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Taro Shuin

Publications and source records attributed to Taro Shuin.

At least 55 records · Page 3Linked to original sources
PubMed2003

Experimental protection of mice against lethal Staphylococcus aureus infection by novel bacteriophage phi MR11.

The protective effects of bacteriophages were assessed against experimental Staphylococcus aureus infection in mice. Of the S. aureus phages isolated in the study, phi MR11 was representatively used for all testing, because its host range was the most broad and it carries no genes for known toxins or antibiotic resistance. Intraperitoneal injections (8 x 10(8) cells) of S. aureus, including methicillin-resistant bacteria, caused bacteremia and eventual death in mice. In contrast, subsequent intraperitoneal administration of purified phi MR11 (MOI > or = 0.1) suppressed S. aureus-induced lethality. This lifesaving effect coincided with the rapid appearance of phi MR11 in the circulation, which remained at substantial levels until the bacteria were eradicated. Inoculation with high-dose phi MR11 alone produced no adverse effects attributable to the phage. These results uphold the efficacy of phage therapy against pernicious S. aureus infections in humans and suggest that phi MR11 may be a potential prototype for gene-modified, advanced therapeutic S. aureus phages.

Animals↗
PubMed2003

Esophagogastric varices due to arterioportal shunt in a serous cystadenoma of the pancreas in von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited disorder characterized by extensively vascularized tumors and cysts in specific organs. Angiogenesis is a striking future of VHL disease with its characteristic cysts and well-vascularized tumors. The hypervascular nature of VHL lesions has been linked to the overproduciton of vascular endothelial growth factor (VEGF) through increased expression of hypoxia inducible factor-1alpha (HIF-1alpha). Here we describe a rare case of VHL disease with esophageal and gastric varices due to arterioportal shunt in a serous cystadenoma of the pancreas, which, upon immunohistochemical examination, exhibited HIF-1alpha and VEGF expression. Rupture of esophageal varices was successfully treated with endoscopic injection sclerotherapy.

Angiography↗
PubMed2003

Molecular detection of von Hippel-Lindau gene mutations in urine and lymph node samples in patients with renal cell carcinoma: potential biomarkers for early diagnosis and postoperative metastatic status.

PURPOSE: Organ confined renal cell carcinoma can be cured in the majority of patients, whereas more extensive lesions have a poor prognosis. Therefore, the development of a useful biomarker for early diagnosis as well as postoperative metastatic status would contribute to the appropriate therapy for renal cell carcinoma. To diagnose renal cell carcinoma preoperatively we developed a novel urinary test and detected occult lymph node micrometastasis using a molecular approach. MATERIALS AND METHODS: Urine samples were obtained preoperatively from 27 patients with renal cell carcinoma and von Hippel-Lindau (VHL) gene mutations in the tumors, and were analyzed for VHL gene mutations using a nested single strand conformational polymorphism analysis. Lymph nodes without evidence of histological metastasis were obtained from 15 patients with renal cell carcinoma and VHL gene mutations, and analyzed for VHL gene mutations using mutation specific nested reverse transcription polymerase chain reaction method. RESULTS: In urine samples 5 of 27 VHL gene mutations (18.5%) were found and each mutation pattern was the same as that detected in each renal cell carcinoma. One lymph node micrometastasis was found. CONCLUSIONS: These data indicate the presence of detectable levels of tumor derived DNA in the urine of patients with renal cell carcinoma and suggest that nested single strand conformational polymorphism analysis of VHL gene of urine samples provides a possible tool for the early detection of renal cell carcinoma. Furthermore, mutation specific nested reverse transcription polymerase chain reaction is useful to detect occult lymph node micrometastasis and may predict patients at risk for local recurrence. These 2 combined approaches using VHL gene mutations may contribute to the total therapy for and prognosis of renal cell carcinoma.

Biomarkers, Tumor↗
PubMed2003

Docetaxel enhances the therapeutic effect of the angiogenesis inhibitor TNP-470 (AGM-1470) in metastatic human transitional cell carcinoma.

