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Biomedical subjects

K Shimokata

Publications and source records attributed to K Shimokata.

At least 37 records · Page 2Linked to original sources
PubMed2000

Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.

Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.

Adult↗
PubMed2000

Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRgamma-deficient mice.

Several recent studies have demonstrated the central role of Fc receptors (FcR) rather than the complement system in triggering hypersensitivity reactions. We investigated the role of FcR for IgG (FcgammaR) using a murine model of accelerated anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis as a representative of type II hypersensitivity diseases. Intravenous injection of rabbit anti-GBM antibody after preimmunization with normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and CD40(+/-) mice but not in FcR gamma chain (FcRgamma)(-/-) mice or CD40(-/-) mice. Light microscopic findings revealed marked tissue damage in the glomeruli of wild-type C57BL/6 and CD40(+/-) mice. However, no tissue damage except polymorphonuclear cell infiltration was observed in the glomeruli of FcRgamma(-/-) mice. The glomeruli of CD40(-/-) mice were almost normal. Immunohistochemistry revealed the binding of rabbit IgG to the GBM in all mice injected with anti-GBM antibody. However, depositions of mouse IgG and complement to the glomeruli were not observed in CD40(-/-) mice, and deposition of fibrin was not observed in FcRgamma(-/-) or CD40(-/-) mice. These findings suggest that FcgammaR may initiate anti-GBM antibody-mediated renal disease. We conclude that FcgammaR rather than the complement system is critically involved in the development of type II hypersensitivity diseases.

Animals↗
PubMed2000

In vivo development of decreased susceptibility to vancomycin in clinical isolates of methicillin-resistant Staphylococcus aureus.

To investigate the possibility of in vivo development of decreased vancomycin susceptibility, the vancomycin susceptibilities of 12 methicillin-resistant Staphylococcus aureus (MRSA) isolates serially recovered from six patients with vancomycin therapy were tested by standard MIC determination method and population analysis. While all of the MRSA isolates were susceptible to vancomycin (MICs, 1-2 microg/ml) by standard method, population analysis showed the upward shifts indicating decreased vancomycin susceptibility among serial isolates from two patients. These bacteria with decreased vancomycin susceptibility could be selected by using vancomycin selection of pre-therapy isolates under laboratory conditions. Furthermore, the reversion phenomenon of decreased vancomycin susceptibility was confirmed after 20 serial passages of the post-therapy isolates on drug-free agar. These data suggest that in vivo isolates may develop decreased vancomycin susceptibility that is not of such magnitude to cross a breakpoint threshold. This resistance may be unstable, and appears to result from a selective or inducible process that occurs in MRSA clinical strains during vancomycin therapy.

Aged↗
PubMed2000

Avoidance of bone marrow suppression using A-5021 as a nucleoside analog for retrovirus-mediated herpes simplex virus type I thymidine kinase gene therapy.

Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene combined with an anti-herpes drug, ganciclovir (GCV), has been applied for human diseases, especially for cancer treatment. However, bone marrow toxicity has been the most consistent adverse effect of GCV treatment in clinical settings. We evaluated the cytotoxic activity of a novel guanosine analog, (1'S,2'R)-9[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanin e (A-5021), against retrovirus-mediated HSV-TK gene-transduced human lung cancer cells. The bone marrow toxicity of A-5021 and GCV was studied by colony formation assay in both rodent and human bone marrow specimens. We demonstrated that A-5021 had potent cytotoxic activity equal to that of GCV against the retroviral vector-mediated HSV-TK gene-transduced lung cancer cell lines. Further, phosphorylated A-5021 could be transferred to neighboring cells, and this analog killed HSV-TK- neighboring cells, as was the case for GCV. In contrast, A-5021 did not exhibit an inhibitory effect on bone marrow progenitor cells and colony formation (the 50% inhibitory concentration of the colony-forming units in culture = >100 microg/mL in human bone marrow specimens and >66 microg/mL in rodent bone marrow specimens). These results indicate that A-5021 has potent cytotoxic activity as a nucleoside analog for gene therapy using HSV-TK gene, and can be used much more safely than GCV.

Adenocarcinoma↗
PubMed2000

Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells.

The infection of recombinant adenovirus expressing wild-type p53 (Ad-p53) to lung cancer cells that harbor mutant p53 genes improves their response to cis-diamminedichloroplatinum(II). In this study, we tested whether this improvement in response is also seen in wild-type p53 (wt-p53)-containing cancer cells and whether this phenomenon is universal with other commonly used chemotherapeutic agents, including etoposide, 7-ethyl-10-hydrocycamptothecin, paclitaxel, and docetaxel. Using a panel of 7 non-small cell lung cancer cell lines with wild-type (2) or abnormal (2 null, 3 point-mutated) p53, we examined in vitro cytotoxicity using a tetrazolium-based colorimetric assay (3-(4,5-diethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide assay) and analyzed the combined effects of Ad-p53 and chemotherapeutic agents using the isobologram method. Ad-p53 and DNA-damaging agents (cis-diamminedichloroplatinum(II), etoposide, and 7-ethyl-10-hydrocycamptothecin) showed synergistic effects in six of seven cell lines but additive effects against a p53-mutated cell line. In contrast, Ad-p53 showed additive effects with the antitubulin agents (paclitaxel and docetaxel) in all four of the cell lines tested. Furthermore, we examined this synergistic interaction between Ad-p53 and DNA-damaging agents by flow cytometric analysis and DNA fragmentation analysis. Both analyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by DNA-damaging agents in six of seven cell lines. Our results suggest that Ad-p53 may synergistically enhance the chemosensitivity of the majority of non-small cell lung cancers to DNA-damaging agents due to augmentation of apoptosis.

