Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary aims of this study were to evaluate the timecourse and dose response of microtubule bundle formationin peripheral blood mononuclear cells (PBMCs) and to correlate these data with BMS-247550 pharmacokinetics. The data presented here were obtained from 17 patients enrolled in a Phase I trial who received five dose levels of BMS-247550 (7.4-59.2 mg/m(2)), given as a 1-h infusion once every 3 weeks. Plasma drug exposure or area under the curve (AUC), and tubulin bundle formation in PBMCs were assessed in cycles 1 and 2. Similar analyses were also performed on tumor biopsies from one eligible patient. PBMCs exhibited dramatic microtubule bundle formation 1 h after infusion that declined by 24 h, showing a positive correlation with AUC((0-24)) for cycles 1 and 2. A similar pattern of tubulin bundle formation also was observed in a smaller proportion of breast tumor cells from one patient who exhibited a partial response to BMS-247550. This patient's tumor expressed multidrug resistance (MDR1) and MDR-associated protein (MRP1), and in addition poly(ADPribose) polymerase cleavage, a marker of cell death, was observed within 23 h after drug infusion. This patient was also heterozygous for a novel polymorphism at the extreme COOH terminus of beta-tubulin (Gly 437 Gly/Ser), although the relevance of the polymorphism to the response is unknown. In summary, microtubule bundle formation in PBMCs occurs within 1 h of treatment with BMS-247550 and is related to plasma AUC. Similar bundle formation was seen in one tumor sample, despite expression of MDR1 and MRP1. Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations.
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PMID:Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study. 1211 1

Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis. Since sporadic colon carcinomas exhibit in 50-60% mutations in the p53 gene and in 10-15% an MSI phenotype due in the great majority of the cases to hMLH1 inactivation, we investigated how these lesions influence the cellular effects of CPT-11 by using colorectal carcinoma cell line HCT116 (which has the genotype p53(+/+),hMLH1(-)) and 2 derivative cell lines with the genotypes p53(+/+),hMLH1(+) and p53(-/-),hMLH1(-). CPT-11 treatment induced G2/M arrest in all 3 cell lines within 48 hr. In the p53(+/+),hMLH1(+) cell line, G2/M arrest was maintained for at least 12 days. There was little concomitant apoptosis, but this was enhanced when the hMLH1 protein was absent. This enhanced apoptosis was accompanied by a shorter duration of the G2/M arrest than in the hMLH1(+) cell line. Partial abrogation of G2/M arrest by caffeine enhanced apoptosis in both hMLH1(+) and hMLH1(-) cells. By contrast, in the p53(-/-) cell line, the G2/M arrest was terminated within 4 days. Termination of the G2/M arrest was accompanied by a high level of apoptosis detectable through poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and by the appearance of cells with a DNA content <2N. The triggering of G2/M arrest was accompanied in the 3 cell lines by a transient phosphorylation of cdc-2, while the maintenance of the arrest in the p53(+/+) cell lines was accompanied by the overexpression of p53 and p21 proteins and, consequently, by the inhibition of cdc-2 kinase activity. These data indicate that: (i) CPT-11 induces long-term arrest in p53(+/+) cells and a short-term arrest followed by apoptosis in p53(-/-) cells; (ii) triggering of the arrest is p53 independent and is associated with a brief increase of phosphorylation of cdc-2, while the p53-dependent maintenance of G2/M arrest is associated with the inhibition of cdc-2 kinase activity by p21; and (iii) lack of hMLH1 protein enhances CPT-11-induced apoptosis. These results may be useful for designing rational therapies dependent on the p53 and mismatch-repair status in the tumor.
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PMID:Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. 1220 84

