ABSTRACT
BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels. PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate. RESULTS: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, P = 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade ≥3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%). CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Pancreatic Neoplasms , Albumins , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/analogs & derivatives , Humans , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , GemcitabineABSTRACT
BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.
Subject(s)
Adenocarcinoma/therapy , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/therapy , Radiotherapy, Intensity-Modulated , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , ErbB Receptors/biosynthesis , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Radiotherapy, Intensity-Modulated/adverse effects , Treatment Outcome , GemcitabineABSTRACT
Toxic compounds such as carcinogens are removed from the body by the action of a series of detoxifying enzymes and transporters expressed in the liver and the small intestine. We have found that intestinal epithelial cells expressing the SV40 large T antigen (TAg) contain significantly lower levels of mRNAs, encoding several drug metabolizing/detoxifying enzymes and transporters compared to their non-transgenic littermates. In addition, TAg blocks the induction of these mRNAs by xenobiotics. The repression depends on an intact LXCXE motif in TAg, suggesting that inactivation of the retinoblastoma (Rb) family of tumor suppressors plays a role in the process. These results imply that a functional Rb pathway in the intestine is necessary for the expression of the detoxification system used to clear carcinogens, and suggest that loss of this tumor suppressor might alter susceptibility to chemical injury. In addition, the effect of TAg on the detoxification pathway appears to be tissue-specific, as its ectopic expression in the liver failed to suppress the P450 enzymes. The TAg-mediated suppression of drug metabolizing/detoxifying enzymes may have broad implications in the metabolism and mechanism of action of both carcinogens and prescription drugs.
Subject(s)
Antigens, Polyomavirus Transforming/metabolism , Cytochrome P-450 Enzyme System/metabolism , Intestinal Mucosa/enzymology , Simian virus 40 , Animals , Antigens, Polyomavirus Transforming/genetics , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme System/genetics , Down-Regulation , Female , Gene Expression Regulation , Inactivation, Metabolic , Liver/enzymology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Xenobiotics/antagonists & inhibitors , Xenobiotics/toxicityABSTRACT
Since they employ host gene expression machinery to execute their genetic programs, it is no surprise that DNA viruses also encode miRNAs. The small size of viral genomes, and the high degree of understanding of the functions of their gene products, make them particularly favorable systems for the examination of miRNA biogenesis and function. Here we review our computational and array-based approaches for viral miRNA discovery, and we discuss the structure and function of miRNAs identified by these approaches in polyomaviruses and herpesviruses.
Subject(s)
MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Viruses/genetics , Viruses/metabolism , Animals , Genome, Viral , Herpesviridae/genetics , Herpesviridae/metabolism , Humans , Mutation , Oligonucleotide Array Sequence Analysis , Polyomavirus/genetics , Polyomavirus/metabolism , Simian virus 40/genetics , Simian virus 40/metabolism , SoftwareABSTRACT
In its native host species, the Rhesus Macaque, simian virus 40 (SV40) forms a persistent infection in the kidneys with no apparent harmful side effects. We show that SV40 infection of growth-arrested monkey kidney epithelial cells results in the specific disruption of certain Rb-E2F family complexes. Throughout the course of infection, p130-E2F and p107-E2F complexes are disrupted, but surprisingly pRb-E2F complexes remain intact. This suggests that the presence of some pRb-E2F complexes is not inhibitory to productive infection. Additionally, while a decrease of p130 steady state levels is observed during the later time points of infection, early during infection, p130 is readily detectable. This suggests SV40 infection overrides p130-mediated growth arrest through a mechanism(s) in addition to the well-documented T antigen-mediated degradation of p130. Finally, infection induces a dramatic relocalization of E2F4 from the nucleus to the cytoplasm. The implications of these observations to the life cycle of the virus are addressed.
Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Cell Cycle Proteins , DNA-Binding Proteins , Phosphoproteins/metabolism , Proteins , Retinoblastoma Protein/metabolism , Simian virus 40/pathogenicity , Transcription Factors/metabolism , Animals , Cell Line , E2F Transcription Factors , Kidney/cytology , Nuclear Proteins/metabolism , Retinoblastoma-Like Protein p130 , Simian virus 40/metabolismABSTRACT
PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. METHODS AND MATERIALS: Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3--6 patients each. Initial gemcitabine dose was 10 mg/m(2), with dose escalation until dose-limiting toxicity was observed. RESULTS: The maximum tolerated dose of gemcitabine was 50 mg/m(2), when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m(2), and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection. CONCLUSION: The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m(2) is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.
Subject(s)
Adenocarcinoma/radiotherapy , Antimetabolites, Antineoplastic/therapeutic use , Chemotherapy, Adjuvant , Deoxycytidine/therapeutic use , Pancreatic Neoplasms/radiotherapy , Radiotherapy, High-Energy , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Bone Marrow Diseases/etiology , Chemotherapy, Adjuvant/adverse effects , Combined Modality Therapy , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Drug Administration Schedule , Fatigue/etiology , Female , Follow-Up Studies , Gastrointestinal Hemorrhage/etiology , Humans , Male , Middle Aged , Nausea/etiology , Pancreatectomy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted , Radiotherapy, High-Energy/adverse effects , Remission Induction , Survival Analysis , Treatment Outcome , GemcitabineABSTRACT
The SV40 large T-antigen (TAg) has proven useful in studying pathways involved with cell division and tissue homeostasis. TAg disrupts the normal action of tumor suppressors pRb and p53. It is unclear whether T-antigen inhibition of p53 and pRb is sufficient for oncogenic transformation or if additional T-antigen activities are required. To pursue this question, cell lines were generated that coexpress an amino-terminal fragment of T-antigen (TAgN136), which has been shown to be sufficient to block pRb function, together with a dominant-negative p53. Neither focus formation nor saturation density was enhanced by coexpression of the dominant-negative p53 molecule, p53DD, along with TAgN136. Furthermore, a full-length TAg mutant incapable of binding p53 was capable of relieving contact inhibition, a hallmark of transformation. These results suggest the presence of a novel transforming activity in addition to the binding and inactivation of p53, requiring TAg amino acids 137 to 708.
Subject(s)
Antigens, Polyomavirus Transforming/physiology , Cell Transformation, Viral/physiology , Retinoblastoma Protein/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Animals , Antigens, Polyomavirus Transforming/genetics , Cell Adhesion , Cell Line, Transformed , Contact Inhibition , Fluorescent Antibody Technique , Immunoblotting , Mice , Plasmids , Rats , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Transfection , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
SV40 induces neoplastic transformation by disabling several key cellular growth regulatory circuits. Among these are the Rb- and p53-families of tumor suppressors. The multifunctional, virus-encoded large T antigen blocks the function of both Rb and p53. Large T antigen uses multiple mechanisms to block p53 activity, and this action contributes to tumorigenesis, in part, by blocking p53-mediated growth suppression and apoptosis. Since the p53 pathway is inactivated in most human tumors, T antigen/p53 interactions offer a possible mechanism by which SV40 contributes to human cancer.
