Belactosin A, a novel antitumor antibiotic acting on cyclin/CDK mediated cell cycle regulation, produced by Streptomyces sp.
Explore the source record for details and available documents.
Anti-Bacterial Agents↗
Biomedical subjects
A Asai
Publications and source records attributed to A Asai.
[An outline of brain tumor classification].
Explore the source record for details and available documents.
Brain Neoplasms↗
2-Phenylquinoline-Carbohydrate Hybrids: Molecular Design, Chemical Synthesis, and Evaluation of a New Family of Light-Activatable DNA-Cleaving Agents.
Artificial intercalator-carbohydrate hybrids such as that shown in the scheme cleave DNA at the site of guanine on irradiation with UV light with a long wavelength. The hybrids also exhibit strong cytotoxicity when irradiated. The hybrid system is very important for DNA cleavage, and the cytotoxic activity correlates with the DNA-cleaving capacity
Journal Article↗
Tight association of loss of merlin expression with loss of heterozygosity at chromosome 22q in sporadic meningiomas.
Mutations of NF2, the gene for neurofibromatosis 2, are detected in 20-30% of sporadic meningiomas, and almost all mutations lead to loss of merlin expression. However, loss of heterozygosity (LOH) at chromosome 22q is found at a much higher frequency, up to 50-70%, and the possibility of another tumor suppressor gene in this region has not been excluded. Furthermore, a recent report proposed that abnormal activation of a protease micro-calpain can be an alternative pathway for merlin loss in meningiomas and schwannomas. To determine the correlation of merlin loss with NF2 genetic alteration or micro-calpain activation, we performed a molecular genetic analysis of 50 sporadic meningiomas and also examined the expression status of merlin and active form micro-calpain. LOH assay of five microsatellite markers franking NF2 revealed LOH in 22 cases, and single-strand conformation polymorphism assay detected six frameshift mutations, two splicing mutations, one nonsense mutation, and one missense mutation, all accompanied by 22q LOH. In addition, a multiplex PCR assay indicated homozygous deletion of NF2 in two cases. Interestingly, a marked decrease of merlin expression was seen exclusively in the 22 cases with 22q LOH. Activated micro-calpain expression was observed in 28 cases at various levels but showed no correlation with merlin status. These data strongly support the notion that NF2 is the sole target of 22q LOH in meningiomas and that loss of merlin expression is always caused by genetic alteration of NF2, following the classic "two hit" theory.
Chromosome Mapping↗
High level calcineurin activity predisposes neuronal cells to apoptosis.
Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.
Adenoviruses, Human↗
Characterization of a duocarmycin-DNA adduct-recognizing protein in cancer cells.
Duocarmycins have been reported to derive their potent antitumor activity through a sequence-selective minor groove alkylation of N3 adenine in double-stranded DNA. We have used gel mobility shift assays to detect proteins that bind to DNA treated in vitro with duocarmycin SA and identified a protein, named duocarmycin-DNA adduct recognizing protein (DARP), which binds with increased affinity to duocarmycin-damaged DNA. Examination with partially purified DARP revealed that the protein recognized not only the DNA adduct of structurally related drug, CC-1065, but unexpectedly, the protein also recognized the DNA adduct of another chemotype of minor groove binder, anthramycin. These results demonstrate that DARP recognizes the structural alteration of DNA induced by these potent DNA-alkylating drugs, suggesting the possibility that the protein might modulate the antitumor activity of these drugs.
Animals↗
Adenovirus-mediated transfer of p33ING1 with p53 drastically augments apoptosis in gliomas.
The p53 tumor suppressor gene is an important target for the gene therapy of cancers, and clinical trials targeting this gene have been conducted. Some cancers, however, are refractory to p53 gene therapy. Therefore, it has been combined with other therapies, including chemotherapy and radiotherapy, to enhance the cytopathic effect of p53 induction. The p33ING1 gene cooperates with p53 to block cell proliferation. In this study, we investigated whether adenovirus (Adv)-mediated coinduction of p33ING1 and p53 enhances apoptosis in glioma cells (U251 and U-373 MG), which showed no genetic alterations but low expression levels of p33ING1. Although the single infection of Adv for p33ING1 (Adv-p33) at a multiplicity of infection (MOI) of 100, or Adv for p53 controlled by myelin basic protein (MBP) promoter (Adv-MBP-p53), a glioma-specific promoter, at a MOI of 50, did not induce apoptosis in U251 and U-373 MG glioma cells; coinfection of Adv-p33 and Adv-MBP-p53 at the same MOIs induced drastically enhanced apoptosis in both cell lines. Apoptosis was not induced in NGF-treated PC-12 cells infected with a high MOI (300) of Adv-p33 nor in those coinfected with Adv-p33 (100) and Adv-MBP-p53 (50). Coinfection of Adv-p33 and Adv-MBP-p53 demonstrated morphological mitochondrial damage during the initial stage of apoptosis, which likely led to apoptotic cell death. Our results indicate that this coinfection approach can be used as a modality for the gene therapy of gliomas, sparing damage to normal tissues.
