Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigated the ability of a recombinant herpes simplex virus type 1 (HSV) vector to deliver genes into disseminated brain tumor foci through intrathecal injection of the vector. The animal model was designed to simulate brain tumors with cerebrospinal fluid (CSF) metastases, which are found especially in the pediatric population. 9L gliosarcoma cells were injected both into the right frontal lobe and in through the cisterna magna of adult rats. The HSV vector, hrR3, was inoculated intrathecally 5 days later. This vector is defective in the gene for ribonucleotide reductase, and, therefore, replicates preferentially in dividing cells; it retains an intact HSV-thymidine kinase gene (HSV-tk). Two days after injection of the vector, immunohistochemical staining for HSV thymidine kinase (HSV-TK) revealed expression in frontal tumors, as well as in leptomeningeal tumor foci along the entire neuroaxis. HSV-TK-immunopositive cells were most frequent in small tumors contacting the CSF pathways. Frontal lobe tumors showed the highest density of HSV-TK-immunopositive cells around their periphery with little expression in central parts. Some paraventricular neurons temporarily showed HSV-TK-immunolabeling at this early time point. The number of HSV-TK-immunopositive tumor cells markedly decreased 5 days after injection of the HSV vector. In all animals, some toxicity was observed in the first 2-4 days after virus injection with extensive leptomeningeal inflammation. In conclusion, intrathecal application of HSV vectors can mediate widespread transfer of the therapeutic HSV-tk gene into disseminated tumors throughout the brain and CSF pathways. Although there was marked toxicity associated with intrathecal injection of this vector, this mode of gene delivery offers a promising approach for treatment of CSF-metastases in conjunction with development of less toxic vectors.
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PMID:Herpes vector-mediated delivery of marker genes to disseminated central nervous system tumors. 883 17

Recombinant adenoviral mediated delivery of suicide and cytokine genes has been investigated as a treatment for hepatic metastases of colon carcinoma in mice. Liver tumors were established by intrahepatic implantation of a poorly immunogenic colon carcinoma cell line (MCA-26), which is syngeneic in BALB/c mice. Intratumoral transfer of the herpes simplex virus type 1 thymidine kinase (HSV-tk) and the murine interleukin (mIL)-2 genes resulted in substantial hepatic tumor regression, induced an effective systemic antitumoral immunity in the host and prolonged the median survival time of the treated animals from 22 to 35 days. The antitumoral immunity declined gradually, which led to tumor recurrence over time. A recombinant adenovirus expressing the mIL-12 gene was constructed and tested in the MCA-26 tumor model. Intratumoral administration of this cytokine vector alone increased significantly survival time of the animals with 25% of the treated animals still living over 70 days. These data indicate that local expression of IL-12 may also be an attractive treatment strategy for metastatic colon carcinoma.
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PMID:Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. 887 30

Metastases of breast cancer are a major cause of treatment failure. To evaluate the therapeutic efficacy of suicide gene therapy in metastatic breast cancer, we used the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) administration to treat breast cancer, generated by an adenocarcinoma cell line MOD in syngeneic mice. The bystander effect of HSV-tk + GCV on tumor cell killing was illustrated by demonstrating complete regression of subcutaneous tumors consisting of 90% parental tumor cells and 10% HSV-tk transformed tumor cells. To establish a model of breast cancer metastases in the liver, tumors were generated by intra-hepatic implantation of MOD cells in syngeneic animals. Two weeks after tumor cell implantation, replication defective adenoviral vectors expressing HSV-tk (ADV.tk), or beta-galactosidease (ADV. beta-Gal) were injected intratumorally, followed by buffer or GCV administration. Treatment with ADV.tk + GCV resulted in significant regression of tumor (P < .001), as assessed by computerized morphometric analysis of residual tumor. This was reflected as a significant prolongation of survival in treated animals (P < .001). These results demonstrate that ADV-mediated suicide gene therapy in vivo can be incorporated in a comprehensive treatment strategy for liver metastases of breast cancer.
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PMID:Adenoviral-mediated suicide gene therapy for hepatic metastases of breast cancer. 889 53

