Biomedical subjects

H Miyake

Publications and source records attributed to H Miyake.

At least 109 records · Page 6Linked to original sources

PubMed2001

Long-term results of neoadjuvant hormonal therapy prior to radical prostatectomy in patients with clinically localized prostate cancer: biochemical and pathological effects.

The objective of this study was to evaluate the long-term biochemical and pathological effects induced by neoadjuvant hormonal therapy (NHT) in patients with clinically localized disease. Between March 1993 and May 1997, 24 patients with clinically localized prostate cancer received NHT for 3 to 11 months (median: 5 months) using luteinizing hormone-releasing hormone analogue prior to radical prostatectomy and pelvic lymphadenectomy. The clinical stage was T1 in 1 patient, T2 in 17 and T3 in 6, the pretreatment serum prostate-specific antigen (PSA) value was < or = 10 ng/ml in 5 patients, 10 to 20 ng/ml in 4 and > 20 ng/ml in 15 (mean: 34.7 micrograms/l), and the Gleason score was < or = 4 in 9 patients, 5 to 7 in 11 and > 8 in 3. The mean prostate specific antigen (PSA) value 3 months after NHT had reduced below 2 ng/ml in 18 of the 24 patients (67%), and finally decreased by an average of 95% (i.e., 1.9 ng/ml) prior to surgery. The pathological stage was pT0 in 2 patients, pT2 in 10 and pT3 in 12. The incidence of organ-confined disease (OCD) was significantly higher in patients with clinical stage T1 or T2a than with T2b or T3, with pretreatment PSA values < or = 10 ng/ml than with PSA values > 10 ng/ml, and with PSA values < or = 2 than with PSA values > 2 at 3 months after NHT; in contrast, the Gleason score had no significant impact on the rate of OCD. After a median follow-up of 49 months (range 34 to 85 months), 6 patients (25%) had a recurrence evidenced by rising PSA, and the 3-year recurrence-free survival rate was 79%. These results suggest that NHT appears not to be of significant additional benefit to patients who have a higher clinical T stage, higher pretreatment PSA values and/or in patients whose PSA values do not normalize early in the treatment process.

Aged↗

PubMed2001

Over expression of inhibitor of caspase 3 activated deoxyribonuclease in human renal cell carcinoma cells enhances their resistance to cytotoxic chemotherapy in vivo.

PURPOSE: We determined whether inhibitor of caspase-3 activated deoxyribonuclease (ICAD) enhances resistance to apoptotic stimuli or inhibits DNA fragmentation by inactivating caspase-3 activated deoxyribonuclease. MATERIALS AND METHODS: The liposome mediated gene transfer method was used to introduce ICAD complementary DNA into ACHN cells and the expression of ICAD protein per clone was evaluated by Western blot analysis. Effects of cisplatin treatment on growth inhibition and apoptosis in the ACHN sublines were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA fragmentation assay and Western blot analysis of poly(ADP-ribose) polymerase protein. The limiting dilution assay was also performed to examine the effect of cisplatin treatment under anchorage independent conditions. Furthermore, nude mice bearing the ACHN sublines were given intraperitoneal injection of 5 mg./kg. cisplatin 1 and 2 weeks after the implantation of tumor cells and changes in tumor volume was measured. RESULTS: ICAD transfected ACHN cells inhibited DNA degradation after cisplatin treatment but not control vector only transfected ACHN cells, whereas a similar degree of apoptotic cell death induced by cisplatin in ICAD and control vector only transfected ACHN cells was observed on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Western blot analysis of poly(ADP-ribose) polymerase protein. However, the limiting dilution assay revealed that ICAD transfected ACHN cells had high resistance to pretreatment with cisplatin compared with control vector only transfected ACHN cells. Moreover, although there was no significant difference in the in vivo growth of ACHN sublines, cisplatin treatment induced the elimination of control vector only transfected ACHN cell tumors. In contrast, most ICAD transfected ACHN cell tumors continued to grow after cisplatin treatment. CONCLUSIONS: These findings suggest that when ICAD is over expressed in tumor cells, it renders them highly resistant to therapy induced apoptosis, resulting in enhanced tumor progression.

Apoptosis Regulatory Proteins↗

PubMed2001

Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model.

