Biomedical subjects

S Nishizuka

Publications and source records attributed to S Nishizuka.

At least 19 recordsLinked to original sources

PubMed2005

RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer.

RASSF2, a member of the RASSF1 family, has recently been identified as a potential tumour suppressor. We examined methylation status in multiple regions which included the CpG island and spanned the transcription start site of RASSF2 in 10 gastric cancer cell lines, as well as 78 primary gastric cancers and corresponding non-neoplastic gastric epithelia. Hypermethylation of RASSF2 in at least one of the regions examined was detected in seven (70%) of the 10 cell lines; two (20%) exhibited hypermethylation in all the regions examined including the transcription start site and lost expression of RASSF2 mRNA, which could, however, be restored by 5-aza-2' deoxycytidine treatment, while the other five (50%) cell lines exhibited hypermethylation at the 5'- and/or 3'- edge, with four of them expressing RASSF2 mRNA. In primary gastric cancers and corresponding non-neoplastic gastric epithelia, frequencies of RASSF2 methylation ranged from 29% (23 out of 78) to 79% (62 out of 78) and 3% (two out of 78) to 60% (47 out of 78), respectively, at different CpG sites examined. Methylation was frequently observed at the 5'- and 3'- edges, and became less frequent near the transcription start site in both the primary gastric cancers and corresponding non-neoplastic gastric epithelia. Hypermethylation near the transcription start site was mostly cancer-specific. We thus showed that RASSF2 is silenced by hypermethylation near the transcription start site in gastric cancer. Hypermethylation was found initially to occur at the 5'- and 3'- furthest regions of the CpG island in non-neoplastic gastric epithelia, to gradually spreads near the transcription start site to shut down RASSF2 expression, and ultimately to constitute a field-defect placing tissue increased risk for development of gastric cancer.

Adult↗

PubMed2004

Promoter hypermethylation of the Chfr gene in neoplastic and non-neoplastic gastric epithelia.

While chromosomal instability is a common feature of human solid tumours, no abnormalities in genes involved in the mitotic checkpoint have been identified. However, recently, Chfr (checkpoint with forkhead associated and ring finger), a mitotic stress checkpoint gene, has been reported to be inactivated due to promoter hypermethylation in several types of human malignancy. To clarify whether Chfr promoter hypermethylation is involved in gastric carcinogenesis, we investigated the promoter methylation status of the Chfr gene in gastric cancer cell lines and primary gastric cancers. Non-neoplastic gastric epithelia from cancer-bearing and noncancer-bearing stomachs were also examined for Chfr promoter hypermethylation to study its cancer specificity. Two of 10 gastric cancer cell lines (20%) showed Chfr promoter hypermethylation with resultant loss of expression, which could be restored by 5-aza-2' deoxycytidine treatment. Chfr promoter hypermethylation was present in 35% (25 of 71) of primary tumours and occurred at similar frequencies in early and advanced stages. As for non-neoplastic gastric epithelia, 1% (one of 91) from noncancer-bearing and 5% (four of 71) from cancer-bearing stomachs exhibited Chfr promoter hypermethylation. Thus, Chfr promoter hypermethylation is mostly cancer specific and frequently leads to chromosome instability in gastric cancer.

Adolescent↗

PubMed2004

Demethylation of MAGE promoters during gastric cancer progression.

Melanoma antigen (MAGE)-encoding genes are expressed in various tumour types via demethylation of their promoter CpG islands, which are silent in all non-neoplastic tissues except for the testis and placenta. The clinicopathological significance of demethylation of MAGE genes in gastric carcinoma is not known. We investigated the promoter methylation status of MAGE-A1 and -A3 in 10 gastric cancer cell lines and in surgical specimens from 84 gastric cancer patients by methylation-specific PCR (MSP). Expression of MAGE-A1 and -A3 in the 10 gastric cancer cell lines was also investigated by RT-PCR. Any correlation between the methylation status of the MAGE promoters and clinicopathological characteristics of the gastric cancer patients was then assessed. Eight of the 10 gastric cancer cell lines showed demethylation of both MAGE-A1 and -A3, and the remaining two cell lines did either of MAGE-A1 or -A3. Expression of MAGE-A1 and -A3 was confirmed in seven and nine of the 10 gastric cancer cell lines, respectively. The MAGE-A1 and -A3 promoters were demethylated in 29% (25 out of 84) and 66% (56 out of 84) of the gastric tumour specimens, respectively. Demethylation of both MAGE-A1 and -A3 promoters (n=22) was found more frequently in gastric cancer patients in advanced clinical stages (P=0.0035), and these patients also exhibited a higher incidence of lymph node metastasis (P=0.0007) compared to those patients without demethylation (n=25). Furthermore, demethylation patients tended to have a worse prognosis, although this difference was not statistically significant (P=0.183). Demethylation of MAGE-A1 and -A3 occurs during progressive stages of gastric cancer, and may be associated with aggressive biological behaviour of gastric cancer.

