Gene/Protein Disease Symptom Drug Enzyme Compound
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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic potential of the antiretroviral drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) for the treatment of human immunodeficiency virus (HIV)- and human hepatitis B virus (HBV) infections is currently being explored in advanced clinical trials. In the present study, we investigated the impact of PMEA on cellular functioning (cell cycle, nucleotide metabolism, nucleic acid synthesis, ...). Moreover, we have unraveled the molecular/biochemical basis underlying the marked differentiation-inducing activity of PMEA (and related analogues) in tumor cells. We could demonstrate that PMEA is endowed with potent antitumor activity in a highly aggressive in vivo tumor model. These findings open new perspectives for the possible application of this type of compounds in cancer chemotherapy. The fact that AIDS patients frequently develop certain types of differentiation-susceptible malignancies (e.g. Kaposi's sarcoma) further attests the clinical relevance of our observations.
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PMID:Mechanistic study on the cytostatic and tumor cell differentiation-inducing properties of 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir)-collected publications. 1114 86

Approximately 15-30% of human non-small cell lung cancers (NSCLC) carry K-ras mutations, among which point mutations at codon 12 are the most common. This study characterizes the anti-tumor effect of an anti-K-ras ribozyme adenoviral vector (KRbz-ADV; replication-deficient, E1-deleted Ad5 backbone) against NSCLC lines that express the relevant mutation (K-ras codon 12 GGT --> GTT; H441 and H1725). KRbz-ADV significantly inhibited tumor cell growth (38-94% reduction by 3H-thymidine uptake) in a time- and dose-dependent manner, but produced minimal growth inhibition on normal epithelial cells, or NSCLC H1650 cells that lack the relevant mutation. The in vivo anti-tumorigenic effect of KRbz-ADV treatment was characterized with cell line xenografts in nu/nu mice. Pre-treatment with KRbz-ADV (10 or 20 p.f.u. per cell) completely abrogated subcutaneous engraftment of H441 (n = 13) or H1725 cells (n = 8), as compared with a 100% tumor take and progressive tumor growth in animals that received untreated tumor cells, or control vector (luciferase-adenovirus/Luc-ADV)-treated tumor cells. Pre-treatment with a mutant anti-K-ras ribozyme adenoviral vector (mutKRbz-ADV), which has the same specificity as KRbz but lacks ribozyme catalytic activity, did not produce an anti-tumorigenic effect. The in vivo effect of KRbz-ADV treatment was further examined by initiating injections (2 x 10(9) p.f.u.) at 7 days after tumor induction. Pre-existing tumor growth was reduced by 39% by a single intratumoral injection. Repeat injections (three or five KRbz-ADV-intratumoral injections at 2 x 10(9) p.f.u. every other day) resulted in complete tumor regression in five of seven mice. In contrast, single or multiple injections of control vector Luc-ADV did not significantly alter tumor xenograft outcome. Ribozyme expression was confirmed in H441 cells that demonstrated reduced growth after KRbz-ADV treatment. Reduced growth corresponded to significantly lowered levels of K-ras mRNA, as defined by RT-PCR (51% of untreated level, n = 3) and RNase protection assay (56% of untreated level, n = 4) analyses. Further, 37.5% of KRbz-ADV-treated cells underwent apoptosis, as compared with 11.7%, and 19.0% in untreated and Luc-ADV-treated cultures, respectively. A significantly higher proportion of KRbz-ADV-treated H441 cells (58.2%) underwent apoptosis when maintained under anchor-independent conditions that simulate in vivo tumorigenesis ('anoikis'). This is the first report that demonstrates that KRbz-ADV can effectively inhibit in vivo tumorigenesis, and produces regression of pre-existing human lung tumor xenografts having the relevant K-ras mutation.
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PMID:Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice. 1117 17