Clusterin expression is highly up-regulated in several normal and malignant tissues undergoing apoptosis. Although recent studies have demonstrated a protective role of clusterin expression against various kinds of apoptotic stimuli, the functional role of clusterin in the acquisition of a therapy-resistant phenotype in bladder cancer remains unknown. The objectives of this study were to determine whether antisense (AS) oligodeoxynucleotide (ODN) targeting the clusterin gene enhances apoptosis induced by cisplatin and to evaluate the usefulness of combined treatment with AS clusterin ODN and cisplatin in the inhibition of KoTCC-1 tumor growth and metastasis in a human bladder cancer KoTCC-1 model. We initially revealed the dose-dependent and sequence-specific inhibition of clusterin expression by AS clusterin ODN treatment in KoTCC-1 cells at both mRNA and protein levels. Clusterin mRNA was increased in a dose-dependent manner by cisplatin treatment at concentrations < or =10 mg/ml, and clusterin mRNA up-regulation induced by 10 mg/ml cisplatin peaked by 48-h post-treatment and began decreasing by 72-h post-treatment. Although there was no significant effect on growth of KoTCC-1 cells, AS clusterin ODN treatment significantly enhanced cisplatin chemosensitivity of KoTCC-1 cells in a dose-dependent manner, reducing the IC(50) by >50%. Characteristic apoptotic DNA ladder formation and cleavage of poly(ADP-ribose) polymerase protein were detected after combined treatment with AS clusterin ODN and cisplatin but not either agent alone. In vivo systemic administration of AS clusterin and cisplatin significantly decreased the s.c. KoTCC-1 tumor volume compared with mismatch control ODN plus cisplatin. Furthermore, after the orthotopic implantation of KoTCC-1 cells, combined treatment with AS clusterin and cisplatin significantly inhibited the growth of primary KoTCC-1 tumors, as well as the incidence of lymph node metastasis. Collectively, these findings demonstrated that clusterin helps confer a chemoresistant phenotype through inhibition of apoptosis and that combined AS clusterin ODN may be useful in enhancing the effects of cytotoxic chemotherapy in patients with bladder cancer.

Animals↗

PubMed2001

[Extracranial carotid artery bypass using artificial vessels--4 case reports].

We successfully completed extracranial carotid artery reconstruction in four cases (case 1: arteriosclerotic occlusion of the left common carotid artery between the origin at the aorta to just below the cervical bifurcation, case 2-4: combined removal of the carotid artery with malignant cervical tumor) using various types of synthetic vessels, e.g. 1) Double Velour Dacron, or 2) Expanded polytetrafluoroethylene. In case 2, Xenon CT under balloon occlusion was useful for revealing the indication for carotid artery reconstruction. Recent progress in the development of materials for use in synthetic vessels has remarkably improved the long-term patency of synthetic vessels, especially in medium to large size ones (larger than 6 mm in diameter). Synthetic vessels have the following advantages: 1. No need to harvest autogenous vessels, 2. An external shunt is available for patients with poor ischemic tolerance to temporary occlusion of the carotid artery, 3. A vessel of the most suitable size can be selected, 4. No risk of tumor invasion, 5. Easy suturing because the orifice of a synthetic vessel does not collapse. We report the usefulness, the indication for, and the surgical procedures of extracranial carotid artery bypass using synthetic vessels.

Blood Vessel Prosthesis↗

PubMed2000

Differential involvement of the Fas receptor/ligand system in p53-dependent apoptosis in human prostate cancer cells.

BACKGROUND: The objective of this study was to characterize the involvement of the Fas receptor/ligand system in p53-dependent apoptosis in human prostate cancer cells. METHODS: The effects of adenovirus-mediated p53 gene transfer (Ad5CMV-p53) into human prostate cancer LNCaP, DU145, and PC3 cells on their growth, apoptosis and Fas receptor/ligand expression were examined by the MTT assay, DNA fragmentation assay, and Northern blot analysis, respectively. The sensitivity of these cells to an agonistic anti-Fas receptor antibody (CH11) and the effects of an antagonistic anti-Fas ligand antibody (4H9) on Ad5CMV-p53-induced apoptosis were analyzed by the MTT assay and DNA fragmentation assay. RESULTS: Ad5CMV-p53 treatment resulted in substantial growth inhibition, induction of apoptosis and up-regulation of Fas receptor as well as Fas ligand mRNA expression in LNCaP, DU145 and PC3 cells. Despite the abundant expression of Fas receptor in all of these cells, CH11 induced apoptosis only in PC3 cells. Furthermore, 4H9 partially blocked the apoptosis induced by Ad5CMV-p53 in PC3 cells, but not in LNCaP and DU145 cells. CONCLUSIONS: The Fas receptor/ligand system is differentially involved in p53-dependent apoptosis in prostate cancer cells; therefore, reintroduction of wild-type p53 into prostate cancer cells may induce apoptosis through Fas receptor/ligand interaction as well as through an alternative pathway.