Adenocarcinoma↗

PubMed2001

Detection of differentially expressed genes in HeLa x fibroblast hybrids using subtractive suppression hybridization.

To understand genetic differences and similarities between tumorigenic and nontumorigenic HeLa x fibroblast hybrid cells, subtractive suppression hybridization (SSH), based on suppression PCR and a combination of normalization and subtraction in a single procedure, was used. Using the nontumorigenic CGL1 and tumorigenic CGL3, forward (CGL1-CGL3) and reverse (CGL3-CGL1) subtracted libraries were constructed. Among 192 clones, seven were identified as differentially expressed genes specific for either CGL1 or CGL3. All seven were not reported previously as differentially expressed genes in this hybrid system. In the forward subtraction, p16 was isolated, indicating the involvement of the loss of tumorigenic phenotype. Subsequent transfection of wild-type p16 to the tumorigenic CGL3 showed growth suppression in colony formation assay; however, no tumor suppression was observed when the transfectant was inoculated into nude mice. These results indicate that: (a) SSH is a suitable method to identify differentially expressed genes in two types of cells; and (b) although p16 plays some roles in growth suppression, the p16-transfected CGL3 is still capable to proliferate in vivo.

Animals↗

PubMed2001

Oligonucleotide microarray expression analysis of genes whose expression is correlated with tumorigenic and non-tumorigenic phenotype of HeLa x human fibroblast hybrid cells.

In order to understand the differences and similarities between tumorigenic and non-tumorigenic HeLaxhuman fibroblast hybrids, gene expression profiles were examined with synthetic oligonucleotide arrays containing nearly 7000 gene probe sets. We used two pairs of genetically related hybrids, each pair representing individual clones of non-tumorigenic and tumorigenic segregant hybrids, respectively. Analysis of six possible comparisons, utilizing two algorithms, identified 204 genes with differential expression. The greater number of differentially expressed genes was observed when non-tumorigenic hybrids were compared with tumorigenic segregants. Fifteen and 14 genes, respectively, were consistently found to be differentially expressed in non-tumorigenic and tumorigenic cells. Among those 29 differentially expressed genes, three (intestinal alkaline phosphatase, caveolin-1, and solute carrier family2, member3) have been reported previously to be associated with the tumorigenic phenotype, using the same hybrid pairs. In addition, among the genes previously detected by differential display, 78% of them exhibited more than 5-fold change, demonstrating a high consistency between the two methods of differential gene expression. These findings suggest that synthetic oligonucleotide arrays are a powerful and highly reproducible tool to identify those genes whose expression is associated with certain phenotypes.

Algorithms↗

PubMed2001

Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia.

