RESUMO
Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo , potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.
Assuntos
Histona Desmetilases , Neoplasias , Humanos , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona Desmetilases/uso terapêutico , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Epigênese Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapêuticoRESUMO
BACKGROUND: MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes. METHODS: MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10µL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS. RESULTS: MDNA55 showed an acceptable safety profile at doses up to 240 µg. In all evaluable patients (nâ =â 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (nâ =â 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26). CONCLUSIONS: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Receptores de Interleucina-4/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Microambiente TumoralRESUMO
: Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. IMPLICATIONS FOR PRACTICE: Because of emerging resistance mechanisms that involve the ligand-binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR-targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration-resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small-molecule agent, EPI-506, represents a new pharmaceutical class, AR N-terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Cloridrinas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/química , Humanos , Masculino , Domínios Proteicos , Receptores Androgênicos/fisiologia , Estudos Retrospectivos , Transdução de Sinais , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidoresRESUMO
GRN1005 is a novel peptide-drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m(2) once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m(2); the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m(2) (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non-small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m(2)) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Encéfalo/metabolismo , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/patologia , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Peptídeos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. EXPERIMENTAL DESIGN: Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). RESULTS: Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. CONCLUSIONS: Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sirolimo/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/patologia , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: A key end point of early cancer clinical trials is the assessment of toxicities and their possible association with new experimental drugs. Therefore, the concurrent use of complementary and alternative medicine (CAM) in patients with advanced malignancies seen in a dedicated phase 1 clinic was evaluated. METHODS: An investigator-designed survey was anonymously completed by patients seen in the phase 1 clinic. Pharmacologic CAM included any oral, topical, or intravenous agent, including vitamins, dietary supplements, and herbal products. Nonpharmacologic CAM included prayer, meditation, hypnosis, massage, and acupuncture. RESULTS: Of the 404 patients approached about completing the CAM survey, 394 (98%) agreed to respond, and 309 (78%) surveys were returned. Of those 309 patients, 162 (52%) used 1 or more CAM. Of the 162 CAM users, 77% utilized pharmacologic CAM, 71% used nonpharmacologic CAM, and 48% used both modalities. The most frequent CAM used were vitamins (70%), prayer (57%), and herbal products (26%). CAM utilization was not significantly associated with race, age, level of education, employment, or income level but was used more by women than men (P < .01). There was no statistically significant association between the use of CAM and quality of life as perceived by patients. Of the CAM users, 43% of patients had been using CAM for >5 years. Only 5% reported having side effects from using CAM, whereas 23% did not fully disclose their CAM use to their physicians. CONCLUSIONS: CAM usage is common in patients with advanced malignancies seen in a phase 1 clinic.
Assuntos
Terapias Complementares/estatística & dados numéricos , Neoplasias/terapia , Ensaios Clínicos Fase I como Assunto , Suplementos Nutricionais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Feline leukemia virus (FeLV)-945, a member of the FeLV-A subgroup, was previously isolated from a cohort of naturally infected cats. An unusual multicentric lymphoma of non-T-cell origin was observed in natural and experimental infection with FeLV-945. Previous studies implicated the FeLV-945 surface glycoprotein (SU) as a determinant of disease outcome by an as yet unknown mechanism. The present studies demonstrate that FeLV-945 SU confers distinctive properties of binding to the cell surface receptor. RESULTS: Virions bearing the FeLV-945 Env protein were observed to bind the cell surface receptor with significantly increased efficiency, as was soluble FeLV-945 SU protein, as compared to the corresponding virions or soluble protein from a prototype FeLV-A isolate. SU proteins cloned from other cohort isolates exhibited increased binding efficiency comparable to or greater than FeLV-945 SU. Mutational analysis implicated a domain containing variable region B (VRB) to be the major determinant of increased receptor binding, and identified a single residue, valine 186, to be responsible for the effect. CONCLUSIONS: The FeLV-945 SU protein binds its cell surface receptor, feTHTR1, with significantly greater efficiency than does that of prototype FeLV-A (FeLV-A/61E) when present on the surface of virus particles or in soluble form, demonstrating a 2-fold difference in the relative dissociation constant. The results implicate a single residue, valine 186, as the major determinant of increased binding affinity. Computational modeling suggests a molecular mechanism by which residue 186 interacts with the receptor-binding domain through residue glutamine 110 to effect increased binding affinity. Through its increased receptor binding affinity, FeLV-945 SU might function in pathogenesis by increasing the rate of virus entry and spread in vivo, or by facilitating entry into a novel target cell with a low receptor density.
