Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary metastases are the main cause of death of patients with several types of cancer, including osteosarcoma, renal cell carcinoma, malignant melanoma, and breast cancer. Previously, we demonstrated that intralesional injection of the recombinant adenovirus (Ad) vector containing the herpes simplex virus thymidine kinase (TK) gene driven by an osteocalcin (OC) promoter (Ad-OC-TK) effectively suppressed the growth of osteosarcoma cells in vitro and tumors in vivo in a tumor-specific manner when supplemented with the prodrug acyclovir (ACV). In this communication, we studied the potential efficacy of the treatment of osteosarcoma pulmonary metastases with a systemic delivery route of Ad-OC-TK supplemented with ACV. We established osteosarcoma lung metastases in nude mice by the intravenous injection of rat osteosarcoma cells, ROS 17/2.8. These cells colonized and formed tumor nodules within 1 week in the lungs of nude mice. Whereas systemic delivery of a recombinant Ad vector containing the Escherichia coli beta-galactosidase (beta-gal) gene driven by a Rous sarcoma virus universal promoter (Ad-RSV-beta-gal) resulted in the nonspecific expression of beta-gal activity in the lung parenchyma, Ad-OC-beta-gal administration resulted in specific beta-gal expression in tumor cells deposited in the lung. When nude mice bearing ROS 17/2.8 lung tumors were treated with systemic Ad-OC-TK through tail vein administration, subsequent intraperitoneal ACV treatment significantly decreased the number of tumor nodules (P < .0001) and the net lung wet weight (P = .0005) while significantly increasing (.005 < P < .01) the survival of animals, when compared with untreated and Ad-OC-TK- or ACV-treated control groups. These results suggest that Ad-OC-TK/ACV may be used as a systemic therapy for the treatment of osteosarcoma lung metastasis.
 ...
PMID:In vivo suppression of osteosarcoma pulmonary metastasis with intravenous osteocalcin promoter-based toxic gene therapy. 982 46

As conventional therapy of osteosarcoma is aggressive and its success relatively poor, notably in cases relapse, we investigated the therapeutic effect of retroviral herpes simplex thymidine kinase (HSV1-TK) gene transfer into a human osteosarcoma cell line. Transfected target cells are sensitive to ganciclovir (GCV) (IC50 0.1 microM), and a potent bystander effect, by which cell death can be induced in HSV1-TK negative dividing cells located in the vicinity of HSV1-TK positive ones, is demonstrated. This is significant for clinical applications as no available gene transfer method can achieve 100% transduction to target cells.
 ...
PMID:Selective killing of osteosarcoma cells in culture after retroviral mediated gene transfer of a herpes simplex thymidine kinase suicide gene. 1022 26

Previous results have demonstrated the efficiency of Herpes simplex type 1 thymidine kinase (HSV1-TK) retroviral gene transfer and ganciclovir (GCV) treatment of a human osteosarcoma cell line resulting in the death of the cell population and a proximal bystander effect; therefore, we investigated gene therapy on an in vivo osteosarcoma rat model. For in vivo experiments, small fragments of tumor were grafted onto rats in a paratibial position. Seven days after the graft, packaging cells (psi CRIP-TK and psi CRIP-LLZ) were inoculated into tumor mass, followed by GCV administration. In vivo results showed the efficiency of this system that allowed the reduction of the tumor mass and prevented lung metastasis appearance, which represents the normal evolution. This type of treatment seems promising for rapidly proliferating tumors such as osteosarcoma; the lower IC50 makes this system particularly attractive as clinically doses may be of low magnitude to prevent secondary effects in patients.
 ...
PMID:Treatment of experimental osteosarcoma tumors in rat by herpes simplex thymidine kinase gene transfer and ganciclovir. 1022 27

2-Acetylpyridine hydrazone derivatives of benzothiazole, benzoxazole, and benzimidazole were found to exhibit potent cytotoxic activity against the growth of suspended leukemia and lymphomas. They were also active in a number of solid tumor screens, e.g. HeLa uterine carcinoma, SOS bone osteosarcoma, lung MB9812, lung A549, Mcf-7 breast growth. In L1210 lymphoid leukemia cells the compounds preferentially inhibited RNA synthesis followed by DNA synthesis at 100 microM after 60 min. The reduction of de novo purine synthesis by the compounds at the regulatory sites PRPP-amido transferase, IMP dehydrogenase and dihydrofolate reductase was responsible for the suppression of nucleic synthesis. Other minor sites where the agents have metabolic effects were thymidylate synthetase and thymidine kinase which would be additive with the overall inhibition of cell growth. The ct-DNA studies suggest that the compounds also interacted with the DNA molecule itself, probably affecting template activity.
 ...
PMID:Investigations on the mechanism of action of the novel antitumor agents 2-benzothiazolyl, 2-benzoxazolyl, and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine. 1032 84