Tolerability of approximately 30 anticancer drugs vary by 50% or more according to circadian rhythms in mice or rats. Despite pharmacokinetics parameters of cytostatic drugs vary according to dosing time in rodents, cellular rhythms appear as the main mechanisms of their chronopharmacology: circadian changes in enzymatic activities involved into fluoropyrimidine (5-fluorouracil-5-FU, or floxuridine-FUdR) catabolism (dehydropyrimidine dehydrogenase) or anabolism (thymidine kinase), rhythms in reduced glutathione, involved into cellular protection against cytotoxic effects of alkylating drugs, platinum complexes and anthracyclines, rhythms in cellular proliferation of rapidly renewing tissues, such as bone marrow or intestinal tract. Furthermore, chemotherapy injection at the least toxic time allows to increase its antitumor efficacy against several transplanted rodent tumor models. Extrapolation of these results for improving therapeutic index of chemotherapy in cancer patients was based upon the hypothesis that rhythms in metabolism or proliferation of healthy tissues were tightly coupled to the circadian sleep-wakefulness cycle, both in rodents and in man. Programmable-in-time pumps allowed to test the clinical relevance of chronotherapy principle in patients with cancer metastases. Phase I clinical trials with 5-FU, FUdR, oxaliplatin-L-OHP, interferon-alpha and doxorubicin suggested that circadian-based chronomodulation of chemotherapy delivery rate both improved drug tolerability and allowed to increase its safe dose. Antitumor activity of such chronomodulated regimens, usually involving several drugs, appeared as superior to that achieved by standard protocols in Phase II clinical trials, especially in patients with renal cell cancer receiving FUdR and in patients with colorectal cancer treated with 5-FU, folinic acid (FA) and L-OHP (so called chrono-FFL regimen). A randomized european multicenter trial validated the clinical relevance of the chronotherapy principle in 278 patients with metastatic colorectal cancer: chrono-FFL was compared to flat FFL infusion and resulted in 2 to 10 times fewer severe toxic effects and a near-doubling of its antitumor efficacy, objective response rate being 51% with chrono-FFL and 30% with flat FFL (p < 0.001). These results have warranted to test further the relevance of chronotherapy in patients with breast, lung or pancreatic cancer metastases and to develop basic research on the role of biological rhythms upon cancer processes.
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PMID:[Chronopharmacology and chronotherapy of cancers]. 897 20

Hepatic metastasis of colon cancer is an important prognostic factor for survival. In this study, we examined the effect of gene therapy using the herpes simplex virus-thymidine kinase (HS-tk) gene with short-course ganciclovir (GCV) treatment for multiple hepatic metastases of murine colon cancer. Colon26 cells transfected with the HS-tk gene were found to be sensitive to GCV in a concentration-dependent way. On the other hand, induction of the HS-tk gene in the cells had no influence on cell growth in vitro. However, multiple hepatic metastases of Colon26 cells transfected with HS-tk gene were significantly suppressed by the GCV treatment. These results thus suggest that HS-tk gene therapy is useful for the treatment of hepatic metastasis in colon cancer.
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PMID:Effect of gene therapy with the herpes simplex virus-thymidine kinase gene on hepatic metastasis in murine colon cancer. 903 98

We analysed the glucocorticoid receptor (GR) function and its ability to modulate cell-cell interactions between the PA-III rat prostate cancer and UMR 106 osteoblast-like rat osteosarcoma cells as an in vitro model for studying GR function in PA-III cell-induced tumor and blastic reaction in rat bone. Intact GR was detected by ligand binding assays, DNA band-shift, and GR trans-activation analysis of PA-III and UMR 106 cells transiently transfected with the mouse mammary tumor virus thymidine kinase-chloramphenicol acetyltransferase reporter gene. Dexamethasone and transforming growth factor beta 1 (TGFbeta1) inhibited the growth of PA-III and UMR 106 cells. Dexamethasone's inhibition of PA-III and UMR 106 cells was reversed by anti-TGFbeta1 antibody and exogenous insulin-like growth factor I (IGF-I). Exogenous IGF-I, urokinase-type plasminogen activator (uPA), UMR 106 conditioned media (CM) and PA-III CM stimulated the proliferation of PA-III and UMR 106 cells. The mitogenic activity exerted by uPA and PA-III CM in UMR 106 cells was completely neutralized by anti-IGF-I specific antibody. In addition, dexamethasone up-regulated TGFbeta1 mRNA and down-regulated uPA mRNA expression in PA-III cells without affecting TGFbeta1 and uPA mRNA expression in UMR 106 cells. These data suggested that TGFbeta1, uPA, and IGF-I mediate at least in part cell-cell interactions and GR function in PA-III prostate cancer and UMR 106 osteosarcoma cells.
Clin Exp Metastasis 1997 May
PMID:Glucocorticoid receptor function possibly modulates cell-cell interactions in osteoblastic metastases on rat skeleton. 917 22

