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Biomedical subjects

M Mai

Publications and source records attributed to M Mai.

At least 19 recordsLinked to original sources
PubMed2005

Antibody against vascular endothelial growth factor (VEGF) inhibits angiogenic switch and liver metastasis in orthotopic xenograft model with site-dependent expression of VEGF.

We previously reported that upregulation of angiogenesis, i.e. angiogenic switch (AS), may occur simultaneously to initiation of invasion in the early development of human colon cancer. We also showed that mRNA upregulation of the gene of vascular endothelial growth factor (VEGF) occurs immediately prior to metastasis in human colon cancer in an orthotopic nude mouse model of colon cancer liver metastasis. In this paper, we studied whether the antibody against VEGF inhibits AS and liver metastasis in an orthotopic xenograft model with site-dependent expression of VEGF. We examined levels of vessel density, VEGF mRNA by in situ hybridization (ISH) method and liver metastasis in pre-AS (on days 8 and 11) and post-AS (on days 15 and 18) treatment groups. The mean vessel density and the intensity of VEGF mRNA by ISH in the pre-AS treatment group were significantly lower than those for the post-AS treatment and the control group. Liver metastases were completely inhibited (0/10) in the pre-AS treatment, while they occurred in 4 out of 10 and 5 out of 10 mice in the post-AS treatment and the control groups, respectively (p<0.01). These results suggest that VEGF antibody treatment performed before AS could efficiently inhibit AS and liver metastasis, which may indicate that VEGF antibody has another potential as a drug for chemoprevention of colon cancer.

Animals↗
PubMed2004

Use of multiple displacement amplification to amplify genomic DNA before sequencing of the alpha and beta haemoglobin genes.

AIMS: To evaluate the technique of multiple displacement amplification (MDA) for whole genome amplification from small volume blood samples before sequencing in a clinical test to identify haemoglobin gene mutations. METHODS: Phage phi29 DNA polymerase was used to perform MDA, starting with either 1 micro l of blood or 1 ng of previously isolated blood DNA from 23 patients. The amplified products were then evaluated using a clinical test that involves sequencing the haemoglobin genes to detect mutations. The results were compared with the current clinical test method that uses genomic DNA isolated using column based technology. RESULTS: The MDA technique produced large quantities (theoretically approximately 2 mg) of DNA. The amplification procedure was extremely easy and took about four hours (less than one hour of hands on technician time and three hours for amplification). When MDA products were used in the same clinical test protocol as genomic DNA isolated using column technology, there was 100% concordance for detection of a variety of point mutations in the alpha1, alpha2, and beta globin genes. CONCLUSIONS: The MDA technique is useful for overcoming the problem of insufficient genomic DNA in clinical specimens requiring haemoglobin gene sequencing and could be useful for other clinical applications.

Base Sequence↗
PubMed2001

Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene.

Conductin is a Wnt signalling protein and serves as a negative regulator of beta-catenin stability. We have previously isolated the human homolog (AXIN2) of the murine conductin gene and shown that it is mutated in colorectal cancer (CRC) with defective mismatch repair (MMR). Here we report the detailed genomic structure of this gene by analysis of cDNA and genomic clones. The gene spans > or =25 kb containing ten exons ranging from 96 bp to 904 bp. All splice donor and acceptor sites conform to the GT/AG rule. FISH (Fluorescence in situ Hybridization) analysis localized this gene to human chromosome band 17q24 and showed that it exists as a single copy in the human genome. Northern blot analysis from different human organs demonstrated that the AXIN2 gene is highly expressed in human thymus, prostate, testis, small intestine and ovarian tissues but expressed at a lower level in colon. The data reported here provides a framework for further analysis of this important Wnt signalling protein in vertebrate development and tumorigenesis.

Axin Protein↗
PubMed2001

Myxedema accompanied by huge portal-systemic shunt without portal hypertension.

