Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acyclic nucleoside phosphonate derivative 9-(2-phosphonylmethoxyethyl) adenine (PMEA) is a strong inducer of differentiation in several tumor cell lines, including human erythroleukemia K562 cells. A PMEA-resistant K562 cell line (designated K562/PMEA-1) was selected in the presence of escalating PMEA concentrations. This cell line proved to be insensitive to the induction of erythroid differentiation by PMEA. It also was 108-fold resistant to the cytostatic effects of PMEA. The K562/PMEA-1 cells showed reduced sensitivity to the differentiation-inducing capacity and cytostatic activity of several closely related PMEA analogs. Furthermore, the mutant cells exhibited a decreased sensitivity to the differentiation-inducing activity of a wide variety of structurally nonrelated antimetabolites targeted at different enzymes of nucleotide biosynthesis. A 5-25-fold higher concentration of each of these compounds was required to obtain the same level of differentiation in the K562/PMEA-1 cells as in the wild-type cells. However, unlike the PMEA derivatives, the antimetabolites remained equally cytostatic for the mutant K562 cells and for the wild-type cells. Our results reveal two unique features of the K562/PMEA-1 cells: (i) specific resistance to both the differentiation-inducing and cytostatic effects of several acyclic nucleoside phosphonate analogs (which can be accounted for by a diminished cellular uptake and subsequent metabolism of the compounds) and (ii) nonspecific resistance to antimetabolites with regard to their differentiation-inducing, but not cytostatic, properties (which must reside in an unspecified alteration of a common site of the differentiation process that is shared by all of these antimetabolites).
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PMID:Evidence for distinction of the differentiation-inducing activities and cytostatic properties of 9-(2-phosphonylmethoxyethyl)adenine and a variety of differentiation-inducing agents in human erythroleukemia K562 cells. 891 55

Recent efforts to treat malignancy using gene transfer have met with varying degrees of success. In this paper, we report the results of studies using two recombinant adenoviral vectors to examine the efficacy of combination gene transfer to cause tumor regression in vivo. One of these vectors encodes the murine MHC class I gene, H-2Kb (ADV-Kb), which induces an immune response that stimulates tumor regression. The second vector encodes the human p21 cyclin dependent kinase inhibitor (ADV-p21). This gene product arrests cell cycle progression and prevents proliferation of tumor cells. Both vectors were tested in a murine model in vivo for antitumor effect. As previously shown, a significant reduction of tumor size was observed with each vector. Combination treatment, in which both vectors were administered, resulted in a trend toward a reduced tumor growth greater than with either vector alone. In order to characterize the mechanism of tumor regression, cytolytic T lymphocyte (CTL) assays against the allogeneic molecule, H-2Kb, were performed. Mice treated with ADV-Kb showed specific CTL activity against the H-2Kb molecule, demonstrating that the immune response against the H-2Kb gene product involved in tumor regression was potentiated by expression of the p21 gene which affects cell cycle progression.
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PMID:Combination gene transfer to potentiate tumor regression. 917 23

PMEDAP and/or PMEA treatment of SD rat lymphomas significantly prolonged the mean survival time of tumor-bearing animals. Dose-dependent genotoxicity of both PMEDAP and PMEA was not observed in in vitro tests on stabilized diploid MRC-5 cell line. The mitotic activity of MRC-5 cells was completely inhibited after 48 hours exposure in culture medium containing PMEDAP (10 micrograms/ml), or PMEA (25 micrograms/ml), respectively. Significant concentration dependent inhibition of cell proliferation caused by PMEDAP and/or PMEA was also observed in murine splenocytes. The analogs specifically inhibit proliferation of mitogen-activated T-lymphocytes. Modulation of subpopulations of peripheral blood cells under in vivo conditions was found in inbred SD animals. Intraperitoneal administration of PMEDAP to young healthy SD animals induced the decrease of the CD4+/CD8+ value from 1.3-1.6 to 0.72 while i.p. application of PMEA caused a decrease of the same ratio to 0.62.
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PMID:Antitumor activity of novel purine acyclic nucleotide analogs PMEA and PMEDAP. 917 10

Our aim was to test the therapeutic effects of adenovirus-mediated gene therapy in an animal model of brain tumor which was obtained by injection of 9L gliosarcoma cells into the caudate nucleus of rat brains. Seven days after the implantation of tumor cells, adenovirus vectors bearing the Escherichia coli beta galactosidase gene (ADV beta-gal) or the herpes simplex virus thymidine kinase gene (ADVtk) were stereotactically injected in the tumor. Injection of the ADV beta gal resulted in the expression of the marker gene in 61% of the animals. Transfer of the ADVtk was followed, 3 days later, by intraperitoneal injection of ganciclovir (GCV) for 10 days. A control group was treated with saline instead of GCV. We observed a significant regression of the tumors in 50% of the rats treated with ADVtk and GCV as compared with control animals. In 4 cases out of 6, the tumor completely disappeared after treatment. These results demonstrate the potential efficacy of adenovirus-mediated transfer of the HSVtk gene following by GCV administration for the treatment of glioblastomas.
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PMID:[Gene therapy of a model of glioblastoma in rats using adenovirus vector encoding the HSVtk gene]. 953 86

The acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective antiretroviral agent which is currently evaluated in its oral prodrug form, bis(POM)PMEA (adefovir dipivoxil), in phase II and III clinical trials in human hepatitis B virus (HBV)- and human immunodeficiency virus (HIV)-infected individuals, respectively. We have now found that PMEA is also a potent inhibitor of growth of the highly aggressive choriocarcinoma tumor arising from rat choriocarcinoma RCHO cells grafted under the kidney capsule of syngeneic WKA/H rats. In untreated rats, massive invasive RCHO tumors, covering the whole surface of the kidney and resulting in a marked enlargement of the kidney, were observed at day 10 after tumor cell grafting. Daily treatment with PMEA at 25 mg/kg/day afforded a marked reduction in tumor size (i.e., smaller tumors and slight, if any, enlargement of the kidney). Increasing the PMEA dose to 50, 100 or 250 mg/kglday resulted in a gradual increase of the antitumor effect of the compound. At the highest dose tested, i.e., 250 mg/kg/day, PMEA completely suppressed tumor growth. The antitumor activity of PMEA persisted for at least 10 days after termination of drug treatment. In addition, delayed treatment with PMEA at a dose of 200 mg/kg/day, started at a time point where choriocarcinoma tumors had already developed, stopped further growth and even induced regression of the tumors. PMPA, a closely related structural analogue of PMEA, failed to inhibit choriocarcinoma tumor growth. This observation points to the specificity of PMEA as an antitumor agent. In view of our findings, the therapeutic potential of PMEA for the treatment of neoplastic diseases appears to merit further investigation.
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PMID:Potent antitumor activity of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine in choriocarcinoma-bearing rats. 959 Jan 39

The acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) has previously been shown to be a strong inducer of differentiation in several tumor cell lines. We have now investigated the in vitro differentiation-inducing and the in vivo antitumor, properties of PMEA in a rat choriocarcinoma tumor cell model. PMEA at 2 to 50 microM induced choriocarcinoma RCHO cell differentiation in vitro in a concentration-dependent manner, as monitored by morphological changes, induction of alkaline phosphatase and production and secretion of progesterone. Likewise, a clear dose-response relationship was established for the in vivo antitumor activity of PMEA in choriocarcinoma-bearing rats. (R)-PMPA, a structural analogue of PMEA which is much less effective than PMEA in inducing differentiation in vitro did not demonstrate any in vivo antitumor activity. This observation points to the specificity of the differentiation-inducing potential of PMEA.
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PMID:In vitro and in vivo inhibitory activity of the differentiation-inducing agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against rat choriocarcinoma. 959 37

The cytomegalovirus(CMV) promoter is considered one of the strongest positive regulators. In this study toxicity, cell killing efficacy and bystander effect of Rous Sarcoma Virus(RSV) driven herpes simplex thymidine kinase(TK) gene therapy was compared with CMV driven TK gene therapy in three ovarian cancer cell lines with different growth patterns using a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetra-zolium bromide (MTT) based assay. ADV/CMV-TK was shown to be 2 to 10 times more effective in tumor cell killing than ADV/RSV-TK. The difference in cell killing efficacy between ADV/CMV-TK and ADV/RSV-TK was dependent on the individual cell line. A CMV promoter dependent eight to ten fold improvement in cell killing efficacy was observed in the relatively slow growing SKOV3 cell line which is not easily transducible, while only a 2 to 4 fold difference was observed in the easily transducible OV-CA-2774 and OV-CA-1225 cell lines. ADV/CMV-TK also showed a stronger bystander effect than ADV/RSV-TK in all three ovarian cancer cell lines. Our data demonstrated that the efficacy of adenovirus-mediated gene therapy of ovarian cancer can be enhanced by using the CMV promoter without increasing toxicity.
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PMID:The efficacy of adenovirus-mediated gene therapy of ovarian cancer is enhanced by using the cytomegalovirus promoter. 961 11

