normal adjacent tissue was analyzed by an ELISA method. We also investigated whether TP expression correlates with clinicopathological findings and clinical outcomes of these patients. Median TP expression was 9-fold (range, 0.5-56) higher in primary tumor than in non-cancerous renal tissue (P < 0.0001). There was a significant difference with respect to tumor venous invasion. TP expression was significantly higher in patients with such venous invasion than in those without (P = 0.018). However, there was no correlation between TP level and other clinicopathological findings and the survival curves. These results suggest that ELISA is useful for evaluating TP expression of human RCC and may provide a novel approach to therapy for patients with RCC.

Adult↗
PubMed2002

Microdeletions in the Y chromosome of patients with idiopathic azoospermia.

AIM: To evaluate the occurrence and prevalence of microdeletions in the gamma chromosome of patients with azoospermia. METHODS: DNA from 29 men with idiopathic azoospermia was screened by polymerase chain reaction (PCR) analysis with a set of gamma chromosome specific sequence-tagged sites (STSs) to determine microdeletions in the gamma chromosome. RESULTS: Deletions in the DAZ (deleted in azoospermia) loci sgamma254 and sgamma255 were found in three patients with idiopathic azoospermia, resulting in an estimated frequency of deletions of 10.7% in idiopathic azoospermia men. CONCLUSION: We conclude that PCR analysis is useful for the diagnosis of microdeletions in the Y chromosome, which is important when deciding the suitability of a patient for assisted reproductive technology such as testicular sperm extracion-intracytoplasmic sperm injection (TESE-ICSI).

Adult↗
PubMed2002

Mechanisms of metastasis suppression by introduction of human chromosome 10 into rat prostate cancer.

AIM: The metastatic ability of a Dunning R-3327 rat prostate cancer subline (AT6.3) was suppressed by the introduction of human chromosome 10, when these hybrid cancer cells were injected subcutaneously into nude mice (Nihei et al., Genes Chromosomes Cancer 14:112-119, 1995). The present study was undertaken to clarify which step of metastasis was suppressed in the human chromosome 10-containing microcell hybrids (AT 6.3-10 clones). METHODS: Gelatin zymography, an in vitro invasion assay using a Boyden chamber and an intravenous metastasis assay involving the injection of hybrid cells into nude mice were performed. RESULTS: Gelatin zymography revealed that AT6.3-10 microcell hybrid clones expressed the 72 kD type IV collagenase (MMP-2) at an almost equal level as control microcell hybrid clones. Both the invasiveness as measured by the invasion assay and the number of lung metastases as measured by the intravenous metastasis assay of AT6.3-10 hybrid clones were significantly less than those of the AT6.3 parental clone. CONCLUSION: The human chromosome 10 suppresses both the local invasion and the metastatic process after entry into the blood circulation of rat prostate cancer. This decrease in local-invasive ability does not seem to require a decrease in MMP-2 activity.

Animals↗
PubMed2002

Suppression of metastasis of rat prostate cancer by introduction of human chromosome 13.

AIM: Chromosome 13 is one of the most frequently altered chromosomes in prostate cancer. The present study was undertaken to examine the role of human chromosome 13 in the progression of prostate cancer. METHODS: Human chromosome 13 was introduced into highly metastatic rat prostate cancer cells via microcell-mediated chromosome transfer. RESULTS: Microcell hybrid clones containing human chromosome 13 showed suppression of metastasis to the lung without any suppression of tumorigenicity, except for one clone, which contained the smallest sized human chromosome 13 and did not show any suppression on lung metastasis. Expression of two known tumor suppressor genes, BRCA2 and RB1, which map to chromosome 13, was examined by reverse transcription- polymerase chain reaction analysis. BRCA2 was expressed only in the metastasis-suppressed microcell-hybrid clones, whereas RB1 was expressed in all clones. CONCLUSION: Human chromosome 13 contains metastasis suppressor gene(s) for prostate cancer derived from rat. Furthermore, the RB1 gene is unlikely to be involved in the suppression of metastasis evident in this system.

Animals↗
PubMedDate not supplied

Genetic polymorphisms of hormone-related genes and prostate cancer risk in the Japanese population.

Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate cancer risk have been reported. Roles for non-androgenic hormones are not well defined, but they also may have an impact judging from epidemiological and animal experimental alphalambda zeta of data. The purpose of the study was to determine whether hormone-related polymorphisms are associated with prostate cancer risk. A case-control study was performed with 147 Japanese prostate cancer patients and 266 urological controls. Polymorphisms of target genes [cytochrome P450 (CYP) 1B1, Leu432Val; debrisoquine hydroxylase, (CYP2D6)*4; aromatase (CYP19), Arg264Cys; estrogen receptor (ER)alpha-Xx (Xba I) and Pp (Pvu II); ERbeta-Rr (Rsa I); progesterone receptor (PR) Alu in intron 7] were examined by PCR-based methods. The capital and small letters signify the absence and presence of restriction sites, respectively. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack. Among the seven examined genetic polymorphisms, significant associations between CYP1B1 Leu432Val (OR 4.80; 95% confidence interval (CI), 1.21-19.05) and Alu in intron 7 of PR (OR 4.17; 95%CI, 1.26-13.85) were found. As for combined effects, the CYP1B1 polymorphisms (Leu/Val+Val/Val) together with heterozygosity for Alu in the PR were more frequent among prostate cancer patients (1.45%) than controls (0.41%), although without significance (OR, 3.99; 95%CI, 0.36-44.8). The combination of ERalpha (P/p+p/p) polymorphisms with heterozygosity for Alu in the PR demonstrated an OR of 4.56 (95%CI, 1.01-20.6). This pilot study showed that CYP1B1 and PR polymorphisms, alone or in combination, might be associated with prostate cancer risk. They might, therefore, have potential as a tool for identifying high-risk individuals.

Adenocarcinoma↗
PubMedDate not supplied

Interleukin-4 in patients with prostate cancer.

BACKGROUND: Ligand-independent activation of the androgen receptor (AR) by cytokines has been implicated in the progression of androgen-independent prostate cancer (PCa). To determine the potential effects of elevated levels of interleukin-4 (IL-4) in patients with PCa, six different cytokines were examined for their ability to activate the AR. MATERIALS AND METHODS: LNCaP cells were transiently transfected with prostate-specific antigen (PSA) (-630 / +12)-luciferase and treated with R1881, six kinds of cytokines including IL-4, or vehicle. Transactivation assays were also performed in LNCaP cells co-transfected with the 5xGal4UAS-TATA-luciferase and AR-(1-558)-Gal4DBD prior to incubation with R1881, IL-4, IL-6, or vehicle. Seventy-two patients with pre-treatment PCa, 17 patients with hormone-refractory metastatic PCa receiving androgen ablation therapy, 20 patients with benign prostatic hypertrophy and 10 healthy male volunteers were enrolled in this retrospective study. The concentration of serum IL-4 was measured by chemiluminescence enzyme immunoassay. RESULTS: IL-4 induced androgen-response element-driven reporters and activated the AR N-terminal domain (NTD) in a ligand-independent manner in transiently transfected LNCaP cells. Levels of IL-4 in the serum were significantly elevated in patients with hormone-refractory PCa as compared to the levels in pre-treatment PCa. CONCLUSION: IL-4 serum levels were demonstrated to be increased in honnone-refractory PCa and IL-4 was shown to enhance PSA reporter gene activity by the activation of AR NTD in human LNCaP cells. These results suggest that the AR can be activated by cytokines, and that this mechanism may play an important role in the transition from androgen-dependent to androgen-independent PCa after patients receive androgen ablation therapy.

Adult↗