Current treatment of osteosarcoma produces disappointing outcomes, and innovative therapies must be investigated. We have used retroviral vectors to transfer the herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human osteosarcoma cells. Each gene was stably transduced and expressed; the HSVtk gene effectively conferred ganciclovir (GCV) susceptibility to transduced cells. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to GCV killing. Human osteosarcoma cells were used to develop a series of experiments in athymic nude mice to treat experimental osteosarcoma. Subcutaneously implanted mixtures of tumor cells and HSVtk vector producer cells developed into tumors that completely regressed upon administration of GCV. Subcutaneously implanted mixtures of transduced and wild-type cells showed a potent bystander effect upon administration of GCV, with complete tumor ablation when as little as 10% of the cells were HSVtk+. A significant (P < .05) antitumoral response was seen against primary tumors composed of unmodified cells when a secondary tumor of transduced cells was implanted at a distance of 1 cm, suggesting a diffusible bystander factor. The presence of interleukin-2-transduced cells improved the efficacy of treatment. A significant (P < .03) antitumoral response was seen in the treatment of established osteosarcomas by the injection of HSVtk vector producer cells.
 ...
PMID:Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes. 1077 Jun 26

Nucleoside kinases from several species are investigated as "suicide genes" for treatment of malignant tumors by combined gene/chemotherapy. We have recently cloned a multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK), and we have shown that the enzyme phosphorylates cytotoxic pyrimidine and purine nucleoside analogs. The broad substrate specificity of the enzyme, as well as its very high catalytic rate, makes it a unique member of the nucleoside kinase enzyme family. In the present study, we evaluated Dm-dNK as a suicide gene by constructing a replication-deficient retroviral vector that expresses the enzyme. The human pancreatic adenocarcinoma cell line MIA PaCa-2 and a thymidine kinase-deficient osteosarcoma cell line were transduced with the recombinant virus. We showed that Dm-dNK can be expressed in human cells, that the enzyme retained its enzymatic activity, and that it is localized in the cell nuclei due to a nuclear localization signal in its C-terminal region. The cells expressing Dm-dNK exhibited increased sensitivity to several cytotoxic nucleoside analogs, such as 1-beta-d-arabinofuranosylcytosine, 1-beta-d-arabinofuranosylthymine, (E)-5-(2-bromovinyl)-2'-deoxyuridine, 2-chloro-2'-deoxyadenosine, and 2',2'-difluorodeoxycytidine. These findings suggest that Dm-dNK may be used as a suicide gene in combined gene/chemotherapy of cancer.
 ...
PMID:Retroviral transduction of cancer cell lines with the gene encoding Drosophila melanogaster multisubstrate deoxyribonucleoside kinase. 1099 93

Herpes simplex virus type 1 (HSV-1) encodes a thymidine kinase (TK) that markedly differs from mammalian nucleoside kinases in terms of substrate specificity. It recognizes both pyrimidine 2'-deoxynucleosides and a variety of purine nucleoside analogs. Based on a computer modeling study and in an attempt to modify this specificity, an HSV-1 TK mutant enzyme containing an alanine-to-tyrosine mutation at amino acid position 167 was constructed. Compared with wild-type HSV-1 TK, the purified mutant HSV-1 TK(A167Y) enzyme was heavily compromised in phosphorylating pyrimidine nucleosides such as (E)-5-(2-bromovinyl)-2'-deoxyuridine and the natural substrate dThd, whereas its ability to phosphorylate the purine nucleoside analogs ganciclovir (GCV) and lobucavir was only reduced approximately 2-fold. Moreover, a markedly decreased competition of natural pyrimidine nucleosides (i.e., thymidine) with purine nucleoside analogs for phosphorylation by HSV-1 TK(A167Y) was observed. Human osteosarcoma cells transduced with the wild-type HSV-1 TK gene were extremely sensitive to the cytostatic effects of antiherpetic pyrimidine [i.e., (E)-5-(2-bromovinyl)-2'-deoxyuridine] and purine (i.e., GCV) nucleoside analogs. Transduction with the HSV-1 TK(A167Y) gene sensitized the osteosarcoma cells to a variety of purine nucleoside analogs, whereas there was no measurable cytostatic activity of pyrimidine nucleoside analogs. The unique properties of the A167Y mutant HSV-1 TK may give this enzyme a therapeutic advantage in an in vivo setting due to the markedly reduced dThd competition with GCV for phosphorylation by the HSV-1 TK.
 ...
PMID:Selective abolishment of pyrimidine nucleoside kinase activity of herpes simplex virus type 1 thymidine kinase by mutation of alanine-167 to tyrosine. 1109 70