A 43-year-old woman with a huge portal-systemic shunt accompanied by myxedema showed slow speech and behavior. Several imaging studies revealed a bold portal-systemic shunt from the splenic vein to the left renal vein. In addition, hypothyroidism caused by chronic thyroiditis was diagnosed, and synthesized thyroxine replacement was effective for the symptoms. However, the serum ammonia and indocyanin green retention remained in the abnormal range, nevertheless the portal vein pressure was normal and findings of liver cirrohsis were not recognized histologically. Surgical shunt closure was performed, resulting in normalized serum ammonia levels and serum branched chain amino acids /aromatic amino acids ratio, and improvement of the ammonia tolerance test.

Adult↗
PubMed2001

[Chemotherapy by combination of low-dose CPT-11 and PSK in an elderly man with liver metastasis from gastric cancer].

We attempted a new regimen of low-dose CPT-11 and PSK against a high age man with liver metastasis from gastric cancer. CPT-11 was administered at 20 mg/m2/day x 2/week, and PSK was given orally 3.0 g/day daily, respectively. Serum CEA level decreased gradually and almost reached normal limits (130 to 3.0 ng/ml). The tumor was reduced more than 50% at 13 weeks after the start of chemotherapy, when it had been continued for more than 8 weeks. There were no adverse effects and this regimen has been continued for more than 20 weeks without missing a week. These results suggest that the combination of low-dose CPT-11 and PSK has fewer side effects even in an elderly patient and may induce not only tumor shrinkage but also a prolonged time to progression.

Aged↗
PubMed2001

[Significance of angiogenesis and clinical application of anti-angiogenesis].

Angiogenesis is essential for tumor growth and metastasis and depends upon the production of angiogenic factors by host and/or tumor cells. Increased vascularity may allow not only an increase in tumor growth but also a greater chance for hematogenous metastasis. We have already reported that vessel density and vascular endothelial growth factor (VEGF) expression are higher in metastatic tumors than in nonmetastatic tumors and that VEGF and its receptor, the KDR ligand/receptor system, also correlate with metastasis. Therefore the anti-VEGF antibody and VEGF receptor antagonist are potential targets for antiangiogenesis therapy in colon cancer. Clinical trials of such agents are continuing to phase II/III in the USA and Europe. In this paper, we introduce data on antiangiogenesis agents in the treatment of metastatic colorectal cancer and point out that the strategy for antiangiogenesis is not tumor shrinkage but tumor dormancy.

Angiogenesis Inhibitors↗
PubMed2000

Analysis of JNK, Mdm2 and p14(ARF) contribution to the regulation of mutant p53 stability.

Identification of Mdm2 and JNK as proteins that target degradation of wt p53 prompted us to examine their effect on mutant p53, which exhibits a prolonged half-life. Of five mutant p53 forms studied for association with the targeting molecules, two no longer bound to Mdm2 and JNK. Three mutant forms, which exhibit high expression levels, showed lower affinity for association with Mdm2 and JNK in concordance with greater affinity to p14(ARF), which is among the stabilizing p53 molecules. Monitoring mutant p53 stability in vitro confirmed that, while certain forms of mutant p53 are no longer affected by either JNK or Mdm2, others are targeted for degradation by JNK/Mdm2, albeit at lower efficiency when compared with wt p53. Expression of wt p53 in tumor cells revealed a short half-life, suggesting that the targeting molecules are functional. Forced expression of mutant p53 in p53 null cells confirmed pattern of association with JNK/Mdm2 and prolonged half-life, as found in the tumor cells. Over-expression of Mdm2 in either tumor (which do express endogenous functional Mdm2) or in p53 null cells decreased the stability of mutant p53 suggesting that, despite its expression, Mdm2/JNK are insufficient (amount/affinity) for targeting mutant p53 degradation. Based on both in vitro and in vivo analyses, we conclude that the prolonged half-life of mutant p53 depends on the nature of the mutation, which either alters association with targeting molecules, ratio between p53 and targeting/stabilizing molecules or targeting efficiency.

Cell Membrane↗
PubMed2000

alpha-difluoromethylornithine induces apoptosis as well as anti-angiogenesis in the inhibition of tumor growth and metastasis in a human gastric cancer model.