Adenoviridae↗
PubMed2000

Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer.

Mitotic checkpoint defects of the cell cycle have been implicated in the development of human cancers. Since hBUB1 and hBUBR1, whose products function in the spindle checkpoint pathway, have been shown to be mutated in a subset of colon cancers with chromosomal instability, we investigated the contribution of these genes to lung cancer development. One hundred and two lung cancer (50 small cell lung cancers and 52 non-small cell lung cancers) and 4 mesothelioma cell line DNAs were analyzed by Southern blot analysis, but no rearrangements or deletions of hBUB1 and hBUBR1 were detected. Using single strand conformation polymorphism analysis, we studied all the 25 exons except exon 1 of the hBUB1 gene in 88 lung cancer DNAs. One lung cancer cell line, NCI-H345, showed a single nucleotide substitution, which resulted in an Arg-to-Gln change at codon 209 (CGA to CAA). Eleven cell line DNAs exhibited a single nucleotide polymorphism in intron 9 of hBUB1, all of which were heterozygous. Similar mutation analysis of hBUBR1 in 47 lung cancer cell line cDNAs revealed a frequent polymorphism at codon 349 (CAA to CGA) leading to a substitution of Gln to Arg but no mutations. Northern blot analyses showed that both hBUB1 and hBUBR1 genes were expressed in all of 31 lung cancer cell lines tested with no significant difference in the expression level. Our results suggest that alterations in hBUB1 and hBUBR1 rarely contributed to the genetic change of lung cancers.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Multi-institutional validation study of carboplatin dosing formula using adjusted serum creatinine level.

Creatinine clearance (Ccr) is widely used as a practical substitute for glomerular filtration rate (GFR) in the Calvert formula: carboplatin dose (mg) = target area under the concentration versus time curve (AUC, mg ml(-1) min) x [GFR (ml min(-1)) + 25]. However, it causes systematic overdosing when the creatinine levels are measured by an enzymatic peroxidase-antiperoxidase method (PAP-Cr). We previously suggested an amended dosing formula to adjust this overdosing: carboplatin dose (mg) = AUC (mg ml(-1) min) x [adjusted Ccr (ml min(-1)) + 25], where the Ccr was adjusted by adding 0.2 (mg dl(-1)) to serum PAP-Cr. In this study, we prospectively validated this formula in 55 patients from six institutions. Target AUC ranged from 3 to 7 mg ml(-1) min, and Ccr was measured by 24-h urine collection. Estimation of carboplatin clearance with the amended formula was unbiased [mean prediction error (MPE) +/- SE = 2.9 +/- 3.4%] and acceptably precise [root mean squared error, (RMSE) = 24.7%], whereas the Calvert formula using non-adjusted Ccr overpredicted carboplatin clearance systematically (MPE +/- SE = 24.9 +/- 4.9% and RMSE = 36.1%). The improvement in the bias and precision of the estimation was seen in all of the participating institutions as shown by decrease in the absolute value of MPE and RMSE for each institution. The Chatelut formula also highly overestimated carboplatin clearance when PAP-Cr was used, but the adjustment of PAP-Cr yielded a decrease in MPE by 30.4% and in RMSE by 21.3%. These results confirmed the necessity of adjusting the serum PAP-Cr in carboplatin dosing formulas.

Adult↗
PubMed1999

Gas chromatographic-mass spectrometric analysis of erythrocyte 3-deoxyglucosone in hemodialysis patients.

The erythrocyte levels of 3-deoxyglucosone (3-DG) were measured by a selected ion monitoring method of gas chromatography-chemical ionization mass spectrometry using [13C6]-3-DG as an internal standard. Because the erythrocyte levels of 3-DG measured after deproteinization using ethanol were 18 times higher than those using ultrafiltration, we used ethanol deproteinization for measurement of total 3-DG in the erythrocytes. The concentration of 3-DG was significantly elevated in hemodialysis (HD) patients compared with healthy subjects. Although HD treatment could remove the erythrocyte 3-DG efficiently, its post-HD levels were still elevated compared with the healthy subjects.

Aged↗
PubMed1999

Constrictive bronchiolitis obliterans and paraneoplastic pemphigus.