The broad substrate specificity of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) has provided the basis for selective antiherpetic therapy and, more recently, suicide gene therapy for the treatment of cancer. We have now constructed an HSV-1 TK mutant enzyme, in which an asparagine (N) residue is substituted for glutamine (Q) at position 125, and have evaluated the effect of this amino acid change on enzymatic activity. In marked contrast with wild-type HSV-1 TK, which displays both thymidine kinase and thymidylate kinase activities, the HSV-1 TK(Q125N) mutant was unable to phosphorylate pyrimidine nucleoside monophosphates but retained significant phosphorylation activity for thymidine and a series of antiherpetic pyrimidine and purine nucleoside analogs. The abrogation of HSV-1 TK-associated thymidylate kinase activity resulted in a 100-fold accumulation of the monophosphate form of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) in osteosarcoma cells transfected with the HSV-1 TK(Q125N) gene compared with osteosarcoma cells expressing wild-type HSV-1 TK. BVDU monophosphate accumulation gave rise to a much greater inhibition of cellular thymidylate synthase in HSV-1 TK(Q125N) gene-transfected cells than wild-type HSV-1 TK gene-transfected osteosarcoma tumor cells without significantly changing the cytostatic potency of BVDU for the HSV-1 TK gene-transfected tumor cells. Accordingly, the presence of the Q125N mutation in HSV-1 TK gene-transfected tumor cells was found to result in a multilog decrease in the cytostatic activity of those pyrimidine nucleoside analogs that in their monophosphate form do not have marked affinity for thymidylate synthase [i.e., 1-beta-D-arabinofuranosylthymine and (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil].
 ...
PMID:Mutation of Gln125 to Asn selectively abolishes the thymidylate kinase activity of herpes simplex virus type 1 thymidine kinase. 1116 Aug 65

In human cells, telomerase activity is regulated by transcriptional control of the telomerase reverse transcriptase gene (hTERT) whose product is the catalytic subunit of the enzyme. The hTERT promoter is active in virtually all types of tumors and immortal cells, but is silent in most adult somatic tissues. In this study, we placed the herpes simplex virus thymidine kinase gene under the control of the hTERT promoter with the aim of restricting its expression to tumor cells. In transfection experiments, the hTERT promoter driven thymidine kinase gene (hTERTp/TK) conferred ganciclovir sensitivity to all tumor and immortal cell lines tested, whereas normal somatic cells remained largely unaffected. Human hTERTp/TK-positive cancer cells implanted in nude mice developed into tumors that could be eradicated by ganciclovir treatment. The hTERTp/TK cassette was inserted into an adenovirus vector and its efficacy in reducing tumor growth was compared with that of an adenovirus carrying the thymidine kinase gene under the control of the cytomegalovirus immediate-early promoter (CMVp/TK). In a xenograft model using the human 143B osteosarcoma cell line, a single injection of either virus resulted in equivalent tumor regression and survival upon ganciclovir treatment. In animals injected intratumorally with the CMVp/TK adenovirus, expression of the thymidine kinase gene was detected in tumors, as well as in liver samples. Expression of the suicide gene in combination with ganciclovir resulted in severe liver histopathology and in an elevation of hepatic enzymes. In sharp contrast, when the hTERT promoter controlled the thymidine kinase gene, transgene expression was observed in tumors, but not in liver samples. Normal liver function in these animals was confirmed by serum levels of hepatic enzymes that were indistinguishable from those of control healthy mice. These results indicate that by restricting thymidine kinase expression to tumor cells, the hTERT promoter allows the tumoricidal effect of the suicidal gene to be exerted without detrimental consequences on healthy tissues and vital organs. The tight specificity of expression imparted by the hTERT promoter will assist the development of novel approaches to the treatment of a broad array of cancer types.
 ...
PMID:The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters. 1131 24

The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) can be expressed in human cells with retained enzymatic activity. The cells expressing Dm-dNK exhibit increased sensitivity to several cytotoxic nucleoside analogs. In this study, we further evaluated Dm-dNK as a potential novel suicide gene in combination with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) as the prodrug. We used two human cancer cell lines transduced with a retrovirus encoding the Dm-dNK cDNA and investigated whether the cells expressing the enzyme can induce cell death of untransduced cells, a phenomenon known as the "bystander effect". A bystander effect was observed in a thymidine kinase-deficient human osteosarcoma cell line but not in the MIA PaCa-2 human pancreatic adenocarcinoma cell line. The cytotoxicity of BVDU increased in both cell lines when the compound was used in combination with subtoxic concentrations of hydroxyurea. Hydroxyurea also enhanced the bystander effect in the osteosarcoma cells, but not in the MIA PaCa-2 cells, treated with BVDU. These findings indicate that BVDU phosphorylated by Dm-dNK in transduced cancer cells may also induce bystander cell death in certain cell lines.
 ...
PMID:Bystander effects of cancer cell lines transduced with the multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster and synergistic enhancement by hydroxyurea. 1145 12


<< Previous 1 2 3 4 5 6 Next >>