RESUMO
AIM: To evaluate tumour angiogenesis as a predictor of prognosis in retinoblastoma. METHODS: This was a retrospective, non-randomised comparative clinicopathological study. The histopathology from 24 cases of Reese-Ellsworth (RE) group V unilateral retinoblastoma treated by enucleation alone was reviewed. Group I consisted of five patients (four RE group Vb and one group Va) who developed disseminated disease at a mean of 10.4 months after enucleation. The remaining 19 patients constitute group II (18 RE group Vb and 1 group Va), none of whom had developed metastatic disease with a mean follow up of 54 months. None of the 24 patients had evidence of extraocular disease at enucleation. The surgical specimens from patients with unilateral retinoblastoma treated by enucleation at Hospital do Cancer AC Camargo between January 1992 and December 1995 were identified, reviewed and the clinical data recorded. Two subsequent histological sections were prepared. One stained with haematoxylin and eosin for assessment of choroidal and optic nerve invasion, and the other for immunoreaction with an endothelium specific marker (antibody anti-CD 34). The main outcome measures were choroidal and/or optic nerve invasion and quantification of the tumour's relative vascular area (TRVA) obtained by Chalkley counting. RESULTS: Choroidal invasion was present in three eyes of group I (all massive) and six eyes of group II (two focal and four massive). Optic nerve invasion was found in two eyes of group I (all post-laminar) and four eyes of group II (three prelaminar and one post-laminar). There was no statistical difference regarding choroidal or optic nerve between the two groups. The TRVA was the only independent variable found to predict disease dissemination (p = 0.008 by Cox analysis). A TRVA equal to or greater than 3.9% had 100% sensitivity and 79% specificity in predicting disease dissemination. CONCLUSIONS: Quantification of angiogenesis, through measurement of the TRVA, can help to identify patients with retinoblastoma at high risk for disease dissemination after enucleation.
Assuntos
Neovascularização Patológica , Neoplasias da Retina/irrigação sanguínea , Retinoblastoma/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Coroide/patologia , Enucleação Ocular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica/diagnóstico , Neovascularização Patológica/patologia , Neoplasias do Nervo Óptico/patologia , Prognóstico , Curva ROC , Neoplasias da Retina/patologia , Neoplasias da Retina/cirurgia , Retinoblastoma/patologia , Retinoblastoma/cirurgia , Fatores de RiscoRESUMO
The conformation and activity of pRb, the product of the retinoblastoma susceptibility gene, is dependent on the phosphorylation status of one or more of its 16 potential cyclin-dependent kinase (cdk) sites. However, it is not clear whether the phosphorylation status of one or more of these sites contributes to the determination of the various conformations and activity of pRb. Moreover, whether and how the conformation of pRb may regulate the phosphorylation of the cdk sites is also unclear. In the process of analyzing the function and regulation of pRb, we uncovered the existence of an unusual structural motif, m89 (amino acids 880-900), the mutation of which confers upon pRb a hypophosphorylated conformation. Mutation of this structural domain activates, rather than inactivates, the growth suppressor function of pRb. In order to understand the effect of the mutation of m89 on the phosphorylation of cdk sites, we identified all the cdk sites (Thr-356, Ser-807/Ser-811, and Thr821) the phosphorylation of which drastically modify the conformation of pRb. Mutation of each of these four sites alone or in combinations results in the different conformations of pRb, the migration pattern of which, on SDS-polyacrylamide gel electrophoresis, resembles various in vivo hypophosphorylated forms. Each of these hypophosphorylated forms of pRb has enhanced growth suppressing activity relative to the wild type. Our data revealed that the m89 structural motif controls the exposure of the cdk sites Ser-807/Ser-811 in vitro and in vivo. Moreover, the m89 mutant has enhanced growth suppressing activity, similar to a mutant with alanine substitutions at Ser-807/Ser-811. Our recent finding, that the m89 region is part of a structural domain, p5, conserved antigenically and functionally between pRb and p53, suggests that the evolutionarily conserved p5 domain may play a role in the coordinated regulation of the activity of these two tumor suppressors, under certain growth conditions.