We have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) that induces apoptosis in a number of malignant cell types. We now describe our studies examining the effects of CD437 and a nonretinoidal analog (MM002) on the in vitro proliferation of the ALL-REH cell line, the in vitro and in vivo growth of a novel Epstein-Barr virus-negative (EBV(-)) B-cell chronic lymphocytic leukemia (B-CLL) cell line (WSU-CLL), and primary cultures of human B-CLL and acute lymphoblastic leukemia (ALL) cells. CD437 and MM002 induce apoptosis in both cell lines, as indicated by the activation of caspase-2 and caspase-3, cleavage of poly(adenosine diphosphate-ribose) (poly(ADP-ribose)) polymerase, increase in annexin V binding, and subsequent nuclear fragmentation. CD437-mediated apoptosis was not associated with the modulation of Bcl-2, Bax, or Mcl-1 levels, but was associated with the cleavage of the antiapoptotic protein Bcl-X(L) to a proapoptotic 18-kD form. This cleavage of Bcl-X(L) was dependent on caspase-3 activation since Bcl-X(L) cleavage and apoptosis were inhibited by the caspase-3 inhibitor Z-DVED-fmk. CD437 markedly inhibited the growth of WSU-CLL cells in severe combined immunodeficiency (SCID) mice. Tumor growth inhibition, growth delay, and log cell kill were 85.7%, 21 days, and 2.1, respectively, in the treated mice. Moreover, 1 of the 5 treated mice was tumor-free longer than 150 days and thus was considered cured. Exposure of primary cultures of both B-CLL and ALL cells obtained from patients to CD437 and MM002 resulted in their apoptosis. These results suggest that CD437 and MM002 analogs may have a potential role in the treatment of B-CLL and ALL.
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PMID:Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog. 1235 3

The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC(50) concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G(1) peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodide- and annexin V-stained cells indicated that the growth-inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased (13)C incorporation and pentose cycle substrate flow into RNA ribose. This decrease in pentose cycle enzyme activities and carbon flow toward nucleic acid precursor synthesis provide the mechanistic understanding of the cell growth-controlling and apoptosis-inducing effects of fermented wheat germ. Avemar exhibits about a 50-fold higher IC(50) (10.02 mg/ml) for peripheral blood lymphocytes to induce a biological response, which provides the broad therapeutic window for this supplemental cancer treatment modality with no toxic effects.
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PMID:Fermented wheat germ extract inhibits glycolysis/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells. 1235 27

Recently, we described a new in vivo pathway in the metabolism of benzo[a]pyrene (BP) that involves an opening of the aromatic ring system. One of the products of this pathway, isolated from rat urine, was the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid (ABADA). We have now investigated the effect of ABADA on several cellular targets, known to be important in tumor formation. ABADA was as efficient as BP-7,8-diol-9,10-epoxide in inducing direct strand breaks but not alkali labile sites in DNA in HT-29 cells and exhibited weak mutagenic activity in Salmonella typhimurium strain TA 102. The cytotoxicity of ABADA to HCT 116 cells appeared to be due to apoptosis, as caspase-3 activity and poly-ADP-ribose polymerase (PARP) cleavage was observed. COX-2 promoter activity was induced by ABADA in HCT 116 cells. In conclusion, this novel metabolic pathway may also be contributing to the carcinogenicity of BP.
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PMID:Toxicological characterization of a novel in vivo benzo[a]pyrene metabolite, 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid anhydride. 1238 25

The arachidonate cascade includes the cyclooxygenase (COX) pathway to form prostanoids and the lipoxygenase (LOX) pathway to generate several oxygenated fatty acids, collectively called eicosanoids. Eicosanoids are suggested to play a dual role in regulating cell survival and apoptosis in various types of cells through an unknown mechanism. We found apoptosis in cultured Madin-Darby canine kidney (MDCK) cells treated with 12-O-tetradecanoylphorbol beta-acetate (TPA), a potent tumor promoter, and nordihydroguaiaretic acid (NDGA), a LOX inhibitor. The effect of TPA was synergistically stimulated along with NDGA. Aspirin, a COX inhibitor, was not effective. The target of NDGA might be different from the mechanism involving a LOX activity in some kinds of carcinoma cells because the increased expression of 12-LOX was not detected in MDCK cells treated with TPA. Caspase and poly(ADP-ribose) metabolites were found to be involved in the signal transduction pathway of the TPA- and NDGA-induced apoptosis in MDCK cells. Alternatively, hydrogen peroxide-induced apoptosis was not affected by NDGA. Thus, the TPA-induced response involved the mechanism independent of the oxidative stress. Obesity is a risk factor for severe diseases including noninsulin-dependent diabetes and atherosclerosis characterized by the changes of cell properties of adipocytes. We found that conjugated linolenic acid from bitter gourd was able to induce apoptosis in mouse preadipogenic 3T3-L1 cells. The findings provide the potential use of conjugated fatty acids to regulate obesity.
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PMID:Regulation of apoptosis through arachidonate cascade in mammalian cells. 1239 27

