Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intrathecal administration of 5-fluoro-2'-deoxyuridine (FdUrd) was performed in patients with meningeal dissemination of malignant tumors during the period from January 1996 to September 1998, and they were followed up until February 1999. The study population consisted of 23 patients: 12 with lung cancer, 4 with breast cancer, 2 with colon cancer, 1 with malignant lymphoma, 2 with glioblastoma and 2 with metastatic brain tumors of unknown origin. FdUrd was administered intrathecally through an Ommaya reservoir placed in the lateral ventricle initially at a dose of 1 microg twice per week, and the dose was increased to 10 microg and administration schedule was also increased every day. Headache and nuchal pain were relieved in all patients regardless of responsiveness to intrathecal FdUrd therapy as determined from the findings in the cerebrospinal fluid (CSF). Patients showed no side effects during the course of intrathecal chemotherapy except for slight nausea in two patients and dull headache in one. Sixteen of the 23 patients showed decreased cell number in the cerebrospinal fluid (CSF). Positive cytological findings in CSF became negative in 6 of the 23 patients, and the levels of CSF tumor markers were decreased in 14. Responsiveness to intrathecal administration of FdUrd was defined as 'response' when both the cell number and tumor markers were decreased in both ventricular and spinal CSF or when the cell number was decreased in cases in which the tumor markers were not detected. Overall, 16 of the 23 patients (70%) showed complete or partial responses to intrathecal FdUrd therapy as determined from CSF findings. These results demonstrated the efficacy of intrathecal FdUrd chemotherapy without apparent neurotoxicity for treatment of meningeal dissemination of malignant tumors.
 ...
PMID:Clinical trial of intrathecal administration of 5-fluoro-2'-deoxyuridine for treatment of meningeal dissemination of malignant tumors. 1077 33

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
 ...
PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

To investigate the factors influencing the bystander effect--a key element in the efficacy of suicide gene therapy against cancer--we compared the effect triggered by four extremely efficient gene/prodrug combinations, i.e., VZVtk/BVDU, the thymidine kinase of Varicella zoster virus associated with (E)-5-(2-bromovinyl)-2'-deoxyuridine; VZVtk/BVaraU, the same enzyme associated with (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil; HSVtk/BVDU, the association of the Herpes simplex virus thymidine kinase with BVDU; and the classical HSVtk/GCV (ganciclovir) paradigm. The cells used, the human MDA-MB-435 breast cancer, and the rat 9L glioblastoma lines were equally sensitive in vitro to these four associations. In both cell types, the combinations involving pyrimidine analogues (BVDU, BVaraU) displayed a smaller bystander killing than the combination involving the purine analogue (GCV). In addition, the bystander effect induced by all the tk/prodrug systems was reduced in MDA-MB-435 cells in comparison to 9L cells; albeit, the viral kinases were produced at a higher level in the breast cancer cells. All systems induced apoptotic death in the two cell types, but the MDA-MB-435 cells, deprived of connexin 43, were noncommunicating in striking contrast with the 9L cells. That functional gap junctions have to be increased in order to improve the breast cancer cell response to suicide gene therapy was demonstrated by transducing the Cx43 gene: this modification enhanced the bystander effect associated in vitro with GCV treatment and, by itself, decreased the tumorigenicity of the untreated cells. However, the noncommunicating MDA-MB-435 cells triggered a significant bystander effect both in vitro and in vivo with the HSVtk/GCV system, showing that communication through gap junctions is not the only mechanism involved.
 ...
PMID:The role of cellular- and prodrug-associated factors in the bystander effect induced by the Varicella zoster and Herpes simplex viral thymidine kinases in suicide gene therapy. 1112 88

The purpose of this article is to provide an overview on the current clinical application of hyperthermia combined with conventional treatment modalities (e.g. ionizing radiation, chemotherapy) in the treatment of malignant disease. The clinical application of hyperthermia with increase of tissue temperatures (range 40-44 degrees C) has been integrated in multimodal anti-cancer strategies. This review describes selected phase I or II (n = 17) and phase III trials (n = 16) investigating the effect of hyperthermia combined with radiotherapy (n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in a total of more than 2200 patients. The trials were performed in a variety of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric or adult patients. Profound research has produced a scientific basis for the simultaneous application of hyperthermia in combination with ionizing radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumours. At present, the combination of hyperthermia and chemotherapy or radiochemotherapy is further tested within clinical protocols (phase II/III) in order to improve local tumour control and relapse-free survival in patients with high-risk or advanced tumours of different entities.
 ...
PMID:Hyperthermia in oncology. 1121 76