Subject(s)
Antigens, Polyomavirus Transforming/physiology , DNA Tumor Viruses/physiology , Neoplasms/metabolism , Retinoblastoma Protein/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Cell Division , Cell Transformation, Neoplastic , Mice , Mice, Knockout , Protein Binding , Retinoblastoma Protein/genetics , Transcriptional Activation , Tumor Suppressor Protein p53/geneticsABSTRACT
Simian virus 40 large T antigen is a multifunctional oncoprotein that is required for numerous viral functions and the induction of cellular transformation. T antigen contains a J domain that is required for many of its activities including viral DNA replication, transformation, and virion assembly. J-domain-containing proteins interact with Hsc70 (a cellular chaperone) to perform multiple biological activities, usually involving a change in the conformation of target substrates. It is thought that Hsc70 associates with T antigen to assist in performing its numerous activities. However, it is not clear if T antigen binds to Hsc70 directly or induces the binding of Hsc70 to other T-antigen binding proteins such as pRb or p53. In this report, we show that T antigen binds Hsc70 directly with a stoichiometry of 1:1 (dissociation constant = 310 nM Hsc70). Furthermore, the T-antigen--Hsc70 complex formation is dependent upon ATP hydrolysis at the active site of Hsc70 (ATP dissociation constant = 0.16 microM), but T-antigen--Hsc70 complex formation does not require nucleotide hydrolysis at the T-antigen ATP binding site. N136, a J domain-containing fragment of T antigen, does not stably associate with Hsc70 but can form a transient complex as assayed by centrifugation analysis. Finally, T antigen does not associate stably with either of two yeast Hsc70 homologues or an amino-terminal fragment of Hsc70 containing the ATPase domain. These results provide direct evidence that the T-antigen--Hsc70 interaction is specific and that this association requires multiple domains of both T antigen and Hsc70. This is the first demonstration of a nucleotide requirement for the association of T antigen and Hsc70 and lays the foundation for future reconstitution studies of chaperone-dependent tumorigenesis induced by T antigen.
Subject(s)
Adenosine Triphosphate/metabolism , Antigens, Polyomavirus Transforming/metabolism , Molecular Chaperones/metabolism , Antigens, Polyomavirus Transforming/chemistry , Antigens, Polyomavirus Transforming/genetics , Baculoviridae/genetics , Centrifugation, Density Gradient , HSC70 Heat-Shock Proteins , HSP70 Heat-Shock Proteins/metabolism , Molecular Chaperones/genetics , Precipitin Tests , Recombinant Proteins/metabolismSubject(s)
Simian virus 40/genetics , Simian virus 40/physiology , Virus Cultivation/methods , Animals , Cell Line , Cell Transformation, Viral , Chlorocebus aethiops , Cytopathogenic Effect, Viral , DNA Replication , Genetic Complementation Test , Mutation , Simian virus 40/growth & development , Simian virus 40/pathogenicity , Transfection , Viral Plaque Assay , Virus ReplicationABSTRACT
We have generated mice deficient in E2F4 activity, the major form of E2F in many cell types. Analysis of newborn pups deficient in E2F4 revealed abnormalities in hematopoietic lineage development as well as defects in the development of the gut epithelium. Specifically, we observed a deficiency of various mature hematopoietic cell types together with an increased number of immature cells in several lineages. This was associated with an increased frequency of apoptotic cells. We also found a substantial reduction in the thickness of the gut epithelium that normally gives rise to crypts as well as a reduction in the density of villi. These observations suggest a critical role for E2F4 activity in controlling the maturation of cells in a number of tissues.
Subject(s)
Abnormalities, Multiple/genetics , DNA-Binding Proteins/metabolism , Hematopoietic Stem Cells/cytology , Intestinal Mucosa/abnormalities , Transcription Factors/metabolism , Animals , Animals, Newborn , Bone Marrow/embryology , Bone Marrow Cells/cytology , Bone Marrow Cells/pathology , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , E2F4 Transcription Factor , Embryonic and Fetal Development/genetics , Growth Disorders/genetics , Mice , Mice, Knockout , Transcription Factors/deficiency , Transcription Factors/geneticsABSTRACT
The simian virus 40 large T antigen (T antigen) inactivates tumor suppressor proteins and therefore has been used in numerous studies to probe the mechanisms that control cellular growth and to generate immortalized cell lines. Binding of T antigen to the Rb family of growth-regulatory proteins is necessary but not sufficient to cause transformation. The molecular mechanism underlying T-antigen inactivation of Rb function is poorly understood. In this study we show that T antigen associates with pRb and p130-E2F complexes in a stable manner. T antigen dissociates from a p130-E2F-4-DP-1 complex, coincident with the release of p130 from E2F-4-DP-1. The dissociation of this complex requires Hsc70, ATP, and a functional T-antigen J domain. We also report that the "released" E2F-DP-1 complex is competent to bind DNA containing an E2F consensus binding site. We propose that T antigen disrupts Rb-E2F family complexes through the action of its J domain and Hsc70. These findings indicate how Hsc70 supports T-antigen action and help to explain the cis requirement for a J domain and Rb binding motif in T-antigen-induced transformation. Furthermore, this is the first demonstration linking Hsc70 ATP hydrolysis to the release of E2F bound by Rb family members.