A significant portion of gastric cancers exhibit defective DNA mismatch repair, manifested as microsatellite instability (MSI). High-frequency MSI (MSI-H) is associated with hypermethylation of the human mut-L homologue 1 (hMLH1) mismatch repair gene promoter and diminished hMLH1 expression in advanced gastric cancers. However, the relationship between MSI and hMLH1 hypermethylation has not been studied in early gastric neoplasms. We therefore investigated hMLH1 hypermethylation, hMLH1 expression and MSI in a group of early gastric cancers and gastric adenomas. Sixty-four early gastric neoplasms were evaluated, comprising 28 adenomas, 18 mucosal carcinomas, and 18 carcinomas with superficial submucosal invasion but clear margins. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, D5S346, D17S250, BAT 25 and BAT 26. Methylation-specific PCR was performed to determine the methylation status of hMLH1. In two hypermethylated MSI-H cancers, hMLH1 protein expression was also evaluated by immunohistochemistry. Six of sixty-four early gastric lesions were MSI-H, comprising 1 adenoma, 4 mucosal carcinomas, and 1 carcinoma with superficial submucosal invasion. Two lesions (one adenoma and one mucosal carcinoma) demonstrated low-frequency MSI (MSI-L). The remaining 56 neoplasms were MSI-stable (MSI-S). Six of six MSI-H, one of two MSI-L, and none of thirty MSI-S lesions showed hMLH1 hypermethylation (P<0.001). Diminished hMLH1 protein expression was demonstrated by immunohistochemistry in two of two MSI-H hypermethylated lesions. hMLH1 promoter hypermethylation is significantly associated with MSI and diminished hMLH1 expression in early gastric neoplasms. MSI and hypermethylation-associated inactivation of hMLH1 are more prevalent in early gastric cancers than in gastric adenomas. Thus, hypermethylation-associated inactivation of the hMLH1 gene can occur early in gastric carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Molecular characterization of undifferentiated-type gastric carcinoma.

As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.

Cadherins↗

PubMed2001

Localization of mitochondrial ribosomal RNA on the chromatoid bodies of marine planarian polyclad embryos.

Electron-dense cytoplasmic structures, referred to as chromatoid bodies, are observed in the somatic stem cells, called neoblasts, and germline cells in adult planarians. Although it has been revealed that the chromatoid bodies morphologically resemble germline granules in Drosophila and Xenopus embryos, what essential role it plays in the planarian has remained unclear. In the present study, to examine whether chromatoid bodies in planarian embryos are responsible for germline formation, the presence and behavior of chromatoid bodies during embryogenesis were examined. Mitochondrial large ribosomal RNA and mitochondrial small ribosomal RNA were used as candidate markers for components of the chromatoid body. Starting from the fertilized egg, extramitochondrial signals of both RNA (mtrRNA) were observed. At the ultrastructural level, mtrRNA were localized on the surface of the chromatoid bodies. At subsequent stages, the signals of mtrRNA were observed in certain restricted blastomeres that contribute to the formation of larval structures. The signals gradually decreased from the gastrula stage. These results suggest that the chromatoid bodies associated with mtrRNA in embryogenesis are not germline granules. The chromatoid bodies of blastomeres may be concerned with the toti- or pluripotency and cell differentiation as proposed in adult planarian neoblasts.

Animals↗

PubMed2001

Examination of the oncogenic potential of H19 gene in HeLa x normal human fibroblast hybrid cells.

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in chromosomally stable non-tumorigenic hybrids. The studies of rare spontaneous tumorigenic segregants from the non-tumorigenic hybrid have implicated the loss of one copy of human fibroblast chromosome 11 with concomitant re-expression of tumorigenicity. In a previous study of differential display screening, we reported the tumorigenic-specific expression of H19 gene as a possible candidate for elicitation of tumorigenic phenotype. In this study, we examined the expression of H19 gene using gamma-ray-induced tumorigenic mutants (GIMs) and non-tumorigenic irradiated control cells (CONs) from the non-tumorigenic hybrids. H19 expression was recognized in all the GIMs with various expression levels, whereas no CONs expressed the H19 gene. To examine the tumorigenic potentials of H19 gene directly, we introduced an H19 gene expression vector into the non-tumorigenic hybrids and assayed the tumorigenicity of the transfectants by s.c. injection into athymic nude mice. However, no transfectants with stable H19 gene expression induced in vivo tumor growth. These results suggest that expression of the H19 gene may be necessary but is not sufficient to confer the tumorigenic phenotype in HeLa x fibroblast hybrids.

Animals↗

PubMed2000

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia.

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

Adolescent↗

PubMed2000

E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas.

BACKGROUND: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas. METHODS: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)-single-strand conformation polymorphism (MSP-SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided. RESULTS: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP-SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P =.0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P =.73, Fisher's exact test). Methylation occurring at all cytosine-guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite-DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation. CONCLUSIONS: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.

