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Yasuo Sakamoto

Publications and source records attributed to Yasuo Sakamoto.

8 recordsLinked to original sources
PubMed2005

MEN4901/T-0128, a new camptothecin derivative-carboxymethyldextran conjugate, has potent antitumor activities in a panel of human tumor xenografts in nude mice.

PURPOSE: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. EXPERIMENTAL DESIGN: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. RESULTS: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. CONCLUSIONS: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

Animals↗
PubMed2005

Transcriptional repression and heterochromatin formation by MBD1 and MCAF/AM family proteins.

DNA methylation cooperates with methylation at lysine 9 of histone H3 (H3-K9), a modified histone molecule that is targeted by heterochromatin protein 1, to form a transcriptionally silent chromatin. Methyl CpG-binding protein MBD1 recognizes methylated CpG dinucleotide and recruits H3-K9 methyltransferases such as SETDB1 to genomic regions. Here we show that MBD1-containing chromatin-associated factor (MCAF) 1, also known as the human homologue of murine ATFa-associated modulator (AM), is required for transcriptional repression and heterochromatin formation by MBD1, together with the involvement of SETDB1. Moreover, the amino acid sequence of MCAF1 shows similarity to a number of sequences of the MCAF/AM-related proteins, resulting in the identification of a new member of the protein family, termed MCAF2. Immunoprecipitation and in vitro binding analyses reveal that both MCAF proteins interact with MBD1, SETDB1, and Sp1 via two evolutionarily conserved distinct domains. Furthermore, MCAF1 enhances transcriptional repression by MBD1 together with SETDB1, and exogenous expression of MCAF2 partly compensates for the repressive activity in MCAF1 knockdown HeLa cells. The expression of MBD1 mutant, which lacks interaction with MCAF proteins, perturbs heterochromatin protein 1-enriched heterochromatin formation at the MBD1-containing chromosomal loci. These data suggest that MBD1.MCAF1.SETDB1 complex facilitates the formation of heterochromatic domains, emphasizing the role of MCAF/AM family proteins in epigenetic control.

Amino Acid Sequence↗
PubMed2004

Dependence of chemotherapy response on p53 mutation status in a panel of human cancer lines maintained in nude mice.

In contrast to findings in vitro, the clinical response to anticancer chemotherapy is not simply associated with the p53 mutation status. To analyze the relationship between the actual response of solid tumors with p53 mutation and other biological characteristics, we used a human cancer-nude mouse panel of 21 lines derived from stomach, colorectal, breast, lung, and liver cancers for experimental chemotherapy. We examined the tumor growth rates of the cancer lines and the effects of nine drugs in clinical use, namely, mitomycin C (MMC), cisplatin (CDDP), nimustine hydrochloride (ACNU), irinotecan (CPT-11), cyclophosphamide (CPA), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), a 4:1 mixture of uracil and FT-207 (UFT), 5'-deoxy-5-fluorouridine (5'-DFUR), and adriamycin (ADM), on these tumors. The chemotherapy response was expressed as the tumor growth inhibition rate (IR). The genomic DNA sequences of the p53 gene in exons 5 through 8 were analyzed in these cancer tissues, and p53 mutations were detected in 10 of the 21 cancer lines (48%). Resistance to MMC was observed in p53 mutant tumors with smaller IRs than those for wild-type tumors (57.7% vs. 79.9%, P < 0.03). No significant differences were noted with the other eight drugs. To explore the role of the p53 function in the chemotherapy response, we calculated the correlation coefficients between chemosensitivity and tumor growth rate separately in p53 mutant and wild-type groups. In the p53 wild-type group, we found a positive correlation for the following drugs: ADM (P < 0.02), ACNU (P < 0.007), CPA (P < 0.011), UFT (P < 0.012), and FT-207 (P < 0.02). In the p53 mutant group, only CPA (P < 0.003) showed a positive correlation. The kinetics suggests that in the wild-type tumors, DNA damage caused by anticancer drugs occurs proportionally to the rate of DNA synthesis, and p53-mediated apoptosis is subsequently induced. The low frequency of positive correlation in the p53 mutant tumors is compatible with the loss of function or malfunction of mutant p53. The present results provide kinetic evidence that p53 function affects the response to anticancer drugs. Preserved p53 function tended to confer good chemosensitivity on rapidly growing tumors. However, the p53 mutation status did not seem to be suitable for use as an exclusive indicator to predict the chemotherapy response of human cancer xenografts.

Animals↗
PubMed2004

Epigenetic system: a pathway to malignancies and a therapeutic target.

Cancer cells possess both genetic and epigenetic alterations that dysregulate essential cellular processes, leading to disordered cell proliferation and differentiation. Oncogenes and tumor suppressor genes have been found to be activated and inactivated, respectively, in malignant cells. Epigenetic regulation of the genome is mediated by interactions between DNA methylation, chromatin, and modifications of histones and various transcriptional regulators. Recent studies have shown that some components of the epigenetic system as well as epigenetically mutated genes are diagnostic and therapeutic targets in cancer. We discuss the molecular basis of the epigenetic mechanism in association with the development of cancer.

DNA Methylation↗
PubMed2002

Anti-tumor effect of intraperitoneal administration of cisplatin-loaded microspheres to human tumor xenografted nude mice.

