Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma multiforme is the most common primary central nervous system neoplasm. Its dismal prognosis has led to investigation of new treatment strategies such as immunogene therapy. We transduced the human glioblastoma cell line D54MG in vitro with genes encoding the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), the T cell co-stimulatory molecule B7-2, or both (in a bicistronic vector) via retroviral vectors. Therapeutic gene expression by D54MG was high after transduction and selection (30 ng/10(6) cells/day for GM-CSF and > 2 orders of magnitude fluorescence shift on flow cytometry for B7-2). The effect of GM-CSF and/or B7-2 transduction on D54MG tumor growth in vivo was monitored in a novel allogeneic human peripheral blood lymphocyte-severe combined immunodeficiency mouse (Hu-PBL-SCID) model. GM-CSF- or B7-2-transduced tumors showed growth suppression in hu-PBL-reconstituted mice compared to untransduced and/or unreconstituted controls. Growth suppression was greatest for B7-2. Furthermore, vaccination with irradiated GM-CSF/B7-2-transduced tumor cells markedly inhibited growth of wild-type tumors at distant sites. Thus, this study illustrates a potential gene therapy strategy for glioblastoma multiforme patients using GM-CSF and/or B7-2 transduced tumor vaccines. Although extension of these allogeneic studies to an autologous system is critical, this is the first demonstration of in vivo efficacy of combination GM-CSF and B7-2 immunogene therapy for human glioblastoma multiforme.
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PMID:Granulocyte-macrophage colony-stimulating factor and B7-2 combination immunogene therapy in an allogeneic Hu-PBL-SCID/beige mouse-human glioblastoma multiforme model. 918 65

Methoxypoly(ethylene glycol) (PEG) modification of Escherichia coli beta-glucuronidase (betaG) was examined as a method to improve the stability and pharmacokinetics of antibody-betaG conjugates for the targeted activation of glucuronide prodrugs at tumor cells. Introduction of 3 PEG molecules did not affect betaG activity whereas higher degrees of PEG modification produced progressively greater loss of enzymatic activity. The enzyme was found to be stable in serum regardless of PEG modification. PEG-modified betaG was coupled via a thioether bond to mAb RH1, an IgG2a antibody that binds to the surface of AS-30D hepatoma cells, to produce conjugates with 3 (RH1-betaG-3PEG), 5.2 (RH1-betaG-5PEG) or 9.8 (RH1-betaG-10PEG) PEG molecules per betaG with retention of 75%, 45% and 40% of the combined antigen-binding and enzymatic activity of the unmodified conjugate RH1-betaG. In contrast to the rapid serum clearance of RH1-betaG observed in mice, the PEG-modified conjugates displayed extended serum half-lives. RH1-betaG-3PEG and RH1-betaG-5PEG also exhibited reduced spleen uptake and greater tumor accumulation than RH1-betaG. BHAMG, the glucuronide prodrug of p-hydroxyaniline mustard (pHAM), was relatively nontoxic in vivo. Injection of 6 mg/kg or 12 mg/kg pHAM i.v. depressed white blood cell numbers by 46% and 71% whereas 80 mg/kg BHAMG reduced these levels by 22%. Although the tumor/blood ratio of RH1-betaG-5PEG was adversely affected by slow clearance from serum, combined therapy of small solid hepatoma tumors with this conjugate, followed 4 and 5 days later with i.v. injections of BHAMG, cured all of seven mice with severe combined immunodeficiency. Combined treatment with a control antibody-betaG conjugate and BHAMG delayed tumor growth and cured two of six mice while treatment with pHAM or BHAMG alone was ineffective.
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PMID:Poly(ethylene glycol) modification of beta-glucuronidase-antibody conjugates for solid-tumor therapy by targeted activation of glucuronide prodrugs. 929 32

We examined the in vivo effects of ONO-5046xNa, a specific neutrophil elastase (NE) inhibitor, on the growth of 2 non-small cell lung cancer cell lines, EBC-1 and PC-3, transplanted into severe combined immunodeficiency (scid) mice. The daily intraperitoneal injection of ONO-5046xNa (50 mg/kg/day) completely suppressed the tumor growth in EBC-1, a human squamous carcinoma cell line which produces immunoreactive NE. By contrast, in PC-3, a human adenocarcinoma cell line which is unable to produce immunoreactive NE, the ONO-5046xNa treatment caused delayed growth of the tumor. These findings suggest that ONO-5046xNa may have a clinical role in preventing the growth of human non-small cell lung cancer.
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PMID:Neutrophil elastase inhibitor (ONO-5046-Na) inhibits the growth of human lung cancer cell lines transplanted into severe combined immunodeficiency (scid) mice. 934 34