9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its closely related structural analogue (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) are potent inhibitors of retroviruses and hepatitis B virus. In its oral prodrug form (adefovir dipivoxil), PMEA is currently the subject of advanced phase II/III clinical trials for the treatment of HIV infections. PMEA has also been shown to be a potent differentiation-inducing agent. In the present study, PMEA was found to have a strong differentiation-inducing effect on rat choriocarcinoma (RCHO) cells, comparable to that of methotrexate, which is the drug of choice for the chemotherapy of choriocarcinoma in humans. PMEA induced differentiation of choriocarcinoma trophoblast cells in a concentration-dependent manner within the 2- to 50-microM concentration range, as ascertained by giant cell formation, alkaline phosphatase induction, progesterone secretion, and the disappearance of a cytotrophoblast-specific surface antigen. PMEA had to be exposed to the rat choriocarcinoma cell cultures for at least 2-3 days to achieve optimal growth inhibition and differentiation of the tumor cells. Unlike PMEA, (R)-9-(2-phosphonylmethoxypropyl)adenine failed to induce differentiation of proliferating cytotrophoblasts into nonproliferating, hormonally active giant cells. This points to the specificity of PMEA as an inducer of choriocarcinoma cell differentiation.
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PMID:Potent differentiation-inducing properties of the antiretroviral agent 9-(2-phosphonylmethoxyethyl) adenine (PMEA) in the rat choriocarcinoma (RCHO) tumor cell model. 977 47

Following exposure to 9-(2-phosphonylmethoxyethyl)adenine (an inhibitor of the cellular DNA polymerases alpha, delta and epsilon), human erythroleukemia K562, human T-lymphoid CEM and murine leukemia L1210 cells markedly accumulated in the S phase of the cell cycle. In contrast to DNA replication, RNA synthesis (transcription) and protein synthesis (mRNA translation) were not affected by 9-(2-phosphonylmethoxyethyl)-adenine. The ribonucleoside triphosphate pools were slightly elevated, while the intracellular levels of all four deoxyribonucleoside triphosphates were 1.5-4-fold increased in 9-(2-phosphonylmethoxyethyl)adenine-treated K562, CEM and L1210 cells. The effect of 9-(2-phosphonylmethoxyethyl)adenine on de novo (thymidylate synthase-mediated) and salvage (thymidine kinase-mediated) dTTP synthesis was investigated using radio-labelled nucleoside precursors. The amount of thymidylate synthase-derived dTTP in the acid soluble pool was 2-4-fold higher in PMEA-treated than in untreated K562 cells, which is in accord with the 3-4-fold expansion of the global dTTP level in the presence of 9-(2-phosphonylmethoxyethyl)adenine. Strikingly, 2-derived dTTP accumulated to a much higher extent (i.e. 16-40-fold) in the soluble dTTP pool upon 9-(2-phosphonylmethoxyethyl)adenine treatment. In keeping with this finding, a markedly increased thymidine kinase activity could be demonstrated in extracts of 9-(2-phosphonylmethoxyethyl)adenine-treated K562 cell cultures. Also, in the presence of 200 microM 9-(2-phosphonylmethoxyethyl)adenine, 14-fold less thymidylate synthase-derived but only 3-fold less thymidine kinase-derived dTTP was incorporated into the DNA of the K562 cells. These data show that thymidine incorporation may be inappropriate as a cell proliferation marker in the presence of DNA synthesis inhibitors such as 9-(2-phosphonylmethoxyethyl)adenine. Our findings indicate that 9-(2-phosphonylmethoxyethyl)adenine causes a peculiar pattern of (deoxy)ribonucleotide metabolism deregulation in drug-treated tumor cells, as a result of the metabolic block imposed by the drug on the S phase of the cell cycle.
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PMID:Impact of 9-(2-phosphonylmethoxyethyl)adenine on (deoxy)ribonucleotide metabolism and nucleic acid synthesis in tumor cells. 1006 80

Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the treatment of HPV-associated diseases. We have evaluated the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV), ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant mycophenolic acid (MPA) on the proliferation of human cervical keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). In vitro incubation of these cell lines with ANPs resulted in a concentration- and time-dependent inhibition of cell proliferation. This inhibitory effect was most striking for HPMPC. The 50% inhibitory concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to 0.6-2 microg/ml at day 7. When the IC50 values of the ANPs for the various HPV-harboring cells were compared with those for primary human keratinocytes isolated from normal cervix, HPMPC emerged as the most selective ANP, with a selectivity index (SI) in the range of 15-42. When IC50 values as a function of time were determined for several tumor cell lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs again showed an antiproliferative effect as a function of time, although of a lower extent (5- to 25-fold decrease in the IC50 values between days 3 and 7) than for the HPV-positive cells. Treatment of SV40- and adenovirus-transformed cells with ANPs resulted in the inhibition of cell proliferation as a function of time, similar to that observed with HPV-positive cells, HPMPC and cHPMPC being the most potent antiproliferative agents. These results suggest that the antiproliferative activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may be explained, at least in part, by a specific inhibitory effect on rapidly proliferating cells, and the presence of the HPV genome might enhance the sensitivity of cells to HPMPC due to interactions of the viral-transforming proteins with products of the tumor suppressor genes.
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PMID:Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell lines. 1033 55


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