Assuntos
Quinases Ciclina-Dependentes/metabolismo , Proteína do Retinoblastoma/metabolismo , Sequência de Aminoácidos , Ciclo Celular , Ciclina A/genética , Ciclina A/metabolismo , Eletroforese em Gel de Poliacrilamida , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Fosforilação , Conformação Proteica , Proteína do Retinoblastoma/química , Proteína do Retinoblastoma/genética , Serina/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismoRESUMO
PURPOSE: To identify growth retardation in the orbits of children who have undergone enucleation and orbital implantation. METHODS: Children who underwent unilateral enucleation for retinoblastoma were examined. Any patient who had received external beam radiation or chemotherapy was excluded. Follow-up time was 5.5 to 10 years (mean, 8.33 years). Several linear measurements were made on the enucleated orbit and the fellow orbit. These measurements were compared using the paired Student t test and multivariate analysis of variance. RESULTS: There was no statistically significant difference in any of the measured orbital dimensions between the enucleated and fellow orbits. CONCLUSIONS: Enucleation in children, when combined with a large orbital implant, does not cause orbital growth retardation.
Assuntos
Enucleação Ocular , Órbita/crescimento & desenvolvimento , Neoplasias da Retina/cirurgia , Retinoblastoma/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Órbita/diagnóstico por imagem , Implantes Orbitários , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To describe platinum-based chemotherapy combined with local treatment modalities as an alternative to external beam radiotherapy for intraocular retinoblastoma. DESIGN: Platinum levels were measured by atomic absorption analysis in the tumors of 2 patients with retinoblastoma given carboplatin 5 or 2.5 hours before enucleation. Platinum levels in heated vs nonheated Greene melanoma tumors in rabbits were compared. A retrospective review of 172 affected eyes in 136 consecutive patients treated for retinoblastoma between January 1990 and December 1995 was performed. From 1990 to 1992, all treatable eyes initially received systemic carboplatin, 560 mg/m2, followed by 15 to 30 minutes of continuous diode laser hyperthermia (thermochemotherapy). Since 1992, larger tumors were treated initially with 3 monthly cycles of carboplatin, etoposide, and vincristine sulfate to reduce tumor volume (chemoreduction) followed by sequential aggressive local therapy (SALT) during examinations under anesthesia every 2 to 3 weeks. OUTCOME MEASURE: Treatment success was defined as eradication of tumor without enucleation or external beam radiotherapy. RESULTS: Significant therapeutic platinum levels were measured in the human tumors 2.5 and 5 hours after carboplatin administration. Increasing the temperature by 9 degrees C for 15 minutes doubled platinum levels in the rabbit model. Of the 38 eyes with Reese-Ellsworth group 1 through 5b tumors that were treated primarily with thermochemotherapy, all 24 eyes with group 1 and 2 tumors were treated successfully and two of the 4 eyes with group 3 tumors and all 10 eyes with group 5b tumors were treated unsuccessfully. Chemoreduction plus SALT was the primary treatment in 35 eyes and was successful in all 10 eyes with group 1 through 4 tumors and unsuccessful in all 7 eyes with extensive subretinal seeding and all 18 eyes with group 5b tumors with vitreous seeding. Seventy patients received carboplatin or carboplatin, vincristine, and etoposide, with myelosuppression, occasionally associated with bacteremia, being the main side effect. Transfusions were required in 15% of patients. Radiation retinopathy occurred in all 6 eyes treated with iodine 125 plaques. CONCLUSIONS: Thermochemotherapy is successful primary treatment for Reese-Ellsworth group 1 and 2 retinoblastomas. For larger tumors in the absence of vitreous or extensive subretinal seeding, 3 cycles of chemoreduction followed by SALT eradicates residual viable tumor. Chemoreduction plus SALT was not successful in eyes with diffuse vitreous or extensive subretinal seeding. Prior chemotherapy increases the risk for radiation retinopathy following 125I plaque therapy. External beam radiotherapy can safely be avoided in the primary treatment of Reese-Ellsworth groups 1 through 4 nondispersed retinoblastoma.
Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Neoplasias Oculares/terapia , Hipertermia Induzida , Retinoblastoma/terapia , Animais , Câmara Anterior/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia , Carboplatina/análise , Terapia Combinada , Crioterapia , Adutos de DNA/análise , DNA de Neoplasias/análise , Etoposídeo/administração & dosagem , Enucleação Ocular , Neoplasias Oculares/química , Humanos , Radioisótopos do Iodo/uso terapêutico , Fotocoagulação a Laser , Melanoma/química , Melanoma/terapia , Coelhos , Retinoblastoma/química , Vincristina/administração & dosagemAssuntos
Celulite (Flegmão)/etiologia , Neoplasias Oculares/complicações , Neoplasias Oculares/diagnóstico por imagem , Doenças Orbitárias/etiologia , Retinoblastoma/complicações , Retinoblastoma/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Lactente , Tomografia Computadorizada por Raios XRESUMO
Episcleral plaque radiotherapy is a widely applied treatment for selected patients with uveal melanomas. This treatment is well tolerated but may produce severe late radiation complications resulting in decreased visual acuity that reduces the attractiveness of conservative therapy. The purpose of this study was to access if the addition of episcleral hyperthermia decreases late radiation complications through radiation dose reduction while maintaining high incidence of local tumor control. In a 3-year period, episcleral plaque thermoradiotherapy was given to 25 patients with uveal melanoma in a Phase I study. The mean tumor height was 6.2 mm and the mean tumor basal area was 173 mm(2). The mean radiation dose given to the tumor apex was 72.2 Gy and the mean hyperthermia temperature, given once for 45 min, was 43.5 degrees C. Of the 25 patients treated, 22 (88%) showed tumor height reduction, 2 (8%) showed no change, and 1 (4%) had an increase in tumor height. At the last follow-up (range, 20-68 months; mean, 31.2 months), a 43% mean tumor height reduction was recorded (p = 0.0002). Of the 22 patients initially showing tumor regression, 2 (9%) had subsequent tumor progression. At least ambulatory vision (>5/200) was maintained by 20 (80%) patients. Severe complications, including hemorrhagic retinal detachment and a large vitreous hemorrhage, were seen in 2 (8%) patients early in this Phase I study. The treatment program was well tolerated by the study patients. Severe late treatment toxicity was sharply reduced by limiting the mean scleral temperature to < or equal to 44 degrees C. This study employing 30% lower radiation doses, showed tumor regression in the majority of patients. Longer follow-up is needed to assess long-term treatment efficacy and late treatment complications.
Assuntos
Braquiterapia , Hipertermia Induzida , Melanoma/radioterapia , Neoplasias Uveais/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Temperatura Corporal , Braquiterapia/efeitos adversos , Terapia Combinada , Progressão da Doença , Hemorragia Ocular/etiologia , Feminino , Seguimentos , Humanos , Masculino , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Lesões por Radiação/prevenção & controle , Dosagem Radioterapêutica , Indução de Remissão , Descolamento Retiniano/etiologia , Hemorragia Retiniana/etiologia , Neoplasias Uveais/patologia , Neoplasias Uveais/terapia , Transtornos da Visão/prevenção & controle , Acuidade Visual/efeitos da radiação , Corpo Vítreo/efeitos da radiaçãoRESUMO
Iris mammillations are rarely described, distinctive villiform protuberances that can cover the iris. In the majority of reported cases they are unilateral and sporadic, and are seen in association with oculodermal melanosis. In past literature and current clinical practice they are frequently confused with the iris nodules seen in neurofibromatosis type 1. Their clinical significance is not established, although it has been suggested that iris mammillations may be an external sign of ocular hypertension or intraocular malignancy. We report a series of 9 patients between the ages of 3 and 28 years with iris mammillations. The mammillations appear as regularly spaced, deep brown, smooth, conical elevations on the iris, of uniform height or increasing in height as the pupil margin is approached. They often overlie a naevus or an exceptionally deeply pigmented iris, such as that seen in melanosis oculi. One case had an associated ciliary body mass. They tend to occur in more highly pigmented ethnic groups and can be dominantly inherited. Iris mammillations may occur in association with systemic conditions including phakomatosis pigmentovascularis type IIb and neurofibromatosis type 1 when they may even coexist with iris hamartomas.
Assuntos
Doenças da Íris/patologia , Iris/patologia , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Doenças da Íris/complicações , Neoplasias da Íris/complicações , Masculino , Melanose/complicações , Melanose/patologia , Neurofibromatose 1/complicações , Nevo/complicações , Neoplasias Cutâneas/complicaçõesRESUMO
Photodynamic therapy (PDT) is a treatment modality that utilizes a photosensitizing drug activated by laser generated light, and is proving effective for oncologic and nononcologic applications. This report provides an overview of photosensitizers, photochemistry, photobiology, and the lasers involved in photodynamic therapy. Clinical and preclinical PDT studies involving Photofrin and various second generation photosensitizers are reviewed.