Subject(s)
Antigens, Viral, Tumor/metabolism , Cell Cycle Proteins , DNA-Binding Proteins , HSP70 Heat-Shock Proteins , Molecular Chaperones/metabolism , Proteins , Simian virus 40/immunology , Adenosine Triphosphate/metabolism , Animals , Antigens, Viral, Tumor/chemistry , Binding Sites , Carrier Proteins/chemistry , Carrier Proteins/metabolism , Carrier Proteins/physiology , Cell Line , E2F Transcription Factors , Electrophoresis, Polyacrylamide Gel , HSC70 Heat-Shock Proteins , Hydrolysis , Insecta , Models, Biological , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Plasmids , Protein Binding , Protein Structure, Tertiary , Retinoblastoma Protein/chemistry , Retinoblastoma Protein/metabolism , Retinoblastoma-Binding Protein 1 , Retinoblastoma-Like Protein p130 , Transcription Factor DP1 , Transcription Factors/chemistry , Transcription Factors/metabolismABSTRACT
The J domain of simian virus 40 (SV40) large T antigen is required for efficient DNA replication and transformation. Despite previous reports demonstrating the promiscuity of J domains in heterologous systems, results presented here show the requirement for specific J-domain sequences in SV40 large-T-antigen-mediated activities. In particular, chimeric-T-antigen constructs in which the SV40 T-antigen J domain was replaced with that from the yeast Ydj1p or Escherichia coli DnaJ proteins failed to replicate in BSC40 cells and did not transform REF52 cells. However, T antigen containing the JC virus J domain was functional in these assays, although it was less efficient than the wild type. The inability of some large-T-antigen chimeras to promote DNA replication and elicit cellular transformation was not due to a failure to interact with hsc70, since a nonfunctional chimera, containing the DnaJ J domain, bound hsc70. However, this nonfunctional chimeric T antigen was reduced in its ability to stimulate hsc70 ATPase activity and unable to liberate E2F from p130, indicating that transcriptional activation of factors required for cell growth and DNA replication may be compromised. Our data suggest that the T-antigen J domain harbors species-specific elements required for viral activities in vivo.
