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1.
Antivir Ther ; 16(8): 1277-86, 2011.
Article in English | MEDLINE | ID: mdl-22155909

ABSTRACT

BACKGROUND: In this study, we investigated the effect of Didox (DX) on the pathogenicity of and host responses to murine cytomegalovirus (MCMV) infection. METHODS: In vitro efficacy of DX against MCMV was determined using plaque reduction assays. For in vivo studies, mice infected with a sublethal dose (10(4) PFU) of MCMV were treated daily with DX (200 mg/kg) using either a prophylactic or delayed protocol. At predetermined intervals, target organs were removed for histopathology. Cytokine transcription and viral load were performed using real-time PCR. Serum cytokine levels were determined by ELISA, and T-cell markers by real-time PCR. RESULTS: DX (0.5-50 µM) inhibited MCMV plaque formation in vitro. However, in vivo, prophylactic DX treatment did not decrease viral load and prolonged hepatic proinflammatory cytokine transcription at days 3 and 5 post-infection, which corresponded with more severe histopathological changes observed in the liver. Significant CD8(+) T-cell marker suppression was seen, in accordance with DX-induced inhibition of lymphocyte proliferation observed in vitro. DX prolonged the recovery of MCMV-infected mice when given after infection was established. CONCLUSIONS: Despite promising MCMV inhibition in vitro, DX had no beneficial effect on MCMV disease in our model and paradoxically had adverse effects when administered prophylactically. The lack of correlation between in vitro activity and in vivo efficacy emphasizes the importance of selecting appropriate antiviral targets and of using animal models when testing new drugs.


Subject(s)
Fibroblasts/drug effects , Herpesviridae Infections/drug therapy , Liver/drug effects , Muromegalovirus/drug effects , Spleen/drug effects , Animals , Antineoplastic Agents , Antiviral Agents/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Cytokines , Enzyme-Linked Immunosorbent Assay , Female , Fibroblasts/immunology , Fibroblasts/virology , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Hydroxamic Acids , Liver/cytology , Liver/immunology , Liver/virology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Muromegalovirus/growth & development , Muromegalovirus/immunology , Real-Time Polymerase Chain Reaction , Spleen/cytology , Spleen/immunology , Spleen/virology , Treatment Failure , Viral Load , Viral Plaque Assay , Virus Replication
2.
J Inflamm (Lond) ; 7: 43, 2010 Aug 18.
Article in English | MEDLINE | ID: mdl-20718971

ABSTRACT

BACKGROUND: Graft-versus-host disease is the single most important obstacle facing successful allogeneic stem cell transplantation (SCT). Even with current immunosuppressive therapies, morbidity and mortality rates are high. Current therapies including cyclosporine A (CyA) and related compounds target IL-2 signaling. However, although these compounds offer great benefit, they are also associated with multiple toxicities. Therefore, new compounds with a greater efficacy and reduced toxicity are needed to enable us to overcome this hurdle. METHODS: The allogeneic mixed lymphocyte reaction (MLR) is a unique ex vivo method to study a drug's action on the initial events resulting in T-cell activation and proliferation, synonymous to the initial stages of tissue and organ destruction by T-cell responses in organ rejection and Graft-versus-host disease. Using this approach, we examined the effectiveness of two ribonucleotide reductase inhibitors (RRI), Didox and Trimidox, to inhibit T-cell activation and proliferation. RESULTS: The compounds caused a marked reduction in the proliferative responses of T-cells, which is also accompanied by decreased secretion of cytokines IL-6, IFN-gamma, TNF-alpha, IL-2, IL-13, IL-10 and IL-4. CONCLUSIONS: In conclusion, these data provide critical information to justify further investigation into the potential use of these compounds post allogeneic bone marrow transplantation to alleviate graft-versus-host disease thereby achieving better outcomes.

3.
Transfus Apher Sci ; 34(1): 25-32, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16376617

ABSTRACT

The most common and widely transplanted tissue world wide is blood, which in 2000 resulted in the transfusion of 12.5 million units of blood in the US alone [Goodnough LT, Shander A, Brecher ME. Transfusion medicine: looking to the future. Lancet 2003;361:161-9]. The current use of donated blood products is relatively safe; however, there are inherent problems with allogeneic blood transfusions. The wide spread use of blood in procedures results in problems involving inadequate supply exacerbated in times of war and disasters and by the limited storage life of blood donations (30-42 days). Blood contamination due to patient pre-disposition, poor collection, sterilization, or storage is the second most common cause of death from transfusion in the US [Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: joint ASH and AABB educational session in transfusion medicine. Hematology (Am Soc Hematol Educ Program) 2003:575-89]. Blood is a complex tissue involved in a plethora of homeostatic roles, including immunity, wound healing and the transport of nourishment, electrolytes, hormones, vitamins, heat, oxygen and the removal of metabolic waste products. However, by far the principle role of blood transfusions is the replacement of red cell volume and the maintenance of oxygen levels within the circulation. Creation of investigational new drugs (INDs) which would function as oxygen carriers and prolong shelf life is now a very active arena of scientific research. Several such IND products are now in clinical trials. This article gives an easy to follow concise evaluation of major areas of focus and current testing for each type of blood substitution molecule.