Chemically modified tetracyclines (CMTs) are promising anti-cancer agents. In this study, we found that CMT-3 and CMT-8 showed dose-dependent cytotoxicities in MDA-MB-468 human breast cancer cells. Moreover, both CMT-3 and CMT-8 significantly inhibited in vitro cell migration and invasion at non-cytotoxic concentrations. Anti-invasion and migration potentials of the CMTs were associated with an increased expression of E-cadherin/catenins (alpha, beta and gamma-catenin) and tumor suppressor BRCA1. In addition, CMT-3 and CMT-8 abolished or reduced spontaneous and HGF/SF-induced cell invasion and migration in U-373 MG human glioblastoma cells. Our current finding is the first demonstration that CMT-3 and CMT-8 can activate the function of invasion suppressor molecules associated with the suppression of breast cancer cell invasion and migration. Thus, clinical application of CMTs may provide potential benefit for suppression of breast cancer growth, invasion and metastasis.
 ...
PMID:Influence of chemically modified tetracyclines on proliferation, invasion and migration properties of MDA-MB-468 human breast cancer cells. 1123 89

We present experimental data which establish the organometallic compounds vanadocene dichloride (VDC) and vanadocene acetylacetonate (VDacac) as potent anti-proliferative agents. We first examined the effects of VDC and VDacac on the rapid embryonic cell division and development of Zebrafish. Both compounds were capable of causing cell division block at the 8-16 cell stage of embryonic development followed by total cell fusion and developmental arrest. We next examined the effect of VDC and VDacac on proliferation of human breast cancer and glioblastoma cell lines using MTT assays. VDC inhibited the proliferation of the breast cancer cell line BT-20 as well as the glioblastoma cell line U373 in a concentration-dependent fashion with IC50 values of 11.0, 14.9 and 18.6 microM, respectively. VDacac inhibited cellular proliferation with IC50 values of 9.1, 26.9 and 35.5 microM, respectively. Whereas in vehicle-treated control cancer cells mitotic spindles were organized as a bipolar microtubule array and the DNA was organized on a metaphase plate, vanadocene-treated cancer cells had aberrant monopolar mitotic structures where microtubules were detected only on one side of the chromosomes and the chromosomes were arranged in a circular pattern. In contrast to control cells which showed a single focus of gamma-tubulin at each pole of the bipolar mitotic spindle, VDC- or VDacac-treated cells had two foci of gamma-tubulin on the same side of the chromosomes resulting in a broad centrosome at one pole. All monopolar spindles examined had two foci of gamma-tubulin labeling consistent with a mechanism in which the centrosomes duplicate but do not separate properly to form a bipolar spindle. These results provide unprecedented evidence that organometallic compounds can block cell division in human cancer cells by disrupting bipolar spindle formation. In accordance with these results vanadocene treatment caused an arrest at the G2/M phase of the cell cycle. This unique mechanism of anti-mitotic function warrants further development of vanadocene complexes as anti-cancer drugs.
 ...
PMID:Vanadocenes as potent anti-proliferative agents disrupting mitotic spindle formation in cancer cells. 1133 94

The phorboxazoles are recently described natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. We report here the results of preliminary structure-activity studies of synthetic analogues of the phorboxazoles against BT-20 breast cancer, NALM-6 B-lineage ALL, U373 brain tumor, and U373 glioblastoma cell lines. These data indicate the importance of several of the natural products' structural moieties for potent anticancer activity.
 ...
PMID:Anticancer activity of synthetic analogues of the phorboxazoles. 1135 72