Blotting, Western↗

PubMed1999

Differential gene expression in tumorigenic and nontumorigenic HeLa x normal human fibroblast hybrid cells.

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in chromosomally stable hybrids that are nontumorigenic and no longer express the HeLa tumor-associated marker intestinal alkaline phosphatase (IAP). Previous studies of spontaneous tumorigenic segregants from the nontumorigenic hybrids implicated the loss of one copy of human fibroblast chromosome 11 in the concomitant reexpression of tumorigenicity. In an attempt to identify genes involved in the control of tumorigenic expression, we performed differential display screening of nontumorigenic hybrid cells and tumorigenic segregants. Subsequent northern blot analyses reproducibly showed 17 differentially expressed genes, eight of which were expressed differentially in the nontumorigenic hybrids and nine of which were expressed differentially in the tumorigenic hybrids. The former were genes for 80K-L protein (a substrate of protein kinase C), AXL/UFO (a receptor tyrosine kinase), insulin-like growth factor binding protein 3, apolipoprotein AI regulatory protein, collagen type I alpha-2 chain, transforming growth factor-beta-induced gene product 3 (BIGH3), pregnancy-specific beta-1-glycoprotein, and fibroblast activation protein alpha. The latter nine genes were genes for serum/glucocorticoid-regulated kinase (SGK; a serine/threonine protein kinase), PTPCAAX1 (a tyrosine phosphatase), CXCR-4 (a G-protein-coupled membrane receptor), L-kynurenine hydrolase, beta-1, 4-galactosyltransferase, keratin 8, keratin 17, and H19 and a novel gene. The differential expression of these genes provided several interesting candidates for regulation of tumorigenic expression, including those involved in signal transduction and the extracellular matrix, cytoskeletal proteins, cell-surface enzyme, and the H19 gene.

Cells, Cultured↗

PubMed1999

Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.

The non-coding control region of mitochondrial DNA (mtDNA), containing the hypervariable regions HV1 and HV2 and the D-loop region, was screened for mutations in 45 gastric tumours (15 tumours each of adenoma, differentiated adenocarcinoma and undifferentiated carcinoma). We found mutations in two of the 45 tumours (4%); a 1 bp A deletion at nucleotide position 248 in a differentiated adenocarcinoma and a G to A transition at nucleotide position 16,129 in an adenoma. We also observed 10 polymorphisms, four of which were not previously recorded. Both mtDNA mutations were present in replication error negative (RER-) tumours. Short mono- or dinucleotide repeats in the control region, such as (C)7, (A)5 or (CA)5, were not altered regardless of nuclear genetic instability. In summary, mtDNA is mutated in a subset of benign and malignant gastric tumours, but, disruption of the mtDNA repair system appears not to be significantly involved in gastric tumours of Japanese patients.

DNA Repair↗

PubMed1998

Tissue-specific involvement of multiple mitochondrial DNA deletions in familial mitochondrial myopathy.

It is still uncertain how deleted mitochondrial DNA (mtDNA) is distributed to each tissue during development, although deletions of mtDNA have been extensively observed in various pathologic conditions. This paper presents two Japanese siblings with progressive external ophthalmoplegia exhibiting multiple mtDNA deletions. In one patient, similar multiple mtDNA deletions were found in skeletal muscle specimens as well as in the spinal cord but not in the myocardium, liver or leukocytes. A similar deletion pattern was found in the skeletal muscle but not in the leukocytes of the other patient. The results suggest the complex mechanism to generate, expand and eliminate the deleted mtDNA in humans.

Adult↗

PubMed1998

Loss of heterozygosity during the development and progression of differentiated adenocarcinoma of the stomach.

In a recent allelotypic analysis of differentiated adenocarcinoma of the stomach, loss of heterozygosity (LOH) was found frequently on chromosomes 2q, 4p, 5q, 6p, 11q, 14q, 17p, 18q, and 21q. To clarify the sequence of these chromosomal losses during gastric carcinogenesis, microsatellite analysis of the chromosome arms described above was performed in 25 early and 29 advanced differentiated adenocarcinomas of the stomach. LOH on these chromosome arms fell within a range of 20-50 per cent. On 4p, 7q, 14q, 17p, and 21q, LOH was detected at a similar frequency in both early and advanced carcinomas, while LOH on 2q, 5q, 6p, 11q, and 18q was observed more than twice as frequently in advanced than in early lesions. Mean fractional allelic losses (FALs) were 0.221 in early and 0.413 in advanced carcinomas, representing a significant difference P < 0.05). These results suggest that LOH on 4p, 7q, 14q, 17p, and 21q is a relatively early event, while LOH on 2q, 5q, 6p, 11q, and 18q typically accumulates during the progression of gastric carcinogenesis.