Subject(s)
Blood Substitutes/chemistry , Blood Transfusion/methods , Oxygen/metabolism , Bacterial Infections , Blood/microbiology , Blood Banks , Blood Component Transfusion , Blood Preservation/methods , Blood Specimen Collection , Blood Substitutes/pharmacology , Drug Design , Hemoglobins , Humans , Models, Chemical
4.
Virus Res ; 114(1-2): 35-44, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16002171

ABSTRACT

Despite the use of antimicrobial prophylaxis, cytomegalovirus (CMV) and Pneumocystis carinii (PC) pneumonia (PCP) are both leading causes of morbidity and mortality in immunocompromised patients. It has previously been reported that CMV infection modulates host immune responses with a variety of mechanisms which include the suppression of helper T cell functions and antigen presenting cell (APC) functions, both of which are critical for PCP resolution. However, the mechanisms of these interactions and other possible immune regulatory effects are not clearly understood. In this study, we investigated the impact of murine CMV (MCMV) induced immunomodulation on the progression of PCP in a co-infection model. Initial results show that dually infected mice had evidence of more severe PC disease, which include a greater loss of body weight, an excess lung PC burden and delayed clearance of PC from lungs, compared to mice with PC infection alone. At day 7 post-infection, dually infected mice had reduced numbers of MHC-II expressing cells in the lung interstitium and lymph nodes and reduced migration of CD11c+ cells to both the tracheobronchial lymph nodes and alveolar spaces. Dual infected mice showed elevated numbers of specific CD8 responses concomitant with a decrease in activated CD4+ T cells in both the lymph nodes and in alveolar spaces when compared to mice infected with MCMV alone. These data suggest that MCMV infection inhibits the immune responses generated against PC which contribute to the delayed clearance of the organism.


Subject(s)
Disease Models, Animal , Herpesviridae Infections/complications , Muromegalovirus/pathogenicity , Pneumocystis carinii/pathogenicity , Pneumonia, Pneumocystis , Animals , CD4-Positive T-Lymphocytes/immunology , Disease Progression , Herpesviridae Infections/physiopathology , Herpesviridae Infections/virology , Humans , Lung/cytology , Lung/immunology , Lung/microbiology , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, SCID , Pneumonia, Pneumocystis/complications , Pneumonia, Pneumocystis/immunology , Pneumonia, Pneumocystis/microbiology , Pneumonia, Pneumocystis/physiopathology , Weight Loss
5.
Virus Res ; 113(1): 1-15, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15869820

ABSTRACT

Murine acquired immunodeficiency syndrome (MAIDS) induced by a defective LP-BM5 murine leukemia virus (MuLV) produces hematopoietic cytopenias similar to HIV in patients with AIDS. The pathogenesis of MAIDS induced cytopenias remains obscure; however, direct retroviral infection of bone marrow stroma has been implicated to play a role. To evaluate the consequential effect of viral infection, primary stromal cell cultures were transiently incubated in vitro with LP-BM5 MuLV viral supernatant. Reverse transcription polymerase chain reaction (RT-PCR) and Southern blot hybridization revealed that defective LP-BM5 MuLV infection resulted in elevated levels of IL-4 and TGFbeta1 transcript expression in infected stromal cells. The increased expression of both IL-4 and TGFbeta1 transcripts was associated with enhanced production of corresponding proteins as determined by quantitative western blot analyses. Hematopoietic reconstitution assays revealed that the hematopoietic support function of stromal cells was significantly reduced following transient exposure to LP-BM5 MuLV. The production of nonadherent mononuclear cells and the growth of myeloid, megakaryocyte and erythroid lineages were all suppressed in infected cultures. Culture supernatant conditioned by infected stromal cells demonstrated growth-inhibitory activity for hematopoietic progenitor colony formation. This growth-inhibitory activity could be significantly abolished by addition of anti-IL-4 and/or anti-TGFbeta1 neutralizing antibodies to the culture supernatant or directly to the stromal cell cultures. This study demonstrates LP-BM5 MuLV increases two known cytokines to suppress hematopoiesis implicating viral infection can directly suppress hematopoiesis mediated by inhibitors released from marrow stroma.