Assuntos
Vírus da Leucemia Felina/patogenicidade , Glicoproteínas de Membrana/metabolismo , Receptores Virais/metabolismo , Proteínas Oncogênicas de Retroviridae/metabolismo , Proteínas do Envelope Viral/metabolismo , Tropismo Viral , Ligação Viral , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Animais , Gatos , Linhagem Celular , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Conformação Proteica , Valina/genéticaRESUMO
IMPORTANCE OF THE FIELD: Farnesyltransferase inhibitors (FTIs) target multiple pathways implicated in the pathogenesis of solid and hematologic malignancies. AREAS COVERED IN THIS REVIEW: Novel preclinical and clinical data on FTIs. WHAT THE READER WILL GAIN: Results of clinical trials of FTIs are critically summarized: Phase I - II studies demonstrated that tipifarnib (the most extensively investigated FTI) had antileukemic activity. The rates of complete response (CR), partial response (PR) and/or CR with incomplete platelet recovery (CRp) in patients with MDS and refractory/poor-risk AML were 5 - 25% and 11 - 14%, respectively (hematological improvement, 17 - 35% and 8 - 9.5%, respectively). A Phase III study comparing tipifarnib with best supportive care, including hydroxyurea in patients with untreated AML ≥ 70 years old showed no survival benefit in the tipifarnib arm. A two-gene classifier (RASGRP1:APTX gene expression ratio) predicted response and survival, indicating that a two-gene expression assay may help select patients with AML who would benefit from tipifarnib. TAKE HOME MESSAGE: Patient selection should become a priority for targeted agent drug development. Clinical trials selecting patients who would benefit from FTIs should be designed to define the role of FTIs in the treatment of hematological malignancies and solid tumors.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Farnesiltranstransferase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/metabolismo , Genes ras/efeitos dos fármacos , Genes ras/fisiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/uso terapêuticoRESUMO
Genomic instability, a hallmark of leukemic cells, is associated with malfunctioning cellular responses to DNA damage caused by defective cell cycle checkpoints and/or DNA repair. Adult T-cell leukemia, which can result from infection with human T-cell leukemia virus type 1 (HTLV-1), is associated with extensive genomic instability that has been attributed to the viral oncoprotein Tax. How Tax influences cellular responses to DNA damage to mediate genomic instability, however, remains unclear. Therefore, we investigated the effect of Tax on cellular pathways involved in recognition and repair of DNA double-strand breaks. Premature attenuation of ATM kinase activity and reduced association of MDC1 with repair foci were observed in Tax-expressing cells. Following ionizing radiation-induced S-phase checkpoint activation, Tax-expressing cells progressed more rapidly than non-Tax-expressing cells toward DNA replication. These results demonstrate that Tax expression may allow premature DNA replication in the presence of genomic lesions. Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Mutadas de Ataxia Telangiectasia , Linhagem Celular , Replicação do DNA , Humanos , Proteínas Nucleares/metabolismo , Linfócitos T/efeitos da radiação , Linfócitos T/virologia , Transativadores/metabolismoRESUMO
The outcome of feline leukemia virus (FeLV) infection in nature is variable, including malignant, proliferative, and degenerative disorders. The determinants of disease outcome are not well understood but are thought to include viral, host, and environmental factors. In particular, genetic variations in the FeLV long terminal repeat (LTR) and SU gene have been linked to disease outcome. FeLV-945 was previously identified as a natural isolate predominant in non-T-cell neoplastic and nonneoplastic diseases in a geographic cohort. The FeLV-945 LTR was shown to contain unique repeat elements, including a 21-bp triplication downstream of the enhancer. The FeLV-945 SU gene was shown to encode mutational changes in functional domains of the protein. The present study details the outcomes of infection with recombinant FeLVs in which the LTR and envelope (env) gene of FeLV-945, or the LTR only, was substituted for homologous sequences in a horizontally transmissible prototype isolate, FeLV-A/61E. The results showed that the FeLV-945 LTR determined the kinetics of disease. Substitution of the FeLV-945 LTR into FeLV-A/61E resulted in a significantly more rapid disease onset but did not alter the tumorigenic spectrum. In contrast, substitution of both the FeLV-945 LTR and env gene changed the disease outcome entirely. Further, the impact of FeLV-945 env on the disease outcome was dependent on the route of inoculation. Since the TM genes of FeLV-945 and FeLV-A/61E are nearly identical but the SU genes differ significantly, FeLV-945 SU is implicated in the outcome. These findings identify the FeLV-945 LTR and SU gene as determinants of disease.