Adenoviridae↗
Synthesis and antitumor activity of water-soluble duocarmycin B1 prodrugs.
The water-soluble duocarmycin B1 prodrugs such as glycoside 3, phosphate 4 and carbamate 5 were synthesized for improving biological and pharmaceutical profiles of duocarmycin. Among these prodrugs, N-methylpiperazinylcarbamoyl derivative 5 exhibited potent antitumor activity against several human tumors in vivo.
Animals↗
Relative level of expression of Bax and Bcl-XL determines the cellular fate of apoptosis/necrosis induced by the overexpression of Bax.
The Bax protein plays a critical role in the apoptosis of cancers induced by radiotherapy or chemotherapy, which induce both apoptosis and necrosis. We transduced various glioblastoma cells with the Bax gene via an adenoviral vector and found that A-172 cells led to necrotic cell death, while U251 cells apoptotic cell death, even though a similar level of Bax protein was introduced. A-172 cells displayed a much higher constitutive expression of the Bcl-XL protein compared with that of U251 cells. Upon simultaneous overexpression of the Bcl-XL and Bax proteins in the U251 cells, Bax-induced apoptosis of U251 cells was suppressed and an increase in the number of necrotic cells was seen. Moreover, induction of a higher amount of Bax protein in A-172 cells increased the percentage of apoptotic cells. In conclusion, if a cancerous cell expresses a high enough amount of Bax to undergo death, apoptosis will be induced. If a cancerous cell expresses a level of Bcl-XL which prevents Bax-induced apoptosis, the overexpression of Bax leads to necrotic cell death.
Apoptosis↗
Expression level of Bcl-2 determines anti- or proapoptotic function.
Bcl-2 is an oncogene with antiapoptotic function. However, Bcl-2 is converted to a Bax-like death effector by caspases, suggesting that the expression of Bcl-2 may not favor the growth of cancers. We introduced the Bcl-2 gene to gliomas via adenovirus (Adv; Adv-Bcl-2) with the Adv for Fas (Adv-Fas) and the Adv for Fas ligand (Adv-FL) to evaluate the antiapoptotic function of Bcl-2. In U251 glioblastoma cells, Bcl-2 at a low level of expression repressed apoptosis induced by Adv-Fas and Adv-FL, whereas Bcl-2 at a high level of expression did not. On the other hand, Bcl-X(L) showed antiapoptotic function against Fas-mediated apoptosis, irrespective of its expression level. In glioblastoma cells, induction of Bcl-2 alone at a high level induced apoptosis, whereas induction of Bcl-X(L) alone did not. As the multiplicity of infection of Adv-Bcl-2 was increased, the quantity of a cleaved product of Bcl-2 increased. Induction of caspase-inhibitory genes (CrmA and p35) inhibited apoptosis induced by Adv-Bcl-2. Induction of Bcl-2 led to alteration of the membrane potential and structure of the mitochondria. In summary, although Bcl-2 at a low level of expression was antiapoptotic, Bcl-2 at a high level of expression was proapoptotic to Fas-mediated apoptosis. Overexpression of Bcl-X(L) was consistently antiapoptotic to Fas-mediated apoptosis.
Apoptosis↗
Mutations of the MEN1 tumor suppressor gene in sporadic pituitary tumors.
Pituitary adenoma is a common neoplasm accounting for 10% of all intracranial tumors. Although the molecular mechanisms underlying the formation of these tumors are largely unknown, a small portion of pituitary adenomas occur in patients with the multiple endocrine neoplasia syndrome type 1 (MEN 1). Although two groups in the United States and Canada have recently reported that sporadic pituitary adenomas very rarely harbor a somatic mutation in the MEN1, MEN1 gene mutation analysis in sporadic pituitary adenomas has not yet been carried out in the Japanese population. To elucidate the potential etiological role of the MEN1 gene in the formation of sporadic pituitary adenomas in Japan, we investigated 40 Japanese patients with sporadic pituitary adenomas (16 hormone-secreting and 24 nonsecreting tumors) for MEN1 gene mutation. Polymerase chain reaction-single-stranded DNA conformation polymorphism analysis and sequencing demonstrated a somatic mutation in the MEN1 gene in only one of the 40 tumors, a prolactinoma, which had a 1-bp deletion in the coding sequence of exon 2. The data suggest that somatic mutations in the MEN1 gene do not play a prominent role in the pathogenesis of sporadic pituitary adenomas.
Adenoma↗
Highly augmented cytopathic effect of a fiber-mutant E1B-defective adenovirus for gene therapy of gliomas.