Subject(s)
Antibodies/immunology , Bone Marrow Cells/virology , Hematopoiesis , Hematopoietic Stem Cells/physiology , Interleukin-4/immunology , Leukemia Virus, Murine/immunology , Transforming Growth Factor beta/immunology , Animals , Blotting, Southern , Blotting, Western , Bone Marrow Cells/immunology , Cells, Cultured , Erythroid Cells , Gene Expression , Interleukin-4/analysis , Interleukin-4/antagonists & inhibitors , Interleukin-4/genetics , Megakaryocytes/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/physiology , Neutralization Tests , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Stromal Cells/immunology , Stromal Cells/virology , Transforming Growth Factor beta/analysis , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1
6.
Antiviral Res ; 65(1): 13-22, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15652967

ABSTRACT

The ribonucleotide reductase inhibitor hydroxyurea (HU) has demonstrated some benefit as a component of drug cocktails for the treatment of HIV-1 infection. However, HU is notoriously myelosuppressive and often administered only as salvage therapy to patients with late-stage disease, potentially exacerbating the bone marrow toxicity of HU. In this report we have compared the antiviral effects of HU and two novel RR inhibitors trimidox (3,4,5-trihydroxybenzamidoxime) and didox (3,4-dihydroxybenzohydroxamic acid) in combination with didanosine (2,3-didoxyinosine; ddI) in the LPBM5 MuLV retrovirus model (murine AIDS). We also evaluated the effects of these drug combinations on the hematopoietic tissues of LPBM5 MuLV-infected animals. The combination of RR inhibitors and ddI was extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced disease (splenomegaly, hypergammaglobulinemia, activated B-splenocytes and loss of splenic architecture). In addition, relative levels of proviral DNA were significantly lower in combination drug-treated animals compared to infected controls. Evaluation of femur cellularity, numbers of marrow-derived myeloid progenitor cells (CFU-GM and BFU-E) and peripheral blood indices revealed that TX and DX in combination with ddI were well-tolerated. However, treatment with HU and ddI induced moderate myelosuppression. These data demonstrate that RR inhibitors in combination with ddI provide significant protection against retroviral disease in murine AIDS. Moreover, the novel RR inhibitors TX and DX appear to be more effective and less myelosuppressive than HU when administered with ddI in this model.


Subject(s)
Antiviral Agents/therapeutic use , Benzamidines/therapeutic use , Didanosine/therapeutic use , Hydroxamic Acids/therapeutic use , Hydroxyurea/therapeutic use , Murine Acquired Immunodeficiency Syndrome/drug therapy , Reverse Transcriptase Inhibitors/therapeutic use , Animals , Antiviral Agents/administration & dosage , B-Lymphocytes/immunology , Benzamidines/administration & dosage , Drug Therapy, Combination , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/therapeutic use , Female , Hydroxamic Acids/administration & dosage , Hydroxyurea/administration & dosage , Leukemia Virus, Murine/drug effects , Leukemia, Experimental/drug therapy , Leukemia, Experimental/virology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Murine Acquired Immunodeficiency Syndrome/virology , Retroviridae Infections/drug therapy , Retroviridae Infections/virology , Ribonucleotide Reductases/antagonists & inhibitors , Treatment Outcome , Tumor Virus Infections/drug therapy , Tumor Virus Infections/virology
7.
Antiviral Res ; 62(3): 111-20, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15130534

ABSTRACT

Inhibition of ribonucleotide reductase (RR) has gained attention as a potential strategy for HIV-1 therapy through the success of hydroxyurea (HU) to potentiate the activity of the nucleoside reverse transcriptase inhibitor (NRTI) didanosine (ddI) in clinical trials. However, the use of HU has been limited by its development of hematopoietic toxicity. In this study, the novel RR inhibitors didox (DX; 3,4-dihydroxybenzohydroxamic acid), and trimidox (TX; 3,4,5-trihydroxybenzamidoxime) were evaluated along with HU for anti-retroviral efficacy in LPBM5-induced retro-viral disease (MAIDS) both as monotherapeutic regimens and in combination with the guanine containing NRTI abacavir (ABC). Anti-retroviral drug efficacy was determined by measuring inhibition of splenomegaly, hypergammaglobulinemia, and splenic levels of proviral DNA. In this study, all RRIs tested showed the ability to improve the efficacy of ABC in the MAIDS model by reducing splenomegaly, hypergammaglobulinemia, and splenic proviral DNA levels.