We demonstrated recently that chronic frequent administration of an adequate biological dose of the angiogenesis inhibitor TNP-470 (AGM-1470, O-chloracetyl-carbamoyl fumagillol) completely inhibits spontaneous lymph node metastasis but does not have a complete response on tumor growth of nonestablished or established human metastatic transitional cell carcinoma (TCC) 253J B-V growing orthotopically into athymic nude mice. Therefore, in this study, we evaluated whether docetaxel (Taxotere) enhances the therapeutic effect of TNP-470, especially on tumor growth. Docetaxel enhanced in vitro antiproliferation but not basic fibroblast growth factor down-regulation by TNP-470 in 253J B-V and human umbilical vascular endothelial cells. Docetaxel significantly enhanced in vitro apoptosis by TNP-470 in human umbilical vascular endothelial cells but not in 253J B-V. In vivo combination was most effective when docetaxel was administered before TNP-470, and increased significantly the complete response on tumor growth of nonestablished and established TCCs growing orthotopically into athymic nude mice compared with either therapy alone (P < 0.05). The incidence of spontaneous lymph node metastasis was inhibited completely by the combination therapy (P < 0.05). Drug-induced body weight loss was not significantly different in any treatment groups. The combination of TNP-470 and docetaxel inhibited intratumor neovascularization, the expression of bFGF and matrix metalloproteinases type-9 compared with controls (P < 0.005), and enhanced apoptosis in tumors compared with each therapy alone (P < 0.005). These studies indicate that docetaxel markedly enhances the ability of TNP-470 to inhibit tumorigenicity and metastasis in both nonestablished and established TCCs. These effects are mediated, in part, by the complementary cytotoxicities of angiogenesis inhibition, down-regulation of bFGF and matrix metalloproteinases type-9, and induction of apoptosis.

Angiogenesis Inhibitors↗
PubMed2003

Analysis of gene-expression profiles in testicular seminomas using a genome-wide cDNA microarray.

To identify new diagnostic markers for testicular germ cell tumors (TGCTs), including seminomas, as well as potential targets of new drugs for treating the disease, we compared gene-expression profiles of cancer cells from 13 seminomas with normal human testis using laser-capture microdissection and a cDNA microarray representing 23,040 genes. We identified 347 genes that were commonly up-regulated in seminoma cells. The functions of 227 were known to some extent; the remaining 120 included 55 ESTs. On the list were cyclin D2 (CCND2), prostate cancer over-expressed gene 1 (POV1), and junction plakoglobin (JUP), all of which were already known to be over-expressed in seminomas. On the other hand, our protocol selected 593 genes as being commonly down-regulated in seminoma cells. That list included 340 functionally characterized genes; the other 253 included 131 ESTs. To confirm the expression data, we performed semi-quantitative RT-PCR experiments with nine highly up-regulated genes, and the results supported those of our microarray analysis. The information provided here should prove useful for identifying genes whose products might serve as molecular targets for treatment of TGCTs.

Adult↗
PubMed2002

Effects of von Hippel-Lindau gene mutation and methylation status on expression of transmembrane carbonic anhydrases in renal cell carcinoma.

PURPOSE: Our primary goal was to determine whether increased expression of the transmembrane carbonic anhydrase (CA) isozymes in renal cell carcinoma (RCC) is regulated by the von Hippel-Lindau (VHL) gene. METHODS: We studied mRNA expression of all three transmembrane CAs - CA IX, XII, and XIV - in 17 RCC cell lines, transformants of the wild-type VHL gene, and normal kidney tissue cultures, and then compared them with the mutation status in the VHL gene. RESULTS: Northern blot analysis showed no detectable signal for CA XIV mRNA expression in normal and cancer cells. CA XII mRNA was ubiquitously expressed except in two cell lines. Although CA XII expression levels tended to be lower in RCC cell lines without the VHL mutation and in transformants of the wild-type VHL gene, the results were not conclusive. Significant expression of CA IX mRNA was seen in eight of 17 RCC cell lines. Among five cell lines which had no VHL mutation, four lines showed no detectable signal and one cell line showed a low amount of CA IX mRNA expression. In patients with RCC, VHL mutations and significant CA IX expression were seen in established tumor cell lines but not in primary tissue cultures from normal counterparts. Further study of methylation status showed that the 5' region in the CA9 gene was hypomethylated in all CA IX-positive cell lines and hypermethylated in all CA IX-negative cell lines. Especially, methylation status at -74 and -6 CpG sites perfectly correlated with CA IX expression. CONCLUSIONS: These findings indicate that VHL suppresses CA IX expression but has no conclusive effect on CA XII and XIV expressions in RCC. CA IX expression is also driven by the methylation status of the CA9 gene.