Hepatocellular carcinoma (HCC) frequently overexpresses the MDR1 gene and is resistant to drugs transported by the multidrug-resistance efflux pump. A xanthine analog, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine (CT-2584,CTI), is cytotoxic to many tumors in culture and was four times more effective than verapamil in inhibiting Rhodamine 123 secretion in MDR1-overexpressing Chinese hamster ovary cells. However, studies using PRF/PLC/5 (Alexander) cells revealed that CT-2584 is cytotoxic by another mechanism not involving inhibition of MDR1 function. Alexander cells have integrated the hepatitis B surface antigen (HBsAg) gene and quantitatively secrete HBsAg. The parent cell line, Alex 0, has low MDR1 expression and is drug-sensitive, whereas a derived line, Alex 0.5, is drug-resistant and overexpresses MDR1 100 times. Both cell lines were similarly killed within 24 or 48 hours by CT-2584. Freshly isolated rat and human hepatocytes were considerably more resistant to killing by CT-2584. In vivo, CT-2584 significantly reduced tumor growth in SCID mice bearing Alex 0 or 0.5 xenografts as determined by serial measurements of HBsAg. Hepatic parenchyma was normal, whereas apoptosis and cellular loss were observed in xenografts. The xenograft model is useful for testing pharmacological therapy of HCC.
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PMID:Effect of a xanthine analog on human hepatocellular carcinoma cells (Alexander) in culture and in xenografts in SCID mice. 936 62

We have previously found that human chromosome 3 was fragmented in the course of in vivo tumor growth of monochromosomal human/mouse (A9 fibrosarcoma parent) microcell hybrids in SCID mice. Marker analysis of tumor cell lines has identified a regularly eliminated 7 cM segment on 3p21.3 referred to as the common eliminated region (CER). The same region is frequently affected by LOH in a variety of human carcinomas. The present study is a comparative chromosome painting, reverse painting, and PCR marker analysis of microcell hybrids (MCHs) that originally contained an intact chromosome 3 from two alternative donors, during and after four passages in SCID mice. We found regular elimination of 3p in parallel with preferential retention of 3q. In addition to CER on 3p, we can now define a common retained region (CRR) on 3q. It includes eight markers between D3S1282 (3q25-q26) and D3S1265 (3q27-qter) and spans approximately 43 cM. These observations are concordant with the frequent loss of corresponding 3p regions and the frequent retention, with occasional amplification, of 3q in several types of human tumors.
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PMID:Differential elimination of 3p and retention of 3q segments in human/mouse microcell hybrids during tumor growth. 936 29

A formulation of metoclopramide (MCA) conformationally altered by neutralization of pH (nMCA, Neu-Sensamide) has been shown to have the same efficacy of enhancing the cytotoxicity of a single dose of 1 Gy radiation as acidic formulations (e.g., Primperan, Sensamide) in a human lung adenocarcinoma (H2981) xenografted into SCID mice. In the present study, 2 x 1 Gy radiation was combined with 2 x 2 mg nMCA/kg body weight injected 2 hr before radiation treatment for evaluation of radiosensitization in SCID mice xenografted with a human brain astrocytoma (T24). Given in this treatment schedule, nMCA alone at 2 mg/kg showed no cytotoxic effect on tumor growth in vivo. When combined with 2 x 1 Gy of radiation, however, the cytotoxicity was significantly increased as measured by tumor growth delay over the radiation-only-treated group. Furthermore, nMCA was absorbed into brains of mice and rats as efficiently as acidic MCA (aMCA) when analyzed 45 min after i.m. injection by high-performance liquid chromatography.
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PMID:Neutral metoclopramide sensitizes cytotoxicity induced by ionizing radiation in SCID mice xenografted with a human brain astrocytoma. 939 68

We have previously identified an approximately 7 cM long common eliminated region (CER), involving the 3p21.3 markers AP20R, D3S966, D3S3559, D3S1029, WI-7947, D3S2354, AFMb362wb9, and D3S32, in human chromosome 3/A9 mouse fibrosarcoma microcell hybrid (MCH) derived SCID mouse tumors. We now report the results of our more detailed analysis on 24 SCID mouse tumors derived from two MCH lines that originally carried intact human chromosomes 3. They were analyzed by fluorescence in situ hybridization (FISH) painting and PCR, using 24 markers covering the region between D3S1611 and D3S13235 at 3p22-p21.2. D3S32 and D3S2354 were regularly eliminated during in vivo tumor growth, whereas the other 22 markers, D3S1611, ACAA, D3S1260, WI-692, AP20R, D3S3521, D3S966, D3S1029, D3S643, WI-2420, MSTI. GNAI2, D3S1235, D3S1298, GLBI, WI-4193, D3S3658, D3S3559, D3S3678, WI-6400, WI-7947, and WI-10865, were regularly retained. We have defined a common eliminated region of approximately 1.6 cM (designated as CER1) inside the 7 cM CER described earlier. CER1 is flanked distally by D3S1029 and proximally by D3S643.
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PMID:Human/mouse microcell hybrid based elimination test reduces the putative tumor suppressor region at 3p21.3 to 1.6 cM. 940 48