Adenoviridae↗

PubMed2000

Synergistic chemosensitization and inhibition of tumor growth and metastasis by adenovirus-mediated P53 gene transfer in human bladder cancer model.

OBJECTIVES: To determine whether an adenovirus-mediated p53 gene (Ad5CMV-p53) transfer enhances cisplatin cytotoxicity in vitro and whether Ad5CMV-p53 and cisplatin synergistically inhibit growth and metastasis in vivo using human bladder cancer KoTCC-1 cells. METHODS: MTT assays and DNA fragmentation assays were used to examine the effects of treatment with Ad5CMV-p53 and/or cisplatin on growth inhibition and induction of apoptosis, respectively, in KoTCC-1 cells. The efficacies of combined Ad5CMV-p53 and/or cisplatin therapy against growth and metastasis of KoTCC-1 tumors were assessed using subcutaneous and orthotopic tumor cell injection models. RESULTS: Ad5CMV-p53 substantially enhanced cisplatin chemosensitivity in a dose-dependent manner, reducing the median IC(50) by more than 50%. Characteristic apoptotic DNA laddering was induced by the combination of sublethal doses of Ad5CMV-p53 and cisplatin, but not by either agent alone. Furthermore, combined Ad5CMV-p53 and cisplatin therapy synergistically inhibited growth of subcutaneous KoTCC-1 tumors and the incidence of metastasis after orthotopic injection. CONCLUSIONS: These findings illustrate that combined treatment with Ad5CMV-p53 and cisplatin could be an attractive strategy for inhibiting progression of bladder cancer through effective induction of apoptosis.

Adenoviridae↗

PubMed2000

Polymeric micellar paclitaxel phosphorylates Bcl-2 and induces apoptotic regression of androgen-independent LNCaP prostate tumors.

BACKGROUND: Paclitaxel has been difficult to evaluate in preclinical tumor model systems because its poor solubility requires a Cremophor EL formulation, which results in lethal anaphylaxis. We tested the effectiveness of a novel polymeric micellar paclitaxel on androgen-independent tumor growth in the LNCaP tumor model. METHODS: Athymic male mice bearing LNCaP tumors were castrated and allowed to grow until their PSA levels increased to three times above precastration levels. The animals were then treated with 0.5 mg intravenous polymeric micellar paclitaxel once daily for the first 5 days of a 3-week cycle. In total, three cycles were given. Tumor volume and serum PSA levels were measured weekly to monitor tumor progression. RESULTS: In vitro mitogenic assays demonstrated that polymeric micellar paclitaxel was effective in inhibiting LNCaP cell growth with an IC(50) of 5 nM. Paclitaxel precipitated apoptosis in vitro at a concentration of 1 nm and higher, confirmed by DNA laddering. Western blotting demonstrated that paclitaxel treatment phosphorylated and inactivated Bcl-2. In mice bearing LNCaP tumors treated with micellar paclitaxel, tumors regressed rapidly with the commencement of micellar paclitaxel treatment. Tumor size decreased 91% and PSA level decreased 96% after three cycles of treatment. TUNEL immunostaining of the tumor treated with micellar paclitaxel showed marked apoptosis when compared with the control. No significant side effects or mortality was observed in the micellar paclitaxel group (n = 7). In contrast, all (n = 7) mice treated with conventional Cremophor EL paclitaxel died within 1 day of injection. CONCLUSIONS: The polymeric micellar paclitaxel formulation is water-soluble and capable of inducing complete response in mice bearing androgen-independent LNCaP tumors. The lack of toxicity of polymeric micellar paclitaxel permits in vivo preclinical testing of paclitaxel-based combination regimens.