An E1B 55-kDa gene-defective adenovirus (Adv), ONYX-015, has been reported to be a highly useful replication-competent Adv that shows cytopathic effect for cancers with an abnormal p53 gene, without damaging normal tissues. In this study, we combined this Adv (Adv-E1AdB) with a fiber mutation, F/K20, which has a stretch of 20 lysine residues added at the COOH-terminus of the fiber and shows high transduction efficiency to gliomas. In U-373 MG glioma cells, the transduction efficiency of Adv-F/ K20 for lacZ was nine times higher than that of the Adv with wild-type fiber (Adv-F/wt) for lacZ. At a multiplicity of infection of 30, the replication efficiency of Adv-E1AdB-F/K20 was 11 times higher than that of Adv-E1AdB with wt fiber (Adv-E1AdB-F/wt). The ED50 value of AdvE1AdB-F/K20 to U-373 MG cells, which is a measure of the in vitro cytopathic effect, was 32 times greater than that of Adv-E1AdB-F/wt. injection of Adv-E1AdB-F/K20 suppressed the in vivo growth of tumors. The antitumoral effect of Adv-E1AdB-F/K20 was remarkably stronger than that of Adv-E1AdB-F/wt. A greater quantity of replicated virus protein (hexon) by infection with Adv-E1AdB-F/K20 was demonstrated in vitro and in vivo, compared with that of Adv-E1AdB-F/wt. In conclusion, gene therapy using Adv-E1AdB-F/K20, which drastically augmented the antitumoral effect of Adv-E1AdB, will be a promising therapeutic approach for gliomas.
Adenovirus E1B Proteins↗
Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway.
The pim-1 oncogene encodes a serine/threonine kinase (Pim-1) involved in the transduction of cytokine-triggered mitogenic signals. Pim-1 is unique in that it closely cooperates with c-Myc not only in oncogenesis, but also in apoptosis induction. However, the molecular basis of Pim-1 function remains poorly understood, largely because the downstream effector molecule(s) for Pim-1 kinase has not been identified. Here we provide several lines of evidence that Cdc25A cell cycle phosphatase, a direct transcriptional target for c-Myc, is a substrate for Pim-1 kinase and functions as an effector for Pim-1. We found that Pim-1 physically interacts with Cdc25A both in vitro and in vivo and phosphorylates Cdc25A. We also observed that Pim-1-mediated phosphorylation of Cdc25A increases its phosphatase activity. In addition, wild-type Pim-1, but not kinase-inactive Pim-1, enhanced Cdc25A-mediated cellular transformation and apoptosis. Our results indicate that Cdc25A might be a key molecule that links Pim-1 and c-Myc and that also ties Pim-1-mediated mitogenic signals to cell cycle machinery.
Animals↗
Postoperative residual tumor growth of meningioma can be predicted by MIB-1 immunohistochemistry.
BACKGROUND: Meningiomas are benign tumors that can be cured by surgical removal. However, tumors located deeply within or close to vital structures cannot be removed completely and require repeated surgery. This study was designed to clarify whether immunohistochemical study using MIB-1 monoclonal antibody is useful for determining the rate of regrowth for this tumor. METHODS: Tumor volume doubling time (Td) was measured by using computed tomography or magnetic resonance imaging neuroimages during 29 different follow-up periods after surgery. MIB-1 monoclonal antibody was used to stain Ki-67 proliferating cell antigen in surgical specimens, and the MIB-1 staining index (SI) was determined independently of neuroimaging analysis. These two values and other clinical parameters were analyzed statistically. RESULTS: The Td values varied from 19-6830 days (median, 350 days); the Td values were <365 days in 15 cases, 365-730 days in 8 cases, and >730 days in 6 cases. There was no significant correlation between age and Td value, but all 6 patients whose Td values were >2 years were age >50. There was a strong inverse correlation between log(Td) and MIB-1 SI (P < 0.001). In three cases, more than three surgical procedures were performed for tumor recurrence. The MIB-1 values did not increase at the time of the first recurrence but increased at later recurrences. The calculated Td values also were not shortened until the second recurrence. CONCLUSIONS: Using the MIB-1 SI makes it possible to predict the regrowth potential of a tumor after initial surgery.
Adult↗
Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells.