Tissue-specific transcriptional regulatory elements can increase the safety of gene therapy vectors. Unlike prostate-specific antigen (PSA/hK3), whose expression displays an inverse correlation with prostate cancer grade and stage, human glandular kallikrein 2 (hK2) is upregulated in higher grade and stage disease. Therefore, our goal was to develop a strong and prostate-specific hK2-based promoter for targeted gene therapy. We identified the minimum "full-strength" hK2 enhancer and built transcriptional regulatory elements composed of multiple tandem copies of this 1.2-kb enhancer, fused to the hK2 minimal promoter. Relative to the weak induction of the minimal hK2 promoter by androgen analog (R1881) in androgen receptor (AR)-positive LNCaP cells, transcriptional activity was increased by 25-, 44-, 81-, and 114-fold when one to four enhancers were spliced to the hK2 promoter, respectively. In contrast, the enhancer/promoter elements were inactive in the AR(-) prostate cancer line PC-3 and in a panel of nonprostate lines, including 293, U87, MCF-7, HuH-7, and HeLa cells. Furthermore, we generated a recombinant adenovirus, ADV.hK2-E3/P-EGFP, expressing enhanced green fluorescent protein (EGFP) under the control of the hK2 triplicate enhancer/promoter, and compared its properties with ADV.CMV-EGFP expressing EGFP under the control of the cytomegalovirus (CMV) enhancer/promoter. Unlike the CMV promoter, the hK2-E3/P promoter was at least 100-fold inducible by R1881 in the adenoviral backbone. Compared with in situ injection of subcutaneous LNCaP tumors with ADV.CMV-EGFP, which led to detectable EGFP expression in tumor, liver, and brain tissue, ADV.hK2-E3/P-EGFP injection led to robust but tumor-restricted EGFP expression. These results suggest that the hk2 multienhancer/promoter should be a powerful novel reagent for safer targeted gene therapy of prostate cancer.
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PMID:Robust prostate-specific expression for targeted gene therapy based on the human kallikrein 2 promoter. 1126 87

Studies of reactions in animals with hereditary diseases (Sapphire minks highly sensitive to Aleutian disease virus, ADV; CBA mice with 60-70% incidence of tumors; AKR mice with 90% incidence of leukemia) showed that serum DNAse activity in these animals dropped after injection of a foreign heterogeneous DNA and remained decreased during 72 h. By contrast, serum DNAse activity considerably and persistently increased after injection of DNA in Standard minks resistant to ADV, C57BI/6J mice with 1% tumor incidence, and random-bred albino mice. Presumably the capacity of standard minks to react to a foreign heterogeneous DNA by increase of DNAse activity ensures their resistance to DNA-containing ADV, while incapacity of Sapphire minks to respond to DNA by DNAse activity induction makes them sensitive to ADV. A similar relationship between the capacity to react to DNA by changes in serum DNAse activity and capacity to inherit a disease was detected in mouse strains.
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PMID:[Dynamic of DNAse activity induction in serum of normal animals after heterogeneous DNA injection and in hereditary pathology]. 1139 67