Animals↗

PubMed2000

Establishment of a CCR5-expressing T-lymphoblastoid cell line highly susceptible to R5 HIV type 1.

The beta-chemokine receptor CCR5 is considered to be an attractive target for inhibition of CCR5-using (R5 or macrophage-tropic) HIV-1. However, R5 HIV-1 cannot replicate in CD4+ T cell or monocyte lines because of the lack of CCR5 expression on their surface, which apparently hampers discovery and development of effective CCR5 antagonists against HIV-1 replication. In this study, we have established the CCR5-expressing T cell line MOLT-4/CCR5, highly permissive to the replication of R5 HIV-1. The cells express a considerable amount of CCR5 on their surface. When the cells were infected with the R5 HIV-1 strains Ba-L and JR-FL, the virus-induced cytopathic effect (syncytium formation) was observed, and the cells produced large amounts of HIV-1 p24 antigen in the culture supernatants. The analyses of progeny viruses for their coreceptor use and gp120 V3 nucleotide sequence revealed that they were R5 HIV-1. The parental cell line MOLT-4 was much less susceptible to Ba-L and totally insusceptible to JR-FL. Furthermore, MOLT-4/CCR5 cells could support the replication of an R5 clinical isolate, but MOLT-4 cells could not. When TAK-779, a novel small-molecule nonpeptide CCR5 antagonist, was examined for its inhibitory effect on R5 HIV-1 replication in MOLT-4/CCR5 cells, the compound displayed potent antiviral activity, as demonstrated in peripheral blood mononuclear cells. These results indicate that the established cell line will be an extremely useful tool for experiments with R5 HIV-1.

Amides↗

PubMed2000

Inhibition of progression to androgen-independence by combined adjuvant treatment with antisense BCL-XL and antisense Bcl-2 oligonucleotides plus taxol after castration in the Shionogi tumor model.

We have reported that antisense Bcl-2 oligodeoxynucleotide (ODN) delays progression to androgen independence in the androgen-dependent (AD) mouse Shionogi tumor model. Here, we characterize changes in bcl-xL, another important anti-apoptotic gene, and test the efficacy of adjuvant antisense Bcl-xL ODN therapy either alone or in combination with antisense Bcl-2 ODN and chemotherapy after castration in the Shionogi tumor model. Bcl-xL mRNA levels increased up to 3-fold postcastration and remained 1. 5-fold higher in androgen-independent (AI) recurrent tumors compared with AD tumors before castration. Treatment of Shionogi cells with antisense Bcl-xL ODN inhibited Bcl-xL expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-xL ODN in mice bearing Shionogi tumors after castration delayed emergence of AI recurrent tumors. We then examined whether combined adjuvant antisense Bcl-xL and/or Bcl-2 ODNs plus taxol (paclitaxel) therapy further delays time to AI progression. Combined treatment of Shionogi cells with antisense Bcl-xL and Bcl-2 ODNs significantly enhanced taxol chemosensitivity compared with either agent alone, reducing the IC(50) of taxol by more than 1 log. Apoptotic DNA laddering and cleavage of poly(ADP-ribose) polymerase were more substantial after treatment with combined antisense Bcl-2 and Bcl-xL ODNs plus taxol than that with either 2 agents. Adjuvant administration of antisense Bcl-xL and Bcl-2 ODNs plus micellar taxol resulted in a significantly delayed time to AI recurrence compared with administration of either 2 agents. Our findings suggest that Bcl-xL represents a suitable molecular target for antisense ODN strategy and illustrate the potential additive effects of multi-target pharmacology for cancer therapy.

Androgens↗

PubMed2000

Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models.