In this study we attempted to develop a new xenochimeric model for HIV infection in SCID mice, characterized by an easy engraftment of target cells, high levels of viremia and long-lasting HIV-1 infection. SCID mice were injected subcutaneously with uninfected human U937 cells and cell-free HIV-1 (IIIB strain) or HIV-1-infected human peripheral blood lymphocytes (PBL). Mice were evaluated for tumor growth, viral infection at the tumor level (DNA-polymerase chain reaction (PCR), RNA-PCR) and immunostaining for the p55/p18 HIV protein) and p24 antigenemia or serum HIV-1 RNA copies. Pretreatment of mice with antibodies to either mouse-IFN alpha/beta or granulocytes resulted in a tumor take and levels of p24 antigenemia higher than in control mice. In mice treated with these antibody preparations, there was a long-lasting HIV infection with the presence of high levels of circulating infectious virus (serum p24 values up to 4000 pg/ml and serum RNA copies up to 5 x 10(7)/ml over 3 months, with the majority of the cells expressing HIV-antigens at the tumor site). Intraperitoneal treatment of SCID mice with AZT (480 mg/kg per day) resulted in a complete inhibition of both p24 and RNA HIV-1 copies in the serum, together with a marked reduction in the number of infected cells and the levels of virus expression at the tumor site. We conclude that some specific features of this model (i.e. easy establishment, high reproducibility, well defined kinetics of virus infection, massive and long persistent viremia) underline the special advantages of its use for testing new antiviral therapies.
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PMID:U937-SCID mouse xenografts: a new model for acute in vivo HIV-1 infection suitable to test antiviral strategies. 944 64

A cell line, designated ISOS-1, was established from a tumor formed by transplantation of a human angiosarcoma into mice with severe combined immunodeficiency (SCID). The cells showed endothelial properties, based on the uptake of Dil-Ac-LDL and binding of UEA-I/GSA-I lectins, but were negative for CD11b and Pan Cytokeratin. However, the cells lost differentiated characteristics such as expression of von Willebrand factor, contact inhibition growth and tube formation activity. These findings indicate that ISOS-1 is a poorly-differentiated endothelial cell line. At the 81st passage, all of the cells were positive for H-2Dd in various intensity, but not HLA-ABC. The metaphase chromosomes consistently showed a characteristic mouse, but not human, telocentric form. Furthermore, this cell line produced fatal tumor growth in SCID mice and also in BALB/c mice. These results suggest that ISOS-1 is a murine-phenotypic angiosarcoma cell line.
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PMID:Establishment of a new murine-phenotypic angiosarcoma cell line (ISOS-1). 945 20

We studied the antitumor effects of dolastatin 10, its structural modification, auristatin PE (TZT-1027), and vincristine alone and in combination with bryostatin 1 on a human diffuse large cell lymphoma line (WSU-DLCL2) in vitro and in vivo. WSU-DLCL2 cells were cultured in RPMI 1640 at a concentration of 2 x 10(5)/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis and apoptosis were assessed. Dolastatin 10 showed no apparent inhibition of cell growth at concentrations less than 500 pg/ ml. Auristatin PE showed significant growth inhibition at concentrations as low as 10 pg/ml, while vincristine had a minimal effect at 50 pg/ml. Dolastatin 10, auristatin PE and vincristine-treated cultures, at 50 pg/ml, exhibited 11, 1.7; 45, 11.8%; and 39, 25% mitosis and apoptosis, respectively. In the WSU-DLCL2 SCID mouse xenograft model, the efficacy of these agents alone or in combination with bryostatin 1 was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C) and log10 kill for dolastatin 10, auristatin PE, vincristine and bryostatin 1 were 30%, 14 days and 1.4; 0.0%, 55 days and 5.5; 29.6%, 16 days and 1.6; and 39%, 7 days and 0.7, respectively. When given in combination, two out of five mice treated with auristatin PE + bryostatin 1 were free of tumors for 150 days and were considered cured. Dolastatin 10 + bryostatin 1 and vincristine + bryostatin 1 combinations were highly active but no cure was observed. We conclude that: (i) auristatin PE is more effective in this model than dolastatin 10, vincristine or bryostatin 1, (ii) auristatin PE can be administered at a concentration 10 times greater than dolastatin 10, and (iii) there is a synergistic effect between these agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be further explored clinically in the treatment of lymphoma.
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PMID:Synergistic interaction of selected marine animal anticancer drugs against human diffuse large cell lymphoma. 951 May 1


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