The compound bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]), exhibits potent cytotoxicity against human cancer cells at low micromolar concentrations. At concentrations > or = 1 microM, METVAN treatment was associated with a nearly complete loss of the adhesive, migratory, and invasive properties of the treated tumor cell populations. METVAN did not cause acute or subacute toxicity in mice at dose levels ranging from 12.5 mg/kg to 100 mg/kg. Therapeutic plasma concentrations > or = 5 microM were rapidly achieved and maintained in mice for at least 24 h after i.p. bolus injection of a single 10 mg/kg nontoxic dose of METVAN. At this dose level, the maximum plasma METVAN concentration was 37.0 microM, which was achieved with a t(max) of 21.4 min. Plasma samples (diluted 1:16) from METVAN-treated mice killed 85% of human breast cancer cells in vitro. METVAN was slowly eliminated with an apparent plasma t(1/2) of 17.5 h and systemic clearance of 42.1 ml/h/kg. In accordance with its potent in vitro activity and favorable in vivo pharmacokinetics, METVAN exhibited significant antitumor activity and delayed tumor progression in CB.17 severe combined immunodeficient (SCID) mouse xenograft models of human glioblastoma and breast cancer. In these experiments, METVAN was administered in daily injections of a single nontoxic 10 mg/kg i.p. dose on 5 consecutive days per week for 4 consecutive weeks beginning the day after the s.c. inoculation of U87 glioblastoma or MDA-MB-231 breast cancer cells. At 40 days after the inoculation of tumor cells, the U87 tumor xenografts in the vehicle-treated control SCID mice were much larger than those of the mice treated with METVAN (4560 +/- 654 mm(3) versus 1688 +/- 571 mm(3); P = 0.003). Similarly, the MDA-MB-231 tumors in SCID mice treated with METVAN were much smaller 40 days after tumor cell inoculation than those of the vehicle-treated control SCID mice (174 +/- 29 mm(3) versus 487 +/- 82 mm(3); P = 0.002). The favorable in vivo pharmacodynamic features and antitumor activity of METVAN warrants further development of this novel oxovanadium compound as a potential new anticancer agent.
 ...
PMID:In vivo antitumor activity of bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]). 1144 32

Random peptide phage display libraries have been employed widely to identify protein-protein interactions, using as targets either purified proteins, intact cells, or organs. To isolate peptides that bind to human neuroblastoma cells, we have used a phage display approach with the neuroblastoma cell line WAC 2 as the target. In particular, two bacteriophages, t147 and t160, displaying peptides p147 and p160, respectively, were isolated by repeated display cycles. Binding of t147 and t160 to WAC 2 cells was abrogated by pretreatment with the peptides p147 and p160, respectively, which strongly support that cellular binding of both phages is dictated by their displayed peptides. Immunofluorescence analysis by confocal light microscopy revealed that the major proportion of t147 remains on the surface of WAC 2 cells and that only a fraction is taken up into the cells. In contrast, the vast majority of t160 is internalized. K(+) depletion reduced the number of the phages internalized by the cells to approximately 20% for t160 and to 10% for t147, indicating that the phage internalization was through receptor-mediated endocytosis. Phage t147 appears to bind to a range of tumor cell lines, including neuroblastoma, breast cancer, glioblastoma and C-cell carcinoma, but less so to non-tumor lines, such as erythrocytes, lymphocytes, monocytes and epithelial cells. Phage t160 bound to a range of neuroblastoma cell lines and a breast cancer cell line, but not to other tested cell lines. While neither of the displayed peptides conferred a narrow tissue specific binding ability, they do provide a basis for targeted drug delivery in selected experimental or natural tumor systems.
 ...
PMID:Neuroblastoma tumor cell-binding peptides identified through random peptide phage display. 1152 May 99

Agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and monotetrahydrofuran compounds (COBRA compounds), targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization and demonstrated potent cytotoxic activity against cancer cells. COBRA-1 inhibited GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other agents that have shown promise for cancer treatment include phorboxazoles, natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. In standard MTT assays, synthetic phorboxazole A exhibited potent cytotoxicity against NALM-6 acute lymphoblastic leukemia cells (IC50 = 1.7 nM), BT-20 breast cancer cells (IC50 = 3.4 nM), and U373 glioblastoma cells (IC50 = 6.7 nM). Structure-activity studies were reported for seven synthetic analogs of phorboxazole A. Out of these, two showed potent anti-cancer activity. Phorboxazole analog 2 was active against NALM-6 cells (IC50 = 4.8 nM), BT-20 cells (IC50 = 12.6 nM) and U373 cells (IC50 = 27.4 nM), as was analog 3 (NALM-6 IC50 = 5.2 nM, BT-20 IC50 = 11.3 nM, and U373 IC50 = 29.2 nM). Anticancer activity of the phorboxazole analogs was correlated to the presence of certain structural moieties such as portions of the macrolide group, the central oxazole group, and the polyene side chain. The requirement of more than one structural element for activity suggested that at least bimodal interactions of the natural product with key cellular components may occur. Promising anti-mitotic agents with pro-apoptotic activity include inhibitors of the tyrosine kinase BTK. The leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells (IC50 = 17 microM). Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
 ...
PMID:Rationally designed anti-mitotic agents with pro-apoptotic activity. 1156 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>