Blotting, Northern↗
PubMed2002

HIF-1alpha-prolyl hydroxylase: molecular target of nitric oxide in the hypoxic signal transduction pathway.

We have investigated inhibitory mechanisms of hypoxic activation of HIF-1alpha by nitric oxide (NO). Using a Hep3B cell-derived cell line, HRE7 cells, we found that the inhibition of HIF-1alpha activity by NO requires a substantial amount of oxygen, albeit at a lower level. We further investigated the effect of NO on the binding activity of the von Hippel-Lindau tumor suppressor protein (pVHL) to the N-terminal activation domain (NAD) overlapping the oxygen-dependent degradation domain (ODD) of HIF-1alpha, because this reaction involves prolyl hydroxylation in NAD that requires oxygen. Although we could not detect any binding activity when NAD was incubated with whole cell extracts from cells treated with CoCl(2) or desferrioxamine, the binding capacity was manifested when Hep3B cells were treated together with NO. This activation was also observed when whole cell extracts from CoCl(2)-treated cells were incubated with NO. The prolyl hydroxylase from Hep3B cells treated with CoCl(2) was partially purified about 80-fold, and several enzymatic properties were examined. The enzyme required ferrous ion and 2-oxoglutaric acid. Strong activation of the prolyl hydroxylase by NO was observed without further addition of ferrous ion.

Blotting, Western↗
PubMed2002

Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters.

To delineate more precisely the somatic von Hippel-Lindau disease (VHL) gene alteration as well as to elucidate its etiologic role in renal tumorigenesis, we examined a total of 240 sporadic renal cell carcinomas (RCCs) for somatic VHL gene alterations by DNA-SSCP followed by sequencing, methylation-specific PCR assay, microsatellite LOH study, and Southern blot analysis. Intragenic mutation of the VHL gene was found exclusively in clear-cell or variant-type RCCs at a frequency of 51% (104/202). Hypermethylation of the VHL promoter region was detected in an additional 11 clear-cell RCCs. Microsatellite analysis demonstrated that LOH of the VHL locus was found in 140/155 (90%) informative clear-cell RCCs. The VHL gene therefore seems to be inactivated in a two-hit manner by intragenic mutation or hypermethylation plus allelic loss in clear-cell RCC. Genomic rearrangement of the VHL gene detected by Southern analysis was not found (0/216 cases); this is in contrast to germ lines in which Southern aberrations consisted of 7-19% of the mutations. Clinicopathologic data demonstrated that VHL mutation/LOH did not vary according to tumor progression in clear-cell RCC, including tumor diameter, stage, grading, distant metastasis, and lymph node metastasis. Interestingly, VHL mutation was significantly less frequent in RCCs occurring in younger (< or = 55 years) than that in older (> or = 56 years) patients. These data suggested that the inactivation of the VHL tumor-suppressor gene is a specific genetic change in clear-cell RCC, and that it may occur at an early or first step in the clear-cell tumorigenic pathway rather than as a late event.

Adult↗
PubMed2002

Frequent phosphorylation at serine 392 in overexpressed p53 protein due to missense mutation in carcinoma of the urinary tract.