Subject(s)
Antigens, Viral, Tumor/physiology , Carrier Proteins , Cell Cycle Proteins , Cell Transformation, Viral , DNA Replication , DNA-Binding Proteins , Proteins , Simian virus 40/immunology , Virus Replication , Amino Acid Sequence , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , E2F Transcription Factors , Escherichia coli Proteins , Fungal Proteins/genetics , Fungal Proteins/metabolism , HSP40 Heat-Shock Proteins , HSP70 Heat-Shock Proteins/genetics , HSP70 Heat-Shock Proteins/metabolism , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , JC Virus/immunology , Mammals , Molecular Sequence Data , Phosphoproteins/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Retinoblastoma-Binding Protein 1 , Retinoblastoma-Like Protein p130 , Saccharomyces cerevisiae Proteins , Simian virus 40/pathogenicity , Species Specificity , Transcription Factor DP1 , Transcription Factors/metabolismABSTRACT
Paragangliomas are rare tumors of the paraganglia composed of specialized neural crest cells arising in association with sympathetic ganglia. Here we report a case of progressive, metastatic paraganglioma (glomus jugulare tumor) responsive to single agent gemcitabine. In addition, a brief review of chemotherapy for paraganglioma follows the case presentation.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Brain Neoplasms/pathology , Deoxycytidine/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Paraganglioma/drug therapy , Paraganglioma/secondary , Adolescent , Brain Neoplasms/diagnosis , Deoxycytidine/analogs & derivatives , Female , Humans , Lung Neoplasms/diagnosis , Magnetic Resonance Imaging , Paraganglioma/diagnosis , Tomography, X-Ray Computed , GemcitabineSubject(s)
Antigens, Polyomavirus Transforming/isolation & purification , Antigens, Polyomavirus Transforming/metabolism , Baculoviridae/metabolism , Genetic Techniques , Animals , Antigens, Polyomavirus Transforming/immunology , Cell Line , Chromatography, Affinity/methods , Insecta/metabolism , Models, GeneticABSTRACT
Serum-free mouse embryo (SFME) cells are a neural stem cell line that is dependent upon epidermal growth factor (EGF) for survival. Removal of EGF results in the G1 arrest and apoptosis of SFME cells. We have shown that the expression of simian virus 40 large T antigen in SFME cells blocks apoptosis and allows cell survival and division in the absence of EGF. Therefore the presence of T antigen abrogates the EGF requirement. The steady-state levels of p53, p21, and mdm-2 do not increase as SFME cells undergo apoptosis upon EGF withdrawal. Furthermore, the amino-terminal 136 amino acids (N136) of T antigen are sufficient to block death and to promote proliferation in the absence of EGF, while the carboxy-terminal fragment (C251-708), which contains the p53 binding site, is unable to block death. Taken together, these data suggest that SFME cells deprived of EGF undergo p53-independent apoptosis. Mutations that disrupt either the J domain or Rb family binding abolish the ability of T antigen to block SFME cell apoptosis and to promote cell growth. We conclude that T antigen must act on one or more members of the Rb family to inhibit SFME cell apoptosis.
Subject(s)
Antigens, Polyomavirus Transforming/metabolism , Apoptosis , Epidermal Growth Factor/metabolism , Neurons/cytology , Nuclear Proteins , Simian virus 40/metabolism , Stem Cells/cytology , Animals , Binding Sites , Cell Division , Cell Line , Cell Survival , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Epidermal Growth Factor/pharmacology , Mice , Neurons/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-mdm2 , Retinoblastoma Protein/metabolism , Stem Cells/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
BACKGROUND AND PURPOSE: Our purpose was to develop a classification scheme and method of presentation of in vivo single-voxel proton spectroscopic data from astrocytomas that most closely match the classification scheme determined from biopsy specimens. Since in vivo proton spectroscopy is noninvasive, it may be an attractive alternative to intracranial biopsy. METHODS: Single-voxel spectra were acquired using the point-resolved spectroscopic pulse sequence as part of the Probe spectroscopy package on a G.E. 1.5-T Signa scanner. Subjects consisted of 27 patients with biopsy-confirmed brain tumors (13 with glioblastoma multiforme, six with anaplastic astrocytoma, and eight with low-grade astrocytoma). The patients were divided into groups based on the histologic subtype of their tumor for different treatment protocols. RESULTS: Metabolic peak areas were normalized for each metabolite (choline, creatine, N-acetylaspartate, lactate) to the area of the unsuppressed water peak and to the area of the creatine peak. Kruskal-Wallis nonparametric analysis of variance (ANOVA) tests showed statistically significant differences among the tumor groups for all the area ratios. The lactate/water ratio could be used to distinguished all three tumor groups, whereas the choline/water ratio distinguished low-grade astrocytomas from the two high-grade groups. Both the choline and lactate ratios could be used to separate the high-grade from the low-grade tumors. CONCLUSION: Specific relative metabolic peak area ratios acquired from regions of contrast-enhancing brain tumor can be used to classify astrocytomas as to histopathologic grade.