Although insulin-like growth factor binding protein-5 (IGFBP-5) has been shown to be implicated in prostate cancer progression, the functional role of IGFBP-5 in progression to androgen-independence remains largely undefined. Here, we demonstrate substantial up-regulation of IGFBP-5 during castration-induced regression and androgen-independent (AI) progression in the mouse androgen-dependent (AD) Shionogi tumor model. To analyze the functional significance of these changes in IGFBP-5, human AD LNCaP prostate cancer cells were stably transfected with IGFBP-5 gene, and IGFBP-5-overexpressing LNCaP tumors progressed significantly faster to androgen independence after castration compared with controls. Antisense mouse IGFBP-5 oligodeoxynucleotides (ODNs) were then designed that reduced IGFBP-5 expression in Shionogi tumor cells in vitro in a dose-dependent and sequence-specific manner. Growth of Shionogi tumor cells was inhibited by antisense IGFBP-5 ODN treatment in a time- and dose-dependent manner, which could be reversed by exogenous IGF-I. However, antisense IGFBP-5 ODN treatment had no additive inhibitory effect on Shionogi tumor cell growth when IGF-I activity was neutralized by anti-IGF-I antibody. Antisense IGFBP-5 ODN treatment resulted in decreased mitogen-activated protein kinase activity and number of cells in the S + G2-M phases of the cell cycle that directly correlated with reduced proliferation rate of Shionogi tumor cells. Systemic administration of antisense IGFBP-5 ODN in mice bearing Shionogi tumors after castration significantly delayed time to progression to androgen independence and inhibited growth of AI recurrent tumors. These findings suggest that up-regulation of IGFBP-5 after castration serves to enhance IGF bioactivity and raise the possibility that the response of prostate cancer to androgen withdrawal can be enhanced by strategies, such as antisense IGFBP-5 ODN therapy, that target IGF signal transduction.

Androgens↗

PubMed2000

Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction.

Myocardial ischemia can cause myocardial infarction and as a consequence, heart failure. 3-(2,2,2-trimethylhydrazinium) propionate (MET-88) inhibits gamma-butyrobetaine hydroxylase and has cardioprotective effects on the ischemic heart. We now examined the effects of MET-88 in rats with congestive heart failure following myocardial infarction. Congestive heart failure was produced by left coronary artery ligation in rats. MET-88 at 100 mg/kg/day was orally administered from the 2nd day after surgery. We performed a survival study for 181 days, and measured ventricular remodeling, cardiac function, and myocardial high-energy phosphate levels after treatment for 20 days. MET-88 prolonged survival with a median 50% survival of 103 days compared to 79 days for the heart-failure control rats. The expansion of the left ventricular cavity (ventricular remodeling) in heart-failure rats was prevented by treatment with MET-88, and the effect of MET-88 was similar to that of captopril at 20 mg/kg. MET-88 attenuated the rise in right atrial pressure in heart-failure rats and augmented cardiac functional adaptability against an increased load. Also, MET-88 improved the myocardial energy state in heart-failure rats. The present results indicate that MET-88 improves the pathosis in rats with heart failure induced by myocardial infarction.

Adenosine Diphosphate↗

PubMed2000

Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models.

Testosterone-repressed prostate message-2 (TRPM-2) expression is highly up-regulated in normal and malignant prostate cells after androgen withdrawal. Although recent studies have suggested a protective role of TRPM-2 expression against apoptosis in several experimental models, the functional role of TRPM-2 in chemotherapy-induced apoptosis remains undefined. Here, we demonstrated that overexpression of TRPM-2 in human androgen-dependent LNCaP prostate cancer cells by stable transfection rendered them highly resistant to paclitaxel treatment than control LNCaP cells, with a 20-fold higher IC50 through the inhibition of apoptotic cell death. In mice bearing TRPM-2-overexpressing LNCaP tumors, tumor volume and serum prostate-specific antigen increased two to three times faster after castration and paclitaxel treatment compared with mice bearing control tumors. We then tested the efficacy of combined treatment with antisense TRPM-2 oligodeoxynucleotide (ODN) and paclitaxel in the mouse androgen-dependent Shionogi tumor model. Antisense TRPM-2 ODN treatment significantly enhanced paclitaxel chemosensitivity of Shionogi tumor cells in a dose-dependent manner, reducing the IC50 by 75%. Combined treatment of Shionogi cells with 500 nM antisense TRPM-2 ODN and 10 nM paclitaxel-induced apoptosis, either agent alone did not. Adjuvant administration of antisense TRPM-2 ODN and polymeric micellar paclitaxel after castration resulted in reduced TRPM-2 levels in vivo and a significant delay of emergence of androgen-independent recurrent Shionogi tumors compared with administration of either agent alone. Furthermore, combined treatment of mice bearing androgen-independent recurrent Shionogi tumors with antisense TRPM-2 ODN and micellar paclitaxel inhibited tumor growth compared with treatment with either agent alone. Collectively, these findings demonstrate that TRPM-2 overexpression helps confer a chemoresistant phenotype through inhibition of apoptosis, and that antisense TRPM-2 ODN may be useful in enhancing the effects of cytotoxic chemotherapy in hormone-refractory prostate cancer.