Assuntos
Fotoquimioterapia , Animais , Ensaios Clínicos como Assunto , Derivado da Hematoporfirina/uso terapêutico , Humanos , Terapia a Laser , Neoplasias/tratamento farmacológico , Fotobiologia , Fotoquímica , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/classificação , Fármacos Fotossensibilizantes/uso terapêutico , Viroses/tratamento farmacológicoRESUMO
In a previous genotypic study of eight families, we described paternal segregation distortion favoring the transmission of mutant alleles at the retinoblastoma gene locus (RB1). In the current study, we reviewed all published retinoblastoma pedigrees with defined ascertainment (n = 150), to determine whether the phenotypic segregation frequency at the RB1 locus is in general influenced by the sex of the transmitting parent. Segregation analysis under complete ascertainment revealed that 49.1% of the offspring of male transmitters were affected, while 44.3% of the offspring of female transmitters were affected. While this difference is not statistically significant, it is consistent with the previous findings. No significant sex distortion could be detected among the progeny of carrier fathers and mothers. In order to quantify the transmission ratio more precisely further prospective molecular genetic analysis is warranted. We propose a biological mechanism to account for a putative segregation distortion, namely that genetic recombination creates clones of spermatogonia that are homozygous for the mutant RB1 allele leading to a non-Mendelian ratio of sperm. This model can be experimentally tested using amplification of DNA from single sperm cells.
Assuntos
Genes do Retinoblastoma/genética , Retinoblastoma/genética , Feminino , Ligação Genética , Heterozigoto , Humanos , Funções Verossimilhança , Masculino , Linhagem , Fenótipo , Estudos Retrospectivos , Fatores Sexuais , Razão de MasculinidadeRESUMO
To characterize the anti-melanoma reactivity of CD8+ cytotoxic T lymphocytes (CTL) from choroidal melanoma patients, CTL clones were isolated from the peripheral blood of three patients after mixed lymphocyte/tumor cell culture (MLTC). Clones were derived from lymphocytes stimulated by allogeneic (OCM-1, A24, A28) or autologous (OCM-3, A1, A30) melanoma cells. Their reactivity against a panel of HLA-typed melanoma and nonmelanoma cells was assessed, to determine whether a single CTL clone could recognize and lyse a variety of allogeneic melanoma cell lines. While proportionately more clones derived from autologous MLTC were melanoma-specific than allogeneic MLTC (42% versus 14%), melanoma-specific CTL were recovered from both. Notably, a novel melanoma specificity was identified. These CTL clones were termed non-fastidious because they were capable of lysing melanoma cells with which they had no HLA class I alleles in common. Nonetheless, lysis was mediated by the HLA class I molecule. Since lysis was specific for melanoma cells, these CTL appeared to recognize a shared melanoma peptide(s). Because of their prevalence, we propose that non-fastidious CTL are integral to human anti-melanoma T cell immunity. This reinforces clinical findings that allogeneic melanomas can substitute for autologous tumors in active specific immunotherapy. By circumventing the need for autologous melanoma, it is possible to treat patients after removal of the primary choroidal melanoma in an attempt to prevent metastasis.
Assuntos
Antígenos CD8/análise , Neoplasias da Coroide/imunologia , Melanoma/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos CD/análise , Genes MHC Classe I , Humanos , Teste de Cultura Mista de Linfócitos , Receptores de Antígenos de Linfócitos T/fisiologiaRESUMO
PURPOSE: To determine whether active specific immunotherapy with lysates of cutaneous melanoma cells, administered with immunologic adjuvant DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT), is effective in shrinking a primary choroidal melanoma, in an elderly patient already blind in the nontumorous eye. An 81-year-old man was referred with a primary choroidal melanoma of the left eye, with virtual blindness of the right eye due to macular degeneration. He was begun on active specific immunotherapy with an experimental melanoma vaccine (melanoma theraccine) and DETOX on weeks 1, 2, 3, 4, and 6, respected after a hiatus of 2 weeks. After a response was noted, monthly injections were given. RESULTS: The patient had a significant shrinkage of his choroidal melanoma from a height of 4.2 mm to 2.4 mm within 2 months. This was sustained by continual treatment for 21 months until September 1991. After the patient failed to return for 9 months while recuperating from a stroke, the lesion regrew to a height of 3.7 mm and developed an additional lobe. On resumption of monthly treatments, the lesion shrank to 3.4 mm within 3 months, lost the additional lobe, and has since remained stable. No