Subject(s)
Antiviral Agents/therapeutic use , Bone Marrow Cells/drug effects , Hydroxyurea/therapeutic use , Murine Acquired Immunodeficiency Syndrome/drug therapy , Ribonucleotide Reductases/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Benzamidines/therapeutic use , Dideoxynucleosides/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Hematopoietic Stem Cells/drug effects , Hydroxamic Acids/therapeutic use , Hydroxyurea/adverse effects , Hydroxyurea/chemistry , Mice , Mice, Inbred C57BL , Murine Acquired Immunodeficiency Syndrome/blood , Murine Acquired Immunodeficiency Syndrome/immunology , Murine Acquired Immunodeficiency Syndrome/pathology , Spleen/pathology , Splenomegaly
8.
Virus Res ; 101(2): 175-84, 2004 May.
Article in English | MEDLINE | ID: mdl-15041185

ABSTRACT

Murine acquired immunodeficiency disease (MAIDS) induced by LPBM5 MuLV is characterized by a late-stage lymphoma and hematopoietic cytopenias similar to those observed in human AIDS. The pathogenesis of MAIDS-related lymphoma/cytopenia is unknown but it has been postulated to involve a defective marrow microenvironment or stroma. The basic Fibroblast Growth Factor (bFGF) of stromal origin is an important stimulator for hematopoietic progenitors of several lineages. Long-term bone marrow cultures (LTBMCs) were established and pure stromal cell cultures were used for in vitro infection hematopoietic reconstitution studies. Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze bFGF gene expression in stromal cells derived from either viral-infected marrow or uninfected marrow. RT-PCR analysis showed a 40% reduction in the expression of bFGF transcript expression from viral-infected stromal cells, however, the levels of bek and flg bFGF receptors remained unchanged indicating virus-infection only inhibited bFGF gene expression in stromal cells. Viral infection was associated with a progressive decrease in bFGF transcript expression 35% of control at day 7, 50% of control at day 14 and 60% of control at day 21 compared to the mock-infected cultures. In addition, for bek and flg the transcript expression in, in vitro-infected primary cultures were comparable to the mock-infected cultures and remained essentially unchanged throughout culture period. Western blot analysis revealed viral-infected stromal cells produced a 45% decrease in bFGF protein production. Reduction of bFGF protein was confirmed by indirect immunofluorescent staining. We report MuLV infection reduces bFGF transcript expression but not its surface-receptors (bek and flg) in infected stromal cells. Impaired hematopoiesis consistently exhibited from MuLV-infected stromal cultures was restored by exogenous bFGF; therefore, bFGF was responsible in restoration of normal marrow stromal support function. These results suggest a role for bFGF deficiency in the pathogenesis of MAIDS-related marrow failure.


Subject(s)
Bone Marrow Cells/virology , Fibroblast Growth Factor 2/genetics , Gene Expression , Leukemia Virus, Murine/pathogenicity , Receptors, Fibroblast Growth Factor/genetics , Stromal Cells/virology , Animals , Blotting, Western , Bone Marrow Cells/metabolism , Cell Line , Colony-Forming Units Assay , Fibroblast Growth Factor 2/analysis , Fibroblast Growth Factor 2/pharmacology , Filaggrin Proteins , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence , Murine Acquired Immunodeficiency Syndrome/virology , RNA, Messenger/analysis , Receptor Protein-Tyrosine Kinases/genetics , Receptor, Fibroblast Growth Factor, Type 2 , Reverse Transcriptase Polymerase Chain Reaction , Stromal Cells/metabolism , Transcription, Genetic
9.
Cancer Biol Ther ; 1(5): 539-45, 2002.
Article in English | MEDLINE | ID: mdl-12496485

ABSTRACT

In this study, we investigated the influence of Bcl-2 overexpression on the radiosensitizing potential of Didox (DX; 3,4-Dihydroxybenzohydroxamic acid), a novel ribonucleotide reductase inhibitor, in p53-null prostate cancer cell line PC-3. The PC-3 cells were transfected with vector alone or ectopically overexpressed with CMV-Bcl-2 construct. The effect of radiation (IR) or DX alone and in combination (pre and post IR exposure of DX) on cell survival was determined by colony-forming assay. The impact of these two treatments on the cell cycle was determined by flow cytometry. To further understand the molecular mechanism of DX-mediated radiosensitization, induction of pro-survival and pro-apoptotic factors were determined by Western blot and gel-shift assays respectively. When compared to PC-3/Bcl-2 cells (SF(2)=0.84; D(0)=437cGy), the PC-3/vector cells (SF(2)=0.4; D(0)=235cGy) were significantly sensitive to ionizing radiation (p<0.001). Exposure of DX at 5 microM concentration prior or post to radiation in both PC-3/vector and PC-3/Bcl-2 transfectants caused an increase in radiation enhancement ratios. A significant reduction in G(2)M phase was observed in cells exposed to DX post IR when compared to cells exposed to IR alone. Exposure to DX after radiation in PC-3/vector significantly abrogated radiation-induced Bcl-2 upregulation, with a concomitant induction of bax protein. In PC-3/Bcl-2 transfectants, DX exposure after IR caused an induction of bax protein. Gel shift assays indicated that in PC-3/vector cells when exposed to IR caused an induction of NFkappa-B activity however, DX down regulated the NFkappa-B activity. Radiation-induced NFkappa-B activity was abrogated in pre and post DX exposure in combination with IR. These findings indicate that DX mediates a potent radiosensitizing effect in p53 null prostate cancer cells by overcoming radiation induced NFkappa-B activity and Bcl-2 expression.


