Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p14(ARF) protein, the product of an alternate reading frame of the INK4A/ARF locus on human chromosome 9p21, disrupts the ability of MDM2 to target p53 for proteosomal degradation and causes an increase in steady-state p53 levels, leading to a G(1) and G(2) arrest of cells in the cell cycle. Although much is known about the function of p14(ARF) in the p53 pathway, not as much is known about its function in human tumor growth and chemosensitivity independently of up-regulation of p53 protein levels. To learn more about its effect on cellular proliferation and chemoresistance independent of p53 up-regulation, human HT-1080 fibrosarcoma cells null for p14(ARF) and harboring a defective p53 pathway were stably transfected with p14(ARF) cDNA under the tight control of a doxycycline-inducible promoter. Induction of p14(ARF) caused a decrease in cell proliferation rate and colony formation and a marked decrease in the level of dihydrofolate reductase (DHFR) protein. The effect of p14(ARF) on DHFR protein levels was specific, because thymidylate kinase and thymidylate synthase protein levels were not decreased nor were p53 or p21WAF1 protein levels increased. The decrease in DHFR protein was abolished when the cells were treated with the proteasome inhibitor MG132, demonstrating that p14(ARF) augments proteasomal degradation of the protein. Surprisingly, induction of p14(ARF) increased resistance to the folate antagonists methotrexate, trimetrexate, and raltitrexed. Depletion of thymidine in the medium reversed this resistance, indicating that p14(ARF) induction increases the reliance of these cells on thymidine salvage.
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PMID:p14ARF expression increases dihydrofolate reductase degradation and paradoxically results in resistance to folate antagonists in cells with nonfunctional p53. 1520 49

Gene therapy and stem cell transplantation safety could be enhanced by control over the fate of therapeutic cells. Suicide gene therapy uses enzymes that convert prodrugs to cytotoxic entities; however, heterologous moieties with poor kinetics are employed. We describe a novel enzyme/prodrug combination for selectively inducing apoptosis in lentiviral vector-transduced cells. Rationally designed variants of human thymidylate kinase (tmpk) that effectively phosphorylate 3'-azido-3'-deoxythymidine (AZT) were efficiently delivered. Transduced Jurkat cell lines were eliminated by AZT. We demonstrate that this schema targeted both dividing and non-dividing cells, with a novel killing mechanism involving apoptosis induction via disruption of the mitochondrial inner membrane potential and activation of caspase-3. Primary murine and human T cells were also transduced and responded to AZT. Furthermore, low-dose AZT administration to non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice injected with transduced K562 cells suppressed tumor growth. This novel suicide gene therapy approach can thus be integrated as a safety switch into therapeutic vectors.
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PMID:Engineered human tmpk/AZT as a novel enzyme/prodrug axis for suicide gene therapy. 1744 72

Molecular targeted therapy is an important, novel approach in the treatment of cancer because it interferes with certain molecules involved in carcinogenesis and tumor growth. Examples include monoclonal antibodies, microvesicles, and suicide genes. Several studies have focused on targeted therapies in prostate cancer, which is a serious cause of cancer death in men. We hypothesize that antibody-coated microvesicles can deliver thymidylate kinase, a suicide protein, to prostate cancer cells, potentiating them to death following azidothymidine (AZT) treatment.
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PMID:Protein Delivery of Thymidylate Kinase Mediated by Tumor-Specific Antibody-Precoated Microvesicles. 2727 81