Animals↗

PubMed2000

Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer.

Although initially reported as an androgen-repressed gene in the rat prostate, the functional role of testosterone-repressed prostate message-2 (TRPM-2) in apoptosis remains undefined. Inhibition of castration-induced apoptosis by calcium channel blocker treatment in androgen-dependent Shionogi tumors resulted in the prevention of TRPM-2 gene up-regulation, suggesting that TRPM-2 is not directly androgen-repressed, but is regulated by apoptotic stimuli. The overexpression of the TRPM-2 gene in human androgen-dependent LNCaP prostate cancer cells by stable transfection rendered them highly resistant to androgen ablation in vivo. We then tested the efficacy of antisense TRPM-2 oligodeoxynucleotide (ODN) therapy in the Shionogi tumor model and demonstrated that the systemic administration of antisense TRPM-2 ODNs in mice bearing Shionogi tumors after castration resulted in a more rapid onset of apoptosis and time to complete regression, as well as a significant delay of emergence of androgen-independent recurrent tumors compared to control ODN treatment. Collectively, these findings illustrate that TRPM-2 is an antiapoptotic rather than an androgen-repressed gene that confers resistance to androgen ablation and thereby helps accelerate the progression to androgen independence.

Animals↗

PubMed2000

Congenital malformations and childhood cancer.

BACKGROUND: We investigated the epidemiology of congenital malformations and childhood cancer. PROCEDURE: By employing the cases of the Registry of Childhood Malignancies in Hokkaido Prefecture, Japan, from 1969 to 1996, the numbers of malignancies in cases (diagnosis at 0-14 years of age) with Down syndrome (DS), mental retardation (MR) excluding DS, luxatio coxae congenita (LCC), congenital heart disease (CHD) excluding DS, undescended testicle (UT), and cleft palate-lip (CPL) were calculated. Using the percentages of malignancies in the 2,349 cases without malformation, expected numbers of malignancies in the cases with the malformations were calculated. The observed numbers were statistically compared to expected ones. RESULTS: In the DS cases, leukemia developed with a significantly high frequency, but no UT cases developed leukemia. No brain tumor was preceded by DS. This could not be explained only by early death from coexisting diseases such as CHD, insofar as the CHD cases without DS developed brain tumors more frequently than expected. The ratio of acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) was different among the malformations. The MR cases developed ANLL more frequently than expected, whereas the CPL cases developed ALL more frequently. The distribution of the age at diagnosis for Wilms' tumor was different according to the underlying malformation. CONCLUSIONS: Malformations might have some factors that inhibit or delay as well as promote the development of certain malignancies.

Adolescent↗

PubMed2000

Stress protein GRP78 prevents apoptosis induced by calcium ionophore, ionomycin, but not by glycosylation inhibitor, tunicamycin, in human prostate cancer cells.

GRP78 induction has recently been shown to play a critical role in maintaining cell viability against several kinds of stress, including depletion of endoplasmic reticulum Ca(2+) and accumulation of unglycosylated proteins, under specific experimental conditions. However, the functional significance of GRP78 induction after stressful treatment has not been well defined. This article characterizes the different biological features associated with GRP78 induction by two kinds of stress agents, calcium ionophore, ionomycin (IM), and glycosylation inhibitor, tunicamycin (TM), focusing on the association with apoptosis in human prostate cancer cells. Both IM and TM treatment resulted in marked induction of GRP78 transcription in androgen-dependent prostate cancer LNCaP cells maintained in medium without androgen, but not in medium containing androgen, as measured by Northern blotting and nuclear run-off assays. After pretreatment with tumor necrosis factor-alpha, which has potent cytotoxic effects on LNCaP cells, both IM and TM could induce substantial increases in GRP78 transcription in LNCaP cells, even in medium containing androgen. Under both experimental conditions described, DNA fragmentation assays showed a direct correlation between the onset of apoptosis in LNCaP cells after IM treatment and the initiation of GRP78 transcript induction, while induction of GRP78 expression preceded TM-induced apoptosis. To elucidate the functional differences of GRP78 induction by IM and TM, an antisense oligodeoxynucleotide (ODN) targeted against the grp78 gene was designed to reduce GRP78 expression in a sequence-specific and dose-dependent manner. Antisense GRP78 ODN treatment substantially enhanced apoptosis of LNCaP cells induced by IM compared with mismatch control ODN treatment, whereas no marked differences were observed in apoptotic features induced by TM with antisense GRP78 and mismatch control ODN treatment. Studies of additional androgen-independent prostate cancer PC3 cells also demonstrated a correlation between GRP78 induction and resistance to apoptosis after IM treatment, but not after TM treatment. These findings suggest that there are at least two GRP78 signaling pathways, which play different roles in resistance against stress-induced apoptosis.