To prevent neoplasia, cells of multicellular organisms activate cellular disposal programs such as apoptosis in response to deregulated oncogene expression, making the suppression of such programs an essential step for potentially neoplastic cells to become established as clinically relevant tumors. Since the mutation of ras proto-oncogenes, the most frequently mutated proto-oncogenes in human tumors, is very rare in some tumor types such as glioblastomas and gastric cancers, we hypothesized that mutated ras genes might activate a cell death program that cannot be overcome by these tumor types. Here we show that the expression of oncogenically mutated ras gene induces cellular degeneration accompanied by cytoplasmic vacuoles in human glioma and gastric cancer cell lines. Cells dying as a result of oncogenic Ras expression had relatively well-preserved nuclei that were negative for TUNEL staining. An immunocytochemical analysis demonstrated that the cytoplasmic vacuoles are derived mainly from lysosomes. This oncogenic Ras-induced cell death occurred in the absence of caspase activation, and was not inhibited by the overexpression of anti-apoptotic Bcl-2 protein. These observations suggested that oncogenic Ras-induced cell death is most consistent with a type of programmed cell death designated 'type 2 physiological cell death' or 'autophagic degeneration', and that this cell death is regulated by a molecular mechanism distinct from that of apoptosis. Our findings suggest a possible role for this non-apoptotic cell death in the prevention of neoplasia, and the activation of the non-apoptotic cell death program may become a potential cancer therapy complementing apoptosis-based therapies. In addition, the approach used in this study may be a valuable way to find genetically-regulated cell suicide programs that cannot be overcome by particular tumor types.
Brain Neoplasms↗
Spontaneous regression of a residual pineal tumor after resection of a cerebellar vermian germinoma.
A case of multiple intracranial germ cell tumor in which a pineal tumor regressed spontaneously after resection of the cerebellar mass is reported. Immunohistochemical staining of the cerebellar mass showed that most of the infiltrating lymphocytes were positive for CD3 and CD8. The anti-Ki-67 monoclonal antibody MIB-1 staining of the resected tumor revealed a high MIB-1 positivity ratio (36.1%) among the large tumor cells, and TUNEL staining demonstrated that positivity in up to 6% of the tumor cells. Possible mechanisms responsible for this spontaneous regression including immunological responses and apoptosis induced by T lymphocytes are discussed.
Adult↗
Expression pattern of chemoresistance-related genes in human malignant brain tumors: a working knowledge for proper selection of anticancer drugs.
BACKGROUND: In addition to traditional modalities such as surgical intervention and radiotherapy, chemotherapy is a common therapeutic method for human malignant brain tumors. However, the effectiveness of chemotherapy is frequently hampered by cancer cell chemoresistance, resulting in an unsatisfactory outcome. To overcome this disadvantage, the proper selection of efficacious anticancer agents is required. METHODS: The expression levels of chemoresistance-related genes, MGMT, mdr1, MRP, MTIIA and GST-pi, in 28 surgical specimens of human brain tumors and in 10 human glioma cell lines were examined by Northern blot analysis. In addition, the SD10 values of human glioma cell lines against ACNU, CDDP, ADM and VP16 were estimated by a cell survival assay. RESULTS: The expression levels of each of the chemoresistance-related genes, except MRP, were generally higher in brain tumors than those in non-neoplastic brain tissues. MGMT expression correlated exclusively with ACNU resistance in all glioma cell lines examined (p = 0.0002). The transcriptional level of mdr1 in the tumor cells correlated with the SD10 values of VCR (p = 0.04) and ADM (p = 0.034). In contrast, the expression levels of MTIIA and GST-pi did not correlate with resistance to any of the drugs tested. A correlation of MRP mRNA expression with multidrug resistance was not apparent in the 10 cell lines tested. CONCLUSIONS: The data indicate that knowledge of the expression levels of MGMT and mdr1 may be particularly useful for a more rational selection of drugs which are not influenced by these resistance genes and which have improved efficacy against human brain tumors.
Antigens, CD↗
Ubiquitin stress response in postischemic hippocampal neurons under nontolerant and tolerant conditions.
Ubiquitin, an essential protein in nonlysosomal proteolytic system, is expressed after metabolic stress to the cell. The authors investigated stress response of ubiquitin in the hippocampus of the Mongolian gerbil after forebrain ischemia. The level of hippocampal ubiquitin was compared with that under ischemic tolerance induced by ischemic preconditioning. The authors also studied ubiquitin gene expression using in situ hybridization method. Transient ischemia resulted in consumption of free ubiquitin and an increase of multiubiquitin chains. These changes were transient in the hippocampus outside of the CA1 region where neurons survived, whereas it was persistent in the CA1 region where neurons were destined to die after ischemia. Under tolerant condition, subsequent ischemia provoked rapid recovery and further increase of free ubiquitin. The signal of ubiquitin messenger ribonucleic acid was continuously detected after ischemia, not only under tolerant conditions, but without tolerance induced by preconditioning. Thus, ubiquitin stress response takes place, at least at a transcriptional level, in dying CA1 neurons. Under tolerant conditions, however, subsequent ischemia in the CA1 region induces the stress response of ubiquitin up to the translational level, leading to the rapid restoration of protein synthesis and to eventual neuronal survival.
Animals↗