Post-transcriptional modification of p53 by phosphorylation has been proposed to be an important mechanism of p53 stabilization and functional regulation. Phosphorylation of p53 Ser392, in particular, activates specific DNA binding functions by stabilizing p53 tetramer formation. This study evaluated the relationship between p53 Ser392 phosphorylation and various types of p53 missense mutation detected in urothelial transitional cell carcinomas (TCCs), with stratification of the mutations according to the functional domains elucidated by the crystal structure of the p53 protein. Of 41 TCCs with missense mutations, 26 (63.4%) exhibited immunopositivity with Ser392 phospho-specific p53 antibody. In comparison to structural mutations, the missense mutations at exon 7 (p=0.0307) or located in regions that affect direct DNA binding ability (p = 0.0273) were significantly associated with Ser392 immunopositivity. No statistically significant relationship was found between Ser392 immunoreactivity and other different types of p53 mutation. The prevalence of cases exhibiting Ser392-positive immunostaining was higher for high-grade (p <0.0001) and advanced-stage TCCs (p =0.0119) than for TCCs with wild-type p53. No significant relationship was found between Ser392 immunoreactivity and apoptotic index in urothelial TCCs. These in vivo findings indicate that Ser392 phosphorylation frequently occurs in mutant form p53 in TCCs. Because mutant form p53 can act dominant-negatively by heterooligomerization with wild-type p53, these findings also suggest that Ser392 phosphorylation might activate tetramer formation to promote the dominant-negative effects of mutant form p53, and thereby contribute to proliferation of aggressive TCCs.

Aged↗
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

Detection of genetic alterations in advanced prostate cancer by comparative genomic hybridization.

In this study, we examined nine cases of advanced Japanese prostate cancer by comparative genomic hybridization (CGH) to detect chromosomal imbalances across the entire genome and to identify several new regions likely to contain genes important to the development and progression of this disease. These cases had been previously examined for numerical chromosomal aberrations by fluorescence in situ hybridization (FISH). By CGH, the following regions were found to be over-represented (gains), with fluorescence ratio values higher than the threshold: 4p, 6p, 8q, 11q, 12q, 15q, 16p, 17q, 20, and 21 (>4 cases); underrepresentation (losses) involved: 1q, 4q, 5q, 6q, 13q, 14q, and 22 (>4 cases). The shortest regions of overlap (SRO) of gains were noted at 8q24.1 through q24.3, 12q23, and 17q23 through q24 (>5 cases). The SRO of losses were seen at 5q14 through q21, 6q16.1 through q21, 13q21.3 through q22, and 14q21 (>5 cases). Notably, the gain of chromosomes 8 and 12 by CGH was in agreement with the FISH data, suggesting that the gain of chromosomes 8 and 12 may play an important role in prostate carcinogenesis. The genes on the SRO regions were also discussed in relation to oncogenes and bone metastases.

Aged↗
PubMed2002

Promoter methylation of TSLC1 and tumor suppression by its gene product in human prostate cancer.

We recently identified TSLC1, a tumor suppressor gene in human lung cancer. Gene silencing by promoter methylation has been observed frequently in adenocarcinoma of the lung, liver, and pancreas. Here, we demonstrate that TSLC1 expression is also absent or markedly reduced in 3 of 4 prostate cancer cell lines. Promoter sequences of TSLC1 were heavily methylated in PPC-1 cells that lacked TSLC1 expression, supporting the idea that promoter methylation is strongly correlated with complete loss of gene expression. Promoter sequences of TSLC1 were also methylated significantly in 7 of 22 (32%) primary prostate cancers. Hypermethylation of the promoter occurred not only in advanced tumors, but also in relatively early-stage tumors. Restoration of TSLC1 expression substantially suppressed tumor formation of PPC-1 cells in nude mice. These findings indicate that alteration of TSLC1 is involved in prostate cancer.

Animals↗
PubMed2002

A case of von Hippel-Lindau disease with bilateral pheochromocytoma, renal cell carcinoma, pelvic tumor, spinal hemangioblastoma and primary hyperparathyroidism.

A rare case of von Hippel-Lindau (VHL) disease with bilateral pheochromocytomas, right renal cell carcinoma, right pelvic carcinoma, spinal hemangioblastoma and primary hyperparathyroidism is described. A 78-year-old woman had a history of hypertension from her forties. She suffered from headache and body weight loss. Abdominal CT revealed bilateral adrenal tumors and right external renal tumors enhanced in early stage. MIBG scintigraphy exhibited a high accumulation of tracer in both adrenal glands. On the basis of the radiographic findings and endocrinological results, the patient was diagnosed as having bilateral pheochromocytomas and right renal cell carcinoma. A bilateral adrenectomy was performed, followed by surgery for resection of the renal cell carcinoma. The other resected right kidney showed a clear cell subtype that was determined to be renal cell carcinoma, and proved that the pelvic tumor was transient cell carcinoma. Spinal MRI showed spinal hemangioblastoma. von Hippel-Lindau (VHL) gene mutation for the patient was found. We diagnosed the patient as VHL because of the existence of spinal hemangioma and a VHL disease gene. Parathyroid echo revealed a hypoechoic space on the back of the left lobe, and serum calcium and intact PTH to be elevated. The patient was diagnosed as primary hyperparathyroidism. We report the first case of a patient with VHL disease complicated with bilateral pheochromocytomas, right renal cell carcinoma, right renal pelvic carcinoma and primary hyperparathyroidism. The life expectancy of affected individuals has been less than 50 years. Since the prognosis may be improved by an early diagnosis, affected individuals with VHL complexes should undergo cranial, spinal MRI and abdomen CT. The families may benefit from presymptomatic detection of affected gene carriers and the exclusion of at-risk family members by negative test results.

Adrenal Gland Neoplasms↗
PubMed2002

p53 mutation arising in Arg72 allele in the tumorigenesis and development of carcinoma of the urinary tract.

PURPOSE: It is known that a common p53 polymorphism, encodingeither proline (Pro) or arginine (Arg) at residue 72, produces marked change in the structure of p53. Furthermore, the Arg72-containing allele is preferentially mutated and retained in various human tumors, suggesting that polymorphic residue within p53 modifies mutant behavior. We studied to determine whether Arg72 could be a risk factor for p53 mutations in human transitional cell carcinomas (TCCs). In addition, the relationship between the status of p53 codon 72 polymorphism and clinicopathological factors of this tumor were also analyzed. EXPERIMENTAL DESIGN: We analyzed the correlation between the p53 mutations and genotypes of its codon 72 using genomic DNAs from the TCCs by direct DNA sequencing. Loss of heterozygosity was determined using a p53 microsatellite marker (TP53) amplified by PCR. RESULTS: There was a bias to mutate and express the Arg allele in the p53 -mutated TCCs arising in individuals with heterozygosity (Pro/Arg). The Arg72-containing allele was preferentially retained in these tumors. The prevalence of cases with p53 mutations within Arg72-containing allele was higher for advanced-stage TCCs (chi(2) = 5.320, P = 0.021) than for TCCs with those arising in Pro72-containing allele. CONCLUSIONS: Our in vivo findings suggested that p53 mutation alleles containing Arg72 are preferentially selected during tumorigenesis and affect mutant behavior in TCCs, and revealed that TCCs with p53 mutation arising in Arg72-containing allele became progressively more abundant with increase in tumor stage.

Aged↗
PubMed2002

Inhibition of angiogenesis by the antiepidermal growth factor receptor antibody ImClone C225 in androgen-independent prostate cancer growing orthotopically in nude mice.

In human androgen-independent prostate cancer (PCa), epidermal growth factor receptor (EGFR) regulates angiogenesis, tumor growth, and progression. In this study, we evaluated whether the blockade of EGFR by the anti-EGFR antibody ImClone C225 (IMC-C225) inhibited tumor growth and metastasis by inhibiting angiogenesis, and whether paclitaxel enhanced the results of therapy in androgen-independent PCa. PC-3M-LN4 PCa cells were implanted orthotopically in athymic nude mice and treated with i.p. IMC-C225 (1 mg twice a week) and/or paclitaxel (200 microg once a week). In vitro treatment of PC-3M-LN4 with IMC-C225 inhibited EGFR autophosphorylation without any significant antiproliferative effect. In contrast, in vivo therapy with IMC-C225 alone (P < 0.05) or in combination with paclitaxel (P < 0.005) significantly inhibited PCa growth and metastasis. Serum levels of interleukin (IL) 8 were lower after therapy, and IL-8 mRNA expression was down-regulated within the tumors after therapy. The down-regulation of IL-8 correlated with reduced microvessel density. IMC-C225 reduced tumor cell proliferation, enhanced p27(kip1) expression, and induced tumor and endothelial cell apoptosis. These studies indicate that IMC-C225 has significant antitumor effect in this murine model, mediated in part by inhibition of cellular proliferation and angiogenesis, and by enhancement of apoptosis. The simultaneous administration of paclitaxel enhanced this effect.

Androgens↗
PubMed2002

The prognostic value of angiogenesis and metastasis-related genes for progression of transitional cell carcinoma of the renal pelvis and ureter.

PURPOSE: We reported previously that angiogenesis evaluated by intratumor microvessel density (MVD), expression of such angiogenic factors as vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF), and the matrix metalloproteinase-9:E-cadherin ratio (M:E ratio) could identify patients with advanced transitional cell carcinoma (TCC) of the bladder for whom chemotherapy and cystectomy will be unsuccessful. In the present study, we evaluated the significance of the M:E ratio as a predictor for prognosis for patients with TCC in the upper urinary tract (TCC-UUT). EXPERIMENTAL DESIGN: We evaluated MVD by immunohistochemistry and the expression of angiogenic and metastasis-related factors by in situ hybridization in 55 nephroureterectomy specimens from patients who received no neoadjuvant therapy. The expression of angiogenesis, angiogenic and metastasis-related factors, and clinicopathological characteristics were evaluated for their correlation with metastasis, recurrence, and disease prognosis. RESULTS: We found that tumor grade and pathological stage were important predictors for metastasis and survival in these patients. The expression level of matrix metalloproteinase type 9 (MMP-9) and type 2 (MMP-2) and the M:E ratio correlated with MVD. Increased MVD, elevated expression levels of MMP-9 and MMP-2, and a higher M:E ratio were associated with poor prognosis. Moreover, lower expression levels of E-cadherin were associated with fewer recurrences in the urinary bladder. Multivariate analysis indicated that the M:E ratio and E-cadherin expression were independent prognostic factors for disease progression and intravesical recurrence, respectively. CONCLUSION: We suggest that the M:E ratio and E-cadherin expression may be targets for novel therapeutic strategies.

Adult↗
PubMed2002

Frequent administration of angiogenesis inhibitor TNP-470 (AGM-1470) at an optimal biological dose inhibits tumor growth and metastasis of metastatic human transitional cell carcinoma in the urinary bladder.

PURPOSE: The angiogenic inhibitor TNP-470 (AGM-1470, O-chloracetyl-carbamoyl fumagillol) has been reported to inhibit the growth of human transitional cell carcinoma (TCC) in the urinary bladder. However, it is still unknown whether TNP-470 inhibits metastasis of TCC. Here, we identify an efficient protocol using TNP-470, and optimize its antitumor and antimetastatic effects on human TCC in the urinary bladder. EXPERIMENTAL DESIGN: In vitro, the human metastatic TCC cell line 253J B-V and human umbilical vascular endothelial cells were treated with TNP-470, and examined for cell growth and protein production of angiogenic factors. To study in vivo effects of TNP-470, 253J B-V cells were implanted orthotopically into athymic nude mice. TNP-470 was administered in several dosing and scheduling regimens, and its effects on tumor growth, metastasis, intratumor neovascularization, and mRNA expression of angiogenic factors were determined in both nonestablished and established tumors. RESULTS: In vitro treatment with TNP-470 inhibited cell growth and production of basic fibroblast growth factor protein in 253J B-V and human umbilical vascular endothelial cells in a dose-dependent manner. In vivo daily administration of TNP-470 significantly inhibited tumor growth (P < 0.001), metastasis (P < 0.05), intratumor neovascularization (P < 0.005), and mRNA expression of basic fibroblast growth factor and MMP-9 (P < 0.005), in both nonestablished and established tumors. Increasing the daily dose did not increase the effect on tumor growth, metastasis, and angiogenesis; however, the drug-induced toxicity did increase in a dose-dependent manner. CONCLUSIONS: Frequent administration of TNP-470 at an optimal biological dose provided maximal antitumor and antimetastatic effects of human TCC of the urinary bladder. It may function by down-regulating angiogenic factors.

Angiogenesis Inhibitors↗