Human non-small cell lung cancer (NSCLC) cells were transfected with recombinant prodrug herpes simplex virus type I thymidine kinase (HSV-tk) cDNA, and the selected clones underwent apoptosis in response to induction by antiviral ganciclovir (GCV). The efficiency of GCV-induced growth inhibition and the extent of the bystander effect were associated with the expression level of HSV-TK in stable transfectants. Development in the HSV-tk/GCV system toward cell death was initiated with cell-cycle accumulation at S and G(2)/M phases, immediately followed by the appearance of sub-G(0)/G(1) cells after drug exposure. To investigate the regulation of cell-cycle modulators during drug treatment, we analyzed release of the apoptosis initiator cytochrome c and activation of the downstream effectors caspase-9, caspase-3 and poly(ADP-ribose)polymerase 16 hr after GCV sensitization, followed by transient escalation of tumor-suppressor p53 and cell-cycle modulators cyclin A and B(1) before committing to programmed cell death. Furthermore, tumor regression was proportional to the degree of ectopic expression of the transferred HSV-tk gene. Our results demonstrate that the HSV-tk/GCV system effectively inhibits the proliferation of NSCLC cells in vitro and in vivo through potent induction of apoptosis, thus providing a rationale for further development.
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PMID:Ectopic expression of herpes simplex virus-thymidine kinase gene in human non-small cell lung cancer cells conferred caspase-activated apoptosis sensitized by ganciclovir. 1240

Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
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PMID:Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. 1246 61

The CD53 antigen is a tetraspanin protein of the lymphoid-myeloid lineage, but its implication in biological effects is hardly known. Radioresistant tumor cells express very high levels of this antigen. We have studied the effect of CD53 antigen ligation on the survival response of tumor cells to serum deprivation, a well-known stimulator of cell death that may mimic the tumor environment; for this aim IR938F and Jurkat cells, a B- and T-cell lymphoma, were used. Ligation of CD53 triggers a survival response and reduces the number of cells that enter apoptosis. In CD53- stimulated cells there is a significant reduction in caspase activation, measured by caspase processing of poly ADP-ribose polymerase, as well as a reduction in the fragmentation of DNA. CD53- stimulated cells also have an increase in the level of bcl-X(L) and a reduction of bax protein, two components of the mitochondrial apoptotic pathway, changing their ratio by 24-fold in the direction of survival. This survival signal appears to be mediated by activation of the AKT, as detected by its phosphorylation in Ser473 upon CD53 ligation. The CD53 antigen interactions might contribute to cell survival in poorly vascularized regions of the tumor mass.
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PMID:Apoptosis protection and survival signal by the CD53 tetraspanin antigen. 1260 48

The role of beta-glucuronidase in genistein biotransformation was investigated in a human breast cancer MDA-MB-231 xenogeneic athymic mouse model. Genistein combined polysaccharide (GCP), a genistein aglycone rich functional food supplement was used in these experiments. Tumor-bearing mice were subjected to oral administration of GCP for 28 days. GCP treatment significantly inhibited tumor growth. Induction of apoptosis by GCP treatment was related to activation of cleavage of poly(ADP-ribose)polymerase, induction of the p21 protein expression and reduction of cyclin B1 expression in the tumor tissues. Genistein exists as a glucuronide conjugate in normal organ tissues, and the conjugated genistein lacks the physiological activity of the aglycone. Tumor tissues contain large amounts of beta-glucuronidase, the enzyme that converts the genistein beta-glucuronide conjugate into genistein aglycone. The resulting genistein aglycone exerts its chemopreventive activities, including the induction of apoptosis in tumor tissues, and, finally, leads to tumor growth inhibition.
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PMID:Inhibition of human breast cancer growth by GCP (genistein combined polysaccharide) in xenogeneic athymic mice: involvement of genistein biotransformation by beta-glucuronidase from tumor tissues. 1262 3


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