Subject(s)
Antineoplastic Agents/therapeutic use , Hydroxamic Acids/therapeutic use , Prostatic Neoplasms/radiotherapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Radiation Tolerance , Apoptosis/radiation effects , Cell Line , Cell Survival/radiation effects , Combined Modality Therapy , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Gene Expression Regulation, Neoplastic/radiation effects , Genetic Vectors , Humans , Male , Mitosis/drug effects , Mitosis/radiation effects , NF-kappa B/drug effects , NF-kappa B/radiation effects , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins/drug effects , Proto-Oncogene Proteins/radiation effects , Proto-Oncogene Proteins c-bcl-2/radiation effects , Radiation, Ionizing , Transfection , Tumor Cells, Cultured , bcl-2-Associated X Protein
10.
Oncogene ; 21(51): 7883-90, 2002 Nov 07.
Article in English | MEDLINE | ID: mdl-12420225

ABSTRACT

Activated ras is known to dysregulate TGF-beta signaling by altering the expression of TGF-beta type II receptor (RII). It is well documented that tumor cells harboring mutant ras are more resistant to radiation than cells with wild-type ras. In this study, we hypothesized that the use of farnesyltransferase inhibitor (FTI, L-744,832) may directly restore TGF-beta signaling through RII expression via ras dependent or independent pathway leading to induction of radiation sensitivity. Two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2 were used in this study. FTI inhibited farnesylation of Ras protein more significantly in MIA PaCa-2 than BxPC-3 cells. In contrast, MIA PaCa-2 cells were resistant to radiation when compared to BxPC-3 cells. BxPC-3 cells were more resistant to FTI than MIA PaCa-2 cells. In combination treatment, no significant radiosensitizing effect of FTI was observed in BxPC-3 cells at 5 or 10 microM. However, in MIA PaCa-2 cells, a significant radiosensitizing effect was observed at both 5 and 10 microM concentrations (P>0.004). The TGF-beta effector gene p21(waf1/cip1) was elevated in combination treatment in MIA PaCa-2 but not in BxPC-3 cells. In MIA PaCa-2 cells, FTI induced TGF-beta responsive promoter activity as assessed by 3TP-luciferase activity. A further induction of luciferase activity was observed in MIA PaCa-2 cells treated with radiation and FTI. Induction of TGF-beta signaling by FTI was mediated through restoration of the RII expression, as demonstrated by RT-PCR analysis. In addition, re-expression of RII by FTI was associated with a decrease in DNA methyltransferase 1 (DNMT1) levels. Thus, these findings suggest that the L-744,832 treatment restores the RII expression through inhibition of DNMT1 levels causing induction of TGF-beta signaling by radiation and this forms a novel molecular mechanism of radiosensitization by FTI.


Subject(s)
Adenocarcinoma/pathology , Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Genes, ras , Methionine/analogs & derivatives , Methionine/pharmacology , Neoplasm Proteins/physiology , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/physiology , Receptors, Transforming Growth Factor beta/biosynthesis , Signal Transduction/drug effects , Adenocarcinoma/metabolism , Alkyl and Aryl Transferases/physiology , Apoptosis/drug effects , Apoptosis/radiation effects , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/biosynthesis , Cyclins/genetics , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/drug effects , Enzyme Induction/drug effects , Farnesyltranstransferase , Humans , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Pancreatic Neoplasms/metabolism , Protein Prenylation/drug effects , Protein Processing, Post-Translational/drug effects , Protein Processing, Post-Translational/physiology , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins p21(ras)/deficiency , Radiation Tolerance/drug effects , Radiation-Sensitizing Agents/pharmacology , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/genetics , Recombinant Fusion Proteins/physiology , Regulatory Sequences, Nucleic Acid , Signal Transduction/physiology , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/pharmacology
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