Pancreatic cancer is the fifth leading cause of cancer death in the United States. Most patients have obvious metastases or locally advanced disease at the time of presentation. Surgical resection does not significantly change the clinical outcome. Combination chemotherapy induces a partial response but overall survival remains low. The aim of this study was to evaluate the feasibility of adenovirus-mediated suicide gene transduction as a therapeutic approach for pancreatic cancer. A cell line was established from a murine pancreatic ductal adenocarcinoma and intrahepatic tumors were generated by inoculation of pancreatic cancer cells into the left lateral liver lobe. Transduction efficiency was characterized in vitro and in vivo. Intrahepatic tumors were treated by intratumoral adenovirus injection in combination with intraperitoneal administration of ganciclovir. Adenovirus-mediated herpes simplex virus (HSV)-thymidine kinase (tk) gene expression followed by ganciclovir treatment was highly efficient in inhibiting pancreatic cancer cell proliferation in vitro. The proliferation of nontransduced cells was significantly reduced in the presence of HSV-tk expressing cells. Intrahepatic inoculation of pancreatic cancer cells leads to successful formation of solid adenocarcinomas in syngeneic recipients. Ad.RSV-tk injection of the tumor followed by intraperitoneal ganciclovir application caused highly significant tumor volume reduction and necrosis. These results indicate that transduction of the HSV-tk gene followed by ganciclovir is highly efficient for growth inhibition of hepatic metastases of pancreatic carcinoma.
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PMID:Adenoviral-mediated herpes simplex virus thymidine kinase gene transfer: regression of hepatic metastasis of pancreatic tumors. 921 89

Metastases of lung cancer are a major cause of treatment failure. To evaluate the therapeutic efficacy of gene therapy in metastatic lung cancer, we used adenoviral (ADV) mediated transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene and the cytokine gene interleukin-2 (IL-2) to treat a murine model of metastatic lung cancer in the liver. Hepatic metastases were established by intrahepatic implantation of LL2 cells in syngeneic recipient mice. One week after tumor implantation, various replication defective ADV vectors were injected intratumorally. Treatment with a vector expressing the HSV-tk followed by ganciclovir administration with ADV.tk resulted in significant regression of tumor (p<0.01) as well as prolongation of survival (p<0.001). While a vector expressing mouse IL-2 ADV.IL-2 alone was ineffective, combination therapy with HSV-tk resulted in further tumor regression and improvement of animal survival (p<0.05). These results demonstrate that suicide and cytokine genes can be utilized in combination to treat metastatic lung cancer in vivo.
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PMID:Combination therapy with suicide and cytokine genes for hepatic metastases of lung cancer. 936 77

Herpes simplex virus-thymidine kinase (HS-tk) gene therapy with ganciclovir (GCV) treatment has been reported to inhibit the tumor growth, which is applied to the gene therapy targeted to the malignant brain tumor. To suppress the tumor growth completely, the authors designed the HS-tk gene therapy in combination with granulocyte macrophage-colony stimulating factor (GMCSF) gene using the hepatic metastatic model of murine colon cancer. The transduction of the HS-tk gene in combination with the GMCSF gene, followed by GCV, showed a complete inhibition of hepatic metastases of murine colon cancer, which was significantly superior to that of HS-tk gene alone. The growth of cancer cells transduced with both HS-tk and GMCSF genes was inhibited in vitro, and long-lasting antitumor immunity after hepatic metastasis of cancer cells transduced with both HS-tk and GMCSF genes was acquired. It is suggested that HS-tk gene therapy in combination with the GMCSF gene is effective for the complete inhibition of hepatic metastasis of murine colon cancer.
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PMID:Inhibition of establishment of hepatic metastasis in mice by combination gene therapy using both herpes simplex virus-thymidine kinase and granulocyte macrophage-colony stimulating factor genes in murine colon cancer. 940 3

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28


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