A novel strategy was developed for the synthesis of N(7)-purine acyclic nucleosides 9 and 14. The key step involved the reaction between [2-(p-methoxyphenyloxy)ethoxy]methyl chloride and N(9)-tritylated nucleobases 6 or 11 followed by concomitant self-detritylation. N(7)-Guanine acyclic nucleoside 9 exhibited antiviral activity, but was phosphorylated by both HSV and Vero cell thymidine kinases. Thus, it showed more potent cellular toxicity than acyclovir (2). N(7)-Adenine acyclic nucleoside 14 was found to be an excellent antiviral agent as well as a good inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows for a greater expression of antiviral activity of antiviral agents, such as N(9)-adenine acyclic nucleoside 1 and ara-A (3). Compound 14 was phosphorylated neither by herpes simplex virus (HSV) thymidine kinase nor by Vero cell thymidine kinase, yet it enhanced the rate constant for the monophosphorylation of acyclovir (2) by HSV thymidine kinase. Consequently, the combination of acyclovir (2) and 14 exhibited greater antiviral activity than acyclovir alone. 7-[2-(Phosphonomethoxy)ethyl]adenine (20) was also synthesized. The key step involved the reaction of 9-(2-cyanoethyl)adenine (15) with methyl iodoacetate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. Unlike 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, 4), the N(7)-isomer 20 was not phosphorylated effectively by 5-phosphoribosyl 1-pyrophosphate synthetase (PRPP synthetase). Thus, it did not exhibit pronounced antiviral activity. Dinucleotide 5'-monophosphate 24 and its butenolide ester 25 were also synthesized. Compound 24 showed substrate activity toward PRPP synthetase and exhibited notable activity against DNA viruses. The antiviral activity of the ester derivative 25 was found to be higher than that of the parent molecule 24. Dinucleotide 5'-monophosphate 24 is susceptible to degradation by snake venom and spleen phosphodiesterases. However, its respective butenolide ester derivative 25 was completely resistant to snake venom and spleen enzymes. Butenolide ester derivatives 28 and 29 were also synthesized and exhibited notable anti-DNA virus and anti-retrovirus activity in vitro. Compounds 2, 4, 9, 14, 20, 24, 25, and 28 were also evaluated for their inhibitory effect on HSV-1-induced mortality in NMRI mice. N(7)-adenine acyclic nucleoside 14 [LD(50) (intraperitoneal, ip) 950 mg/kg], nucleotide-containing butenolide 25 [LD(50) (ip) 675 mg/kg], and butenolide 28 [LD(50) (ip) 710 mg/kg] were found to be potent anti-HSV-1 agents in vivo. In addition, butenolide 28 efficiently decreased tumor formation induced by Moloney murine sarcoma virus (MSV) in NMRI mice while significantly increasing the survival time of MSV-infected mice.
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PMID:Design, synthesis, and biological evaluation of novel nucleoside and nucleotide analogues as agents against DNA viruses and/or retroviruses. 1160 36

Nasopharyngeal carcinoma (NPC) is universally associated with EBV infection. We have shown that the phosphonated nucleoside analog, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)-propyl]cytosine (HPMPC) strongly inhibits growth of NPC xenografts in nude mice by causing apoptosis (J. Neyts et al., Cancer Res., 58, 384-388, 1998). We, therefore, tested two additional members of this drug family that have different degrees of antiviral activity, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-2-(R)-(phosphonomethoxy)propyladenine (PMPA). Intratumoral injection of PMEA (75 microl of 2% solution) in C15 NPC xenografts, which are latently infected with EBV, slowed tumor growth moderately, whereas PMPA (75 microl of 2% solution) slowed tumor growth only marginally. Compared with the previous results showing complete regression of tumor, PMEA had less antitumoral effect than HPMPC, and PMPA had the least. After 4 weeks of preventive treatment, tumors formed in 12.5, 50, and 100% of mice treated with HPMPC, PMEA, and PMPA, respectively, in contrast to the development of tumors in all of the PBS-treated control mice. We also investigated the effect of each drug on the EBV-positive epithelial cell line NPC-KT in vitro. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed inhibition of growth of NPC-KT cells by HPMPC and PMEA, but not by PMPA, which correlates with the results observed in tumor xenografts. Growth inhibition was attributable to induction of apoptosis in NPC-KT cells as indicated by a DNA fragmentation assay. Cleavage of poly(ADP-ribose) polymerase after treatment of NPC-KT cells with HPMPC was observed, which suggested that the apoptosis may be mediated by caspase(s). The apoptotic effects of the drugs are independent of any effects on EBV DNA polymerase, which is not expressed in these latently infected NPCs. These results suggest that HPMPC as well as PMEA could provide an adjunctive treatment for NPC.
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PMID:Prevention and inhibition of nasopharyngeal carcinoma growth by antiviral phosphonated nucleoside analogs. 1169 6

Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog ([((1)31)I]-FIAU) serving as a substrate for HSV-tk. [((1)31)I]-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.
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PMID:Tumor-specific transcriptional targeting of suicide gene therapy. 1185 19