This study evaluates the anti-tumor effect of cisplatin-loaded microspheres (CDDP-MS) against peritoneal carcinomatosis using human tumor xenografts. The incorporated CDDP was released from CDDP-MS for 3 weeks in vivo as well as in vitro. CDDP-MS at a dose of 35 mg/kg (at maximal tolerable dose (MTD)) showed effective anti-tumor activity (tumor growth inhibition rate (IR)=70.3%) against Li-7 (human liver cancer) xenografts transplanted into the peritoneal cavity. This procedure also resulted in increased life span (ILS (%)=47.2%), whereas CDDP dissolved in saline solution (CDDP-SOL) at a dose of 8 mg/kg (at MTD) was ineffective (IR=15.7%, ILS=2.6%). Likewise, CDDP-MS (35 mg/kg) significantly prolonged the mean survival time (ILS=50.8%) compared with a CDDP-SOL group (8 mg/kg) (ILS=13.1%) in the mice with Li-7 xenografts transplanted into the spleen. Furthermore, CDDP-MS showed markedly effective anti-tumor activity (IR=82.2%) against H-154 (human stomach cancer) xenografts, in which CDDP-SOL was effective (IR=69.5%) at the MTDs. The suppressive effect of CDDP-MS on accumulation of malignant ascites was intimately related to unchanged CDDP concentration in ascites. These results demonstrated that the administration of CDDP-MS resulted in an unchanged CDDP concentration in ascites, and induced a sustained tumor growth inhibition along with a prolonged survival time.

Animals↗
PubMed2002

The effects of protective eyewear on glare and crystalline lens transparency.

PURPOSE: Sunglasses have generally been used to protect against glare. Various kinds of sunglasses which correspond to the visual environment are on the market (e.g. for driving, fishing, skiing, etc.). As for the spectral transmission factor of sunglasses, the differences that occur in user's eyes with aging have not been fully considered. We investigated the relationship between different levels of crystalline lens transparence and the effects of glare protection using two kinds of filters. SUBJECTS AND METHODS: A Tri-Blocker filter (TB) and general driving filter (ActiveDrive, ADR) were used. The TB absorbs three spectral wavelengths (below 400 nm, blue light, 575 nm) and can be transparent for other visible light. The ADR reduces the light below 650 nm. TB and ADR transmit 52.5 and 29.0% of the visible light, respectively. Twenty-five normal volunteers with transparent lenses (n = 48 eyes, aged from 22 to 68 years) and 10 cortical cataract patients (n = 18 eyes, aged from 48 to 71 years) were selected. The visual acuity of all subjects was 1.0 or better with the best correction. Contrast sensitivity function (CSF) was measured in four simulated light conditions (daylight, daylight with peripheral glare, twilight, twilight with central glare) by MCT8000 (Vistech). The light scattering intensity of the crystalline lens was measured by EAS-1000 (Nidek). RESULTS: The TB improved the CSF of the elderly volunteers under daylight conditions and of 1 of the cataract patients under all conditions. In the younger group, the CSF did not change under daylight conditions and deteriorated under twilight conditions. Although the ADR was effective for glare protection in the young volunteers, the protective effects of the TB were better than those of ADR for the middle-aged group. CONCLUSION: Sunglasses not only protect against glare but also stabilize visual quality under various light conditions (e.g. passing through a tunnel while driving). Aging changes in lens transparency should be specially considered when developing protective eyewear.

Adult↗
PubMedDate not supplied

Predicting postoperative anterior chamber depth in cataract patients using Scheimpflug slit photography.

PURPOSE: To predict the postoperative anterior chamber (AC) depth from the preoperative in situ position of the lens central clear zone (CCZ) using Scheimpflug slit photography. METHODS: 111 eyes of 78 cases that underwent phacoemulsification and intraocular lens (IOL) implantation were examined. 748 eyes of 383 healthy subjects with transparent lenses were used as the control. Scheimpflug slit photography was done under maximal mydriasis, and biometry was performed on the photographs. Two types of acrylic IOLs (MA30BA and MA60BM, both from Alcon) were used in this study. The preoperative AC depth (L1), the distance between the anterior lens capsule and lens CCZ (L2) and the postoperative AC depth (I1) were determined. I2, the predicted postoperative AC depth, was then determined from a linear regression of L1 + L2 and I1. RESULTS: L2 thickened by 0.014 mm/year, and L1 decreased by 0.016 mm/year in the transparent lenses. L1 + L2 changed little with aging in both cataractous and transparent lenses. L1 + L2 and I1 showed a linear correlation with r = 0.80 in the MA30BA and r = 0.77 in the MA60BM groups. The mean error values between I1 and I2 were 0.095 +/- 0.096 and 0.123 +/- 0.114 mm in MA30BA and MA60BM, respectively. The error between I1 and I2 was within +/- 0.17 and +/- 0.33 mm or less in 72.9 and 91.5% of MA30BA and in 82.7 and 96.2% of MA60BM. In contrast, the error between I2 and I1 when calculated using the SRK/T formula was much larger - in excess of +/- 0.33 mm in 38.7% of the eyes. CONCLUSIONS: L1 + L2 changes little with aging and is considered a useful marker of the position of the crystalline lens in situ. There was a high correlation between I1 and L1 + L2. These allow a far more accurate prediction of I1 than previous methods. In combination with the conventional regression formula and ray tracing, a highly accurate IOL power calculation can be attained.

Aged↗