Assuntos
Genes Virais , Vírus da Leucemia Felina/genética , Infecções por Retroviridae/virologia , Sequências Repetidas Terminais , Infecções Tumorais por Vírus/virologia , Proteínas do Envelope Viral/genética , Animais , Animais Recém-Nascidos , Gatos , Modelos Animais de Doenças , Vírus da Leucemia Felina/patogenicidade , Dados de Sequência Molecular , Recombinação Genética , VirulênciaRESUMO
FeLV-945 is a representative isolate of the natural feline leukemia virus (FeLV) variant predominant in non-T-cell malignant, proliferative, and degenerative diseases in a geographic cohort. The FeLV-945 surface glycoprotein (SU) is closely related to natural horizontally transmissible FeLV subgroup A (FeLV-A) but was found to differ from a prototype to a larger extent than the members of FeLV-A differ among themselves. The sequence differences included point mutations restricted largely to the functional domains of SU, i.e., VRA, VRB, and PRR. Despite the sequence differences in these critical domains, measurements of receptor utilization, including host range and superinfection interference, confirmed the assignment of FeLV-945 to subgroup A. Other proviruses isolated from the cohort contained similar sequence hallmarks and were assigned to FeLV subgroup A. A provirus from cat 1046 contained a histidine-to-proline change at SU residue 6 within an SPHQ motif that was previously identified as a critical mediator of fusion events during virus entry. The 1046 pseudotype virus entered cells only in the presence of the soluble cofactor FeLIX provided in trans, but it retained an ecotropic host range even in the presence of FeLIX. The mutational changes in FeLV-945 were shown to confer significant functional differences compared to prototype FeLV-A viruses. The substitution of FeLV-945 envelope gene sequences for FeLV-A/61E sequences conferred a small but statistically significant replicative advantage in some feline cells. Moreover, substitution of the unique FeLV-945 long terminal repeat and envelope gene for those of FeLV-A/61E altered the disease spectrum entirely, from a thymic lymphoma of a T-cell origin to an as yet uncharacterized multicentric lymphoma that did not contain T cells.
Assuntos
Glicoproteínas/genética , Vírus da Leucemia Felina/patogenicidade , Mutação , Infecções por Retroviridae/fisiopatologia , Infecções Tumorais por Vírus/fisiopatologia , Proteínas do Envelope Viral/genética , Animais , Doenças do Gato/fisiopatologia , Doenças do Gato/virologia , Gatos , Linhagem Celular , Cães , Feminino , Glicoproteínas/metabolismo , Humanos , Vírus da Leucemia Felina/genética , Linfoma/fisiopatologia , Linfoma/virologia , Linfoma de Células T/fisiopatologia , Linfoma de Células T/virologia , Dados de Sequência Molecular , Infecções por Retroviridae/virologia , Análise de Sequência de DNA , Timo/virologia , Neoplasias do Timo/fisiopatologia , Neoplasias do Timo/virologia , Infecções Tumorais por Vírus/virologia , Proteínas do Envelope Viral/metabolismoRESUMO
It is estimated that 15% of all cancers are etiologically linked to viral infection. Specific cancers including adult T-cell leukemia, hepatocellular carcinoma, and uterine cervical cancer are associated with infection by human T-cell leukemia virus type I, hepatitis B virus, and high-risk human papilloma virus, respectively. In these cancers, genomic instability, a hallmark of multistep cancers, has been explicitly linked to the expression of oncoproteins encoded by these viruses. This review discusses mechanisms utilized by these viral oncoproteins, Tax, HBx, and E6/E7, to mediate genomic instability and cellular transformation.
Assuntos
Transformação Celular Neoplásica/metabolismo , Instabilidade Genômica , Neoplasias/etiologia , Proteínas Oncogênicas/metabolismo , Vírus Oncogênicos/metabolismo , Transcrição Gênica/genética , Ciclo Celular/fisiologia , Transformação Celular Neoplásica/genética , Reparo do DNA/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/virologia , Vírus Oncogênicos/genética , Papillomaviridae/genética , Papillomaviridae/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Feline leukaemia virus (FeLV)-945 was previously identified in natural multicentric lymphomas and contains a 21 bp tandem triplication in the LTR. In the present study, FeLV LTR variation was examined in the cohort from which FeLV-945 was identified. The objectives of the study were to evaluate FeLV LTR variation within the cohort, to determine whether the FeLV-945 LTR was associated uniquely with multicentric lymphoma and to evaluate functional attributes that may have contributed selective advantage to the predominant LTR variants observed. T-cell tumours uniformly contained LTRs with duplicated enhancer sequences, although enhancer duplications conferred little transcriptional advantage. Non-T-cell malignant, proliferative and degenerative diseases contained LTRs with two, three or four tandemly repeated copies of the 21 bp sequence originally identified in FeLV-945. While the length and termini of enhancer duplications were variable, the 21 bp repeat unit was invariant. Triplication of the 21 bp repeat conferred the optimal replicative advantage in feline cells.