Constrictive bronchiolitis obliterans is rare, and the pathogenesis of the disease often remains unknown. This study reports on the case of a 38 yr-old female with constrictive bronchiolitis obliterans and paraneoplastic pemphigus associated with malignant lymphoma. The patient developed progressive obstructive lung disease. The chest radiograph showed almost normal lungs. Paraneoplastic pemphigus is a newly described syndrome in which patients have autoantibodies binding to some epithelia, including in the respiratory tract. The disease develops in association with non-Hodgkin's lymphomas or other malignant neoplasms. The case presented here suggests that constrictive bronchiolitis obliterans associated with paraneoplastic pemphigus may be one of the facets of autoimmune responses in this context.

Adult↗
PubMed1999

Increased erythrocyte 3-DG and AGEs in diabetic hemodialysis patients: role of the polyol pathway.

BACKGROUND: 3-Deoxyglucosone (3-DG) accumulating in uremic serum plays an important role in the formation of advanced glycation end products (AGEs). To determine if 3-DG is involved in the formation of intracellular AGEs, we measured the erythrocyte levels of 3-DG and AGEs such as imidazolone and N epsilon-carboxymethyllysine (CML) in hemodialysis (HD) patients with diabetes. Further, to determine if the polyol pathway is involved in the formation of erythrocyte 3-DG and AGEs, an aldose reductase inhibitor (ARI) was administered to these patients. METHODS: The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were measured in ten diabetic HD patients before and after treatment with ARI (epalrestat) for eight weeks, and were compared with those in eleven healthy subjects. 3-DG was incubated in vitro with hemoglobin for two weeks to determine if imidazolone and CML are formed by reacting 3-DG with hemoglobin. RESULTS: The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were significantly elevated in diabetic HD patients as compared with healthy subjects. The erythrocyte levels of 3-DG significantly decreased after HD, but sorbitol, imidazolone or CML did not. The administration of ARI significantly decreased the erythrocyte levels of sorbitol, 3-DG and imidazolone, and tended to decrease the CML level. Imidazolone was rapidly produced in vitro by incubating 3-DG with hemoglobin, and CML was also produced, but less markedly as compared with imidazolone. CONCLUSION: The erythrocyte levels of 3-DG and AGEs are elevated in diabetic HD patients. The administration of ARI reduces the erythrocyte levels of 3-DG and AGEs, especially imidazolone, as well as sorbitol. Thus, 3-DG and AGEs, especially imidazolone, in the erythrocytes are produced mainly via the polyol pathway. ARI may prevent diabetic and uremic complications associated with AGEs.

Adult↗
PubMed1999

Oral adsorbent ameliorates renal TGF-beta 1 expression in hypercholesterolemic rats.

BACKGROUND: A spontaneously hypercholesterolemic Imai rat has recently been reported as a model of focal glomerulosclerosis that causes nephrotic syndrome followed by renal failure. This study was designed to determine if an oral adsorbent, AST-120, ameliorates renal lesions and TGF-beta 1 expression in the rats. METHODS: AST-120 was given orally to the Imai rats for 32 weeks, and renal function and pathology were compared between the AST-120-administered and control Imai rats. RESULTS: AST-120-administered rats showed significantly lower level of blood urea nitrogen, serum creatinine, urinary protein, serum total-cholesterol, serum triglyceride, and serum and urinary indoxyl sulfate, and significantly higher levels of serum albumin and creatinine clearance than control rats. AST-120 reduced the glomerular sclerosis index, interstitial fibrosis area, and the extent of glomerular lipid deposition. Immunohistochemistry demonstrated that AST-120 reduced the expression of transforming growth factor (TGF)-beta 1 and tissue inhibitor of metalloproteinase (TIMP)-1 as well as interstitial infiltration of macrophages in the renal cortex of the Imai rats. CONCLUSIONS: AST-120 prevented the progression of nephrotic syndrome and renal failure in the Imai rats by ameliorating glomerular sclerosis and interstitial fibrosis, accompanied with reduced expression of TGF-beta 1 and TIMP-1, and reduced infiltration of macrophages in the kidneys.

Administration, Oral↗
PubMed1999

Prognostic factors for short-term survival in patients with stage IV non-small cell lung cancer.

Prognostic factors which can forecast short-term survival in patients with stage IV non-small cell lung cancer have not been well evaluated. Characteristics of such factors may be different from those for overall survival, and would be an important eligibility criterion for clinical trials of chemotherapy. We retrospectively analyzed the data of 158 patients with stage IV non-small cell lung cancer whose performance status was 0, 1 or 2. Univariate and multivariate logistic regression models revealed demographic variables which significantly correlated with the survival at 8 or 12 weeks. The univariate model showed the following significant variables: T factor, N factor, number of organs with metastases, grade of performance status, weight loss within 6 months, evidence of metastasis either at bone or lymph node, and lactate dehydrogenase level. The subsequent multivariate model demonstrated that both grade of performance status under 2 and number of metastasized organs less than 3 are important factors for 8- or 12-week survival. The survival rate in patients meeting the two criteria (grade of performance status under 2 and number of metastasized organs less than 3) and in those meeting only one of them was 93% versus 80% at 8 weeks (P = 0.030) and 88% versus 62% at 12 weeks (P < 0.001), respectively. Grade of performance status and number of organs with metastases appear to be important prognostic factors for short-term survival in patients with stage IV non-small cell lung cancer.

Adult↗