Adenocarcinoma↗

PubMed1998

Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs.

Frequent frameshift mutations of simple nucleotide repeats in the protein-encoding regions, as well as replication errors (RERs) at microsatellite loci, have recently been demonstrated in gastrointestinal tumors. These genetic instabilities have been considered indicative of an increased risk of accumulating mutations in cancer-associated genes and of developing multiple cancers. We studied frameshift (or insertion/deletion) mutations of simple nucleotide repeats in five genes (TGFbeta type II receptor [TGFbetaRII], E2F4, MSH2, MSH3, and MSH6) in 23 tumors from 12 patients who had synchronous cancers of the esophagus and other organs. Genetic instability at four microsatellite loci, as well as mutations in the TP53, APC, and KRAS2 genes, were also studied. No frameshift mutations were observed in the TGFbetaRII, MSH3, and MSH6 genes. RER and a deletion mutation of BAT26 in MSH2 were present in one (1/23; 4%) gastric cancer. This tumor also carried a deletion mutation in the serine (AGC) repeat of the E2F4 gene. Mutation screening of the TP53, APC, and KRAS2 genes revealed that the synchronous cancers did not carry the same mutations. Our results suggested that genetic instability, such as insertion/deletion mutations in simple nucleotide repeats, is not significantly associated with the development of multiple primary cancers of the esophagus and other organs, and that these synchronous cancers developed independently according to their different environmental factors.

Colonic Neoplasms↗

PubMed1998

Mutations in the human homologue of the Drosophila patched gene in esophageal squamous cell carcinoma.

The human homologue (PTCH) of the Drosophila segment polarity gene patched has recently been identified as a tumor-suppressor gene for nevoid basal cell carcinoma syndrome and for sporadic basal cell carcinomas of the skin. We analyzed 30 esophageal squamous cell carcinomas (ESCC) for intrageneic mutations of the PTCH gene by polymerase chain reaction-single-strand conformation polymorphism analysis followed by DNA sequencing. We identified two somatic PTCH mutations (7%) in 30 ESCC. These were a nonsense mutation (CAG to TAG at codon 361) in exon 8 and a missense mutation (CAG to CTG, Gln to Leu at codon 816) in exon 14. These tumors exhibited loss of heterozygosity at the polymorphic site of the PTCH gene. These results indicate that inactivation of the PTCH gene via a two-hit mechanism occurs in a subset of ESCC.

Amino Acid Substitution↗

PubMed1998

[Pharmacokinetic analysis of low-dose intra-peritoneal cis-platinum administration].

Pharmacokinetic parameters after intra-peritoneal administration of low-dose cis-platinum (CDDP) were analysed in order to evaluate the possibility of applying low-dose 5-FU/CDDP therapy (1-FP) for outpatients. Four patients with advanced gastric cancer were the subjects of this study. CDDP at a dose of 20 mg/body was administered intra-peritoneally, and peripheral venous blood was collected at 30 min, 4, 8, 24, 48, 72, 96 and 120 hr after drug administration. The plasma platinum (Pt) concentration was determined by atomic absorption spectrometry. Pharmacokinetic parameters were calculated using a two-compartment open model. C max, AUC, t1/2 alpha and t1/2 beta of total-Pt were 1. 27 +/- 0.21 micrograms/ml, 95.28 +/- 16.93 micrograms.hr/ml, 1.91 +/- 0.76 hr and 190.2 +/- 125.6 hr, respectively. Total-Pt concentration at 120 hr, after administration was 0.54 +/- 0.14 microgram/ml. This result suggests that intraperitoneal low-dose CDDP administration is a promising method for 1-FP therapy for outpatients, because the plasma total-Pt level is maintained at a sufficiently high level for a long period.

Aged↗