Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six patients with liver metastases from carcinoid or colon carcinoma underwent hepatic derterialization. This operation, known to cause both tumor necrosis and liver cell damage, caused considerable increases of several lysosomal acid hydrolases in the circulation. Thus, beta-glucosidase showed a small temporary increase during the operation, followed by a slower but higher reaction reaching a maximum 12 to 36 hours postoperatively. Similar reactions were noted for beta-glucuronidase, acid phosphatase, beta-galactosidase, arylsuphatase A, and N-acetyl-beta-glucosaminidase while no reactions were found for cathepsin D. Very high enzyme levels occurred in a patient dying from bleeding complications in the postoperative period.
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PMID:Plasma activities of lysosomal enzymes after hepatic dearterialization in man. 0 1

We have achieved efficient transduction of tumour metastases in vivo by the vascular delivery of retroviral producer cells. Experimental liver metastases in mice were created by intrasplenic injection of tumour cells into the portal venous circulation. Following the establishment of micrometastases, delivery of retroviral producer cells by the same route with a vector containing the Escherichia coli beta-galactosidase (lacZ) gene demonstrated selective in vivo gene transfer to tumour deposits. By this approach, two retroviral producer cell lines encoding cytokines (IL-4 and IL-2) directed tumoricidal inflammatory responses to established metastases. Cytokine gene targeting inhibited metastasis formation and caused significant overall reduction in tumour burden. These results suggest a novel therapeutic approach for the treatment of disseminated cancer.
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PMID:Gene therapy of metastatic cancer by in vivo retroviral gene targeting. 767 Apr 93

To better understand the events occurring during immunotherapy of liver metastases with effector cells, we have developed a clinically relevant animal model in which both effector-tumor cell interactions and survival can be evaluated. A cell line of human gastric carcinoma (HR) metastatic to the liver has been established from a patient's liver biopsy. HR cells (10 x 10(6)) injected intrasplenically metastasize into the liver of immunosuppressed nude mice, with micrometastases detectable histologically by day 4 and macrometastases by day 7. The animals subsequently develop ascites and die between days 30 and 40 after tumor injection. To investigate early metastatic events in the liver, HR cells were transduced with a plasmid containing both the lacZ gene under the control of the CMV promoter and NeoR gene. Transfectants selected for neomycin resistance were lacZ gene positive and stained blue in the presence of a beta-galactosidase substrate, 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal). These transfectants (HRLZ) remained lacZ gene positive for at least 25 passages in vitro. Injected intrasplenically, an HRLZ clone grew invasively in nude mice and formed liver metastases comparably to parental tumor cells. The number and localization of blue X-Gal-positive tumor cells were followed in liver tissues of animals sacrificed at various times, from 1 h to 28 days postinjection of HRLZ cells. HRLZ cells were seen in liver blood vessels and sinusoids within 1 h after injection, and the progressive growth of micrometastases and macrometastases could be followed with precision by X-Gal staining. On day 3 after injection of HRLZ cells, numerous micrometastases were established containing 12-16 tumor cells. When these 3-day established HRLZ micrometastases were treated by the intrasplenic infusion of interleukin 2 (IL2)-activated human natural killer (NK) cells selected by IL2-induced adherence to plastic (A-NK) and systemic IL2, nearly all liver micrometastases were eliminated within 24 h after a single transfer of A-NK cells (P < 0.001). This xenogeneic model was also used for adoptive immunotherapy of 7-day established liver macrometastases with human A-NK cells injected intrasplenically and exogenous IL2 given i.p. A significant decrease in the number of hepatic metastases and the weight of livers (P < 0.003) in comparison with those of control mice was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Immunotherapy of liver metastases of human gastric carcinoma with interleukin 2-activated natural killer cells. 803