Polyamines are essential in various biological systems such as cellular proliferation including tumor growth, differentiation and neoplastic transformation including carcinogenesis. alpha-Difluoromethylornithine (DFMO) is a specific irreversible inhibitor of ornithine decarboxylase, a key enzyme in polyamine biosynthesis, and has been used for clinical chemotherapy and chemoprevention trials against several tumors with various effects. The cellular mechanisms of DFMO action are unclear. Because our hypothesis with regard to polyamine-directed chemoprevention includes anti-angiogenesis and apoptosis as essential parts of the cellular mechanism of action of DFMO, we examined these effects in our human gastric cancer model. In our initial experiments, DFMO inhibited the growth of both human umbilical vein endothelial cells (HUVEC), angio-endothelial cells in vitro, and KKLS, a gastric cancer cell line, in culture, and also the growth of KKLS cells transplanted into nude mice. DFMO also inhibited liver metastasis of KKLS orthotransplanted in the stomach of nude mice. The vessel density of DFMO-treated tumors was significantly lower than that of non-treated tumors. The apoptotic index was significantly greater in DFMO-treated tumors than in non-treated tumors. These results suggest that anti-angiogenesis and apoptosis play significant roles in the DFMO inhibition of the growth and metastasis in this human gastric cancer model and provide evidence that DFMO induces apoptosis.

Animals↗
PubMed2000

Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury.

BACKGROUND: We investigated whether monocyte chemoattractant protein-1 (MCP-1) is expressed in hypertensive nephrosclerosis, and tested the effect of angiotensin II type 1 receptor blockade on MCP-1 expression and macrophage (MPhi) infiltration. METHODS: Rats with two-kidney, one-clip (2K1C) hypertension with and without treatment with the angiotensin II type 1 receptor antagonist valsartan (3 mg/kg/day) were studied. In these animals as well as in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), hypertensive mRen-2 transgenic rats (TGR), and respective control strains, MCP-1 expression in the kidney was investigated by Northern and Western blots and by immunohistochemistry. Glomerular and interstitial MPhis were counted. RESULTS: In the nonclipped kidney of 2K1C rats, MCP-1 expression was elevated at 14 and 28 days when significant MPhi infiltration was present. MCP-1 was localized to glomerular endothelial and epithelial cells, interstitial and tubular cells, MPhis, and vascular smooth muscle cells. A similar pattern of MCP-1 staining was present in TGR kidneys, whereas MCP-1 expression was not increased in SHR and SHR-SP. Valsartan reduced but did not normalize blood pressure, blocked the induction of MCP-1 protein in 2K1C kidneys, and decreased interstitial MPhi infiltration significantly. CONCLUSION: MCP-1 expression is increased in angiotensin II-dependent models of hypertensive nephrosclerosis and is temporally and spatially related to MPhi infiltration. The angiotensin II type 1 receptor mediates the induction of MCP-1.

Angiotensin Receptor Antagonists↗
PubMed2000

Prolonged stable disease effects survival in patients with solid gastric tumor: analysis of phase II studies of doxifluridine.

We have previously reported that the survival time of most patients with solid tumors depend primarily on the length of the cytostatic phase rather than the extent of reduction induced. We analyzed a phase II study of doxifluridine, an intermediate metabolite of capecitabine, in gastric cancer to confirm our concept, because doxifluridine has shown low response rates (14%; 20/140) and long median survival times (371 days). The time to progression curves between the responder and stable disease were almost the same. The survival curves of the patients with stable disease of more than 90 days to progression (32 pts.) and responders were not significantly different.

Antimetabolites, Antineoplastic↗
PubMed2000

Differential expression and allelotyping of the p73 gene in neuroblastoma.

p73 has recently been identified as a candidate imprinted tumor suppressor gene in neuroblastoma. To determine the possible involvement of this gene in the pathogenesis of neuroblastoma, we analyzed allelic expression, screened for mutations and determined MYCN copy numbers in 31 primary neuroblastoma tumor samples. Interestingly, the gene was biallelically expressed in 50% (4/8) of informative neuroblastomas, which suggests that activation of the normally silenced allele of this gene plays an important role in the tumorigenesis of neuroblastoma. However, no tumor-specific mutations were identified although 15 polymorphisms were detected in this gene. We also detected a very strong association between a C91T polymorphism and MYCN copy number in this tumor. The T allele was detected in 8/17 (47%) neuroblastomas without MYCN amplifications but not detected in cases with MYCN amplifications (0/14). The biological significance of this association, however, is unknown. Overall the data suggest that p73 may play an important role in the pathogenesis of neuroblastoma but that the true tumor suppressor gene localized to this area still remains to be identified.