Herpes simplex virus (HSV) thymidine kinase (tk) gene incorporated into adenovirus was delivered intraperitoneally (ip) followed by an antiherpetic prodrug and topotecan in patients with recurrent epithelial ovarian cancer. Tissue response was evaluated. Ten patients underwent secondary debulking with subsequent delivery of ADV-HSV-tk therapy. Two patients each were treated at dose level 1 (2 x 10(10) vector particles = VP), 2 (2 x 10(11) VP), and 3 (2 x 10(12) VP); four patients were treated at dose level 4 (2 x 10(13) VP). Five patients underwent second-look surgery about one month after gene therapy (GT). Treatment response, presence of vector DNA, protein expression of steroid hormone receptors, p53, c-erbB2 and Ki67 protein were analyzed. At second-look, two out of five patients were tumor-free and none of their peritoneal biopsies showed vector DNA. After GT, the vital tumor mass was smaller, desmoplastic reaction had increased, and tumors were less differentiated with an increase of Ki67 expression. There was no change in expression of hormone receptors, p53, or c-erbB2. ADV-HSV-tk GT appears to eliminate cells with higher differentiation first and might induce fibrosis. Dedifferentiation might render residual cells more sensitive to chemotherapy secondary to their subsequent higher mitotic activity.
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PMID:Histologic and immunohistochemical analysis of tissue response to adenovirus-mediated herpes simplex thymidine kinase gene therapy of ovarian cancer. 1186 May 38

We have shown that interleukin-12 (IL-12) generated a strong, albeit transient, anti-tumor response, mostly mediated by natural killer (NK) cell. T cell participation, in addition to NK cells, was essential for persistence of the anti-tumor response. Ligation of 4-1BB, a co-stimulatory receptor expressed on activated T cells, is known to amplify T cell-mediated immunity. In this study, we compared the effect of a systemically delivered agonistic anti-4-1BB monoclonal antibody (anti-4-1BB mAb) with intra-tumoral adenoviral-mediated gene transfer of the 4-1BB ligand (ADV/4-1BBL) to liver metastases in a syngeneic animal model of breast cancer. Both treatments induced a dramatic regression of pre-established tumor. When combined with intra-tumoral delivery of the IL-12 gene, both anti-4-1BB mAb and ADV/4-1BBL were synergistic and led to survival rates of 87% and 78%, respectively. The anti-tumor immunity is mainly mediated by CD4+ T cells in IL-12 plus 4-1BB ligand-treated animals, and CD8+ T cells in IL-12 plus anti-4-1BB mAb-treated animals. However, only long-term survivors after treatment with IL-12 and 4-1BBL genes have showed significantly potent, systemic, and tumor-specific T cell-mediated immunity.
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PMID:T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer. 1204 Apr 60

The transduction efficiencies of adeno-associated viral vectors (AAV, serotype 2) and adenovirus vectors (ADV, serotype 5) were examined in three different models of cancer. First, we used flow cytometry to quantitate AAV-GFP or ADV-GFP transduction in 13 cell lines derived from malignant tissue (6 gliomas, 6 mammary cancers, and 1 leukemia). These experiments showed variable transduction efficiency (0%-81%) between the cell lines, with ADV being more effective compared to AAV in 9 of 13 cell lines. Second, spheroids prepared from human glioblastomas were infected with ADV or AAV expressing GFP or lacZ cassettes, and after 2 weeks, uniform reporter gene expression was observed on the spheroid. Whereas AAV produced consistent transduction throughout the spheroids, ADV infection was mainly limited to the outer cell layers of the spheroids, suggesting that AAV were more efficient at penetrating solid tumor tissue. Third, human biopsies from glioblastoma multiforme patients were xenografted into nude rats and grown for 4 weeks followed by viral vector injection. Combined use of high-resolution magnetic resonance imaging (MRI) and histologic analysis allowed the identification of transduced cells and their spatial distribution within the tumors. AAV-mediated transgene expression was observed in cell clusters through the entire tumor, while ADV-mediated transduction was restricted to cells at the tumor periphery. Thus, while AAV and ADV vectors may infect tumor-derived cell lines to a similar degree, AAV penetrated glioblastoma spheroids and xenografts more efficiently compared to ADV vectors. These results suggest that AAV may be suitable for therapeutic gene delivery to malignant tumors.
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PMID:Adeno-associated viral vectors penetrate human solid tumor tissue in vivo more effectively than adenoviral vectors. 1206 44


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