Androgens↗

PubMed2000

En bloc surgery for colon cancer: report of a case.

We report herein the case of a 57-year-old woman in whom successful en bloc surgery was performed for locally advanced colon cancer. A fixed tumor was palpable in the right subcostal region, and computed tomography (CT) showed that it originated in the ascending colon and invaded the right kidney, duodenum, head of the pancreas, and liver. A right hemicolectomy with D3 lymphadenectomy was performed combined with resection of the right kidney, duodenum, head of the pancreas, and liver. On microscopic examination, well-differentiated adenocarcinoma of the ascending colon widely invaded the parenchyma of the kidney, the parenchyma of the pancreatic head, and the duodenal wall. Lymph node metastasis was found in one paracolic node. This case report outlines the procedures involved in this extended surgery.

Adenocarcinoma↗

PubMed2000

Hepatocellular carcinoma effectively treated by intravenous infusion of cisplatin.

We report a rare case of hepatocellular carcinoma (HCC) for which intravenous administration of cisplatin (CDDP) was effective. A 48-year-old woman with recurrent HCC was admitted to our hospital. She had undergone right hepatectomy 1 year previously. A large tumor in the liver and multiple lung metastases were found by computed tomography in June 1995. She was icteric, and titers of serum alpha-fetoprotein (AFP; 214 ng/ml) and protein induced vitamin K absence or antagonist-II (PIVKA-II; 80 AU/ml) were high. According to these findings, she was diagnosed as having nonresectable recurrent HCC with extrahepatic lesions. She was treated by intravenous administration of CDDP. The dose of CDDP was 50 mg and it was infused once a week. One kur of CDDP was 4 weeks, and a total of four kur were administered. We noted that the lung metastases and primary liver tumor resolved after 1 kur of chemotherapy. The levels of serum AFP and PIVKA-II decreased markedly, to 26 ng/ml and <0.07 AU/ml, respectively. A complete response was obtained, and she maintained a good state of health for the next 6 months, until brain metastases occurred. She died 13 months after the initiation of treatment with CDDP. In general, intravenous CDDP cannot be recommended as a single agent for HCC therapy, but CDDP showed good antineoplastic activity in our patient.

Antineoplastic Agents↗

PubMed2000

Intraoperative microwave coagulation therapy for large hepatic tumors.

We report new surgical techniques for intraoperative microwave coagulation therapy (IMCT), conducted in three patients with large liver neoplasms with poor liver function or difficult tumor location. Anterolateral thoracotomy was performed for tumors in the right lobe to obtain a good operative field. Four electrode needles were inserted for microwave irradiation, with settings of 60 W, 45 s for coagulation and 1 s for dissociation. Clamping of the hepatoduodenal ligament was performed during IMCT. We began the coagulation at the bottom of the tumor, irradiating the tumor and the surrounding parenchyma to create regional necrosis with a safe margin. With these methods, we treated two women diagnosed with large hepatocellular carcinoma with liver cirrhosis and a man with liver metastasis from rectal cancer. The postoperative course of these patients was uneventful. A marked low-density area was seen in the region of therapy and no enhanced findings were observed on enhanced computed tomography postoperatively. However, in one patient, transcatheter embolization (TAE) was performed 1 month postoperatively because recurrence was noted on the bottom of the tumor. Thus, IMCT destroys the peripheral part of the tumor that may remain viable after TAE, but combination therapy with TAE is preferable, especially when a viable part exists within tumors. IMCT is an active, safe, and nontoxic therapeutic modality for large hepatic tumors, and is particularly applicable in patients with large hepatocellular carcinomas and poor liver function.

Aged↗