Expression of urokinase-type plasminogen activator (uPA) by malignant cells correlates with an aggressive phenotype, including increased invasiveness, tumor-associated angiogenesis, and metastases. Plasminogen activator inhibitor type 1 (PAI-1) is undetectable in cells of some aggressive malignancies, but present in the stroma of tumor-associated microvasculature. This analysis of an athymic mouse model of prostate carcinoma further defines the role of the uPA/PAI-1/plasmin system in primary growth and metastasis. A marked increase in PAI-1 expression was induced in clones of the aggressive human prostate carcinoma line, PC-3, by stable transfection. Primary PC-3 tumors, in mice, were significantly smaller when derived from PAI-1 expressing versus control cells. PAI-1 expression reduced the density of tumor-associated microvasculature by 22-38%. Microscopic metastases were quantitated using stable expression of the chromogenic label (beta-galactosidase) in control and PAI-1 expressing cells. PAI-1 expression resulted in a significant inhibition of lung metastases, and liver metastases. Expression of PAI-1 by malignant prostate cells resulted in a less aggressive phenotype, presumably by inhibition of uPA activity, suggesting pharmacologic or molecular inhibition of uPA activity as a potential therapeutic target.
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PMID:Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. 867 23

Disseminated colon carcinoma metastases in the liver are associated with low cure rates and constitute a serious therapeutic problem. Appropriate experimental models which mimic metastases development and outgrowth can provide insight into the mechanism of this lethal process and facilitate the finding of new approaches for its control. We established an orthotopic liver metastases model based on CC531 rat colon adenocarcinoma cells which were transfected with a beta-galactosidase gene as marker to facilitate their detection. Intraportal injection of CC531-lac-Z cells resulted in a rapid and locally aggressive growth within the liver and was characterised by a tumour volume doubling time of 20 h and abundant angiogenesis. A commercially available chemi-luminescence assay allowed rapid, quantitative and sensitive detection of the diffusely growing tumour cells. Immunogenicity of CC531-lac-Z cells induced by the marker gene was significantly reduced by co-administering the tumour cells with matrigel. Within an observation period of three weeks following tumour cell injection only 6% of the animals showed lung involvement, thus indicating a specific homing of CC531-lac-Z cells to the liver. This period appears long enough to allow therapeutic manipulations at various stages of tumour growth in the liver. It is envisaged that the model will have applications for various therapeutic strategies.
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PMID:Quantitative detection of lac-Z-transfected CC531 colon carcinoma cells in an orthotopic rat liver metastasis model. 1065 3

Systemic chemotherapy has limited success in treating liver metastasis of colorectal cancer. Alternative approaches such as hepatic arterial infusion or trans arterial chemoembolisation aim to deliver the chemotherapy locally to address the predominant liver disease. Chemoembolisation with drug eluting beads (DEB) designed to deliver drug at the target over a protracted period of time is a new strategy to reduce the tumor burden of liver metastases. To test this hypothesis, DEB possessing anionic groups capable of ionically complexing with cationic drugs were synthesised by a suspension polymerisation method and were fractionated to produce an average size of 75 microm. The DEB were loaded with the desired concentration of either doxorubicin hydrochloride or irinotecan hydrochloride prior to administration by immersion in the drug solution, yielding essentially 100% loading efficiency. To determine their effect in vivo, a transplantable orthotopic and isogenic rat liver metastasis model was used which is based on intraportal injection of 4 x 10(6) beta-galactosidase transfected CC531 rat colorectal cancer cells into male WAG/Rij rats. By MTT assay, the cells were shown to be sensitive to both drugs in vitro with the IC(50) being by two orders of magnitude lower for doxorubicin (110 nM after 72 h) compared to irinotecan (25 microM after 72 h). For the in vivo phase, a differential expression of the ERK MAP kinase between tumor cells cultured in vitro and those inoculated in vivo was noted using Western blotting techniques. This was considered to be indicative of passage-induced cell senescence that reduced the sensitivity of the tumor cells to DEB chemoembolisation. This notwithstanding, administration of DEB loaded with irinotecan or doxorubicin by single injection into the hepatic artery showed significant anticancer activity, as measured by a reduction in the tumor burden of the liver and a corresponding reduction in liver weight. Comparing the two agents, irinotecan appears more advantageous because of its significant activity and excellent tolerability following administration at two dosages of either 20 or 30 mg/kg. Doxorubicin showed a narrower window of activity, being effective at 4 mg/kg but ineffective at the lower dose of 2 mg/kg. We conclude that chemoembolisation with DEB with either agent may have potential for treating patients with colorectal liver metastasis, although irinotecan DEB appeared to have a more favourable safety profile.
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PMID:Chemoembolisation of rat colorectal liver metastases with drug eluting beads loaded with irinotecan or doxorubicin. 1825 82