Alleles↗
PubMed2000

K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers--a review.

Multiple genomic alterations are involved in the development of most human cancers. They include alterations in oncogenes, tumor suppressor genes, DNA mismatch repair and excision repair genes. Genetic testing for susceptibility has been a part of the management of patients with well-defined but uncommon hereditary cancers in which certain susceptible gene mutations are determined in the germ line. However, a molecular diagnostic approach to sporadic cancers, which comprise the vast majority of malignant tumors in human beings, is still under development. One of the best characterized tumor-related genes is K-ras, which somatically mutates in several types of sporadic human cancers. Since mutations of this gene occur exclusively in three hot spots (codons 12, 13 and 61), and are frequently detected and well characterized in colorectal, pancreas and lung cancers, molecular diagnosis and susceptibility (risk) assessment targeting K-ras mutations are being developed. For this purpose, sample collection methods that reflect the state of the entire affected organ are important. Clinical samples used for molecular diagnosis and risk assessment include stool and lavage fluid, pancreatic and duodenal juices, and sputum and lavage fluids for colorectal, pancreas and lung cancers, respectively. The reported incidence of K-ras mutations detected in these samples ranges from 7% to 80% for colorectal cancers, 25% to 87% for pancreatic cancers, and 25% to 48% for lung cancers. Incidence of mutations clearly depends on the sensitivity of the method for detecting the mutant K-ras allele, as well as the nature and the quality of the clinical samples. Various methods including plaque hybridization, dot blot hybridization, combined PCR and RFLP or SSCP, and sensitive PCR have been used, and they exhibited high specificity (75 to 100%) in detecting mutations. Molecular analysis is demonstrating promise in assessing susceptibility to, or risk of developing, sporadic cancers.

Biomarkers, Tumor↗
PubMed2000

[Significance of prolonged NC as an endpoint of chemotherapy for solid tumors].

The goals of chemotherapy in patients with cancer should be both tumor shrinkage and extension of survival time. Believing that there is a clear correlation between the extent of treatment-induced tumor reduction and survival time, we have made an effort to reduce tumor size. However, many investigators have found no positive correlation between response rate and median survival time in various cancers, including non-small cell lung cancer and gastric cancer. If this is the case, we should reconsider our therapeutic strategy. We previously reported that doctors should induce a prolonged dormant phase rather than strive to shrink tumor mass in "Tumor Dormancy Therapy," because the survival of most patients with solid tumors depends on the length of the induced dormant phase rather than on induced tumor reduction. In this paper, we analyzed two Japanese phase II studies of gastric cancer. There were no significant differences between the survival of NC patients with TTP of more than 90 days and CR + PR patients in either study. These results suggest prolonged NC could contribute to longer survival, and we concluded that NC patients with greater than 90 days of TTP, that is "prolonged NC," exhibited similar survival relative to those with effective treatments and tumor shrinkage, and should be evaluated as a positive response.

Antineoplastic Agents↗
PubMed2000

[Weekly chemotherapy with alternating low-dose CPT-11 and low-dose FP against a far advanced pancreatic cancer--a case report].

We attempted a new regimen of weekly chemotherapy with alternating low-dose CPT-11 and low-dose FP against a case of far advanced pancreatic cancer with invasion to the super mesentric artery, celiac artery, and left renal vein. CPT-11 was administered at 25 mg/m2/day x 3/week, and CDDP and 5-FU were administered at 7 mg and 350 mg/m2/day x 3/week by intravenous infusion. These regimens were alternated every week. The serum CA19-9 level decreased gradually with a half time of approximately 2 months (from 972 to 126 U/ml). The tumor was reduced more than 50% 4 months after chemotherapy, and continuing decreasing for more than 6 months. There were no adverse effects except mild leukopenia (less than Grade 1). These results suggest that the combination of low-dose chemotherapy with fewer side effects may be effective not only for tumor shrinkage, but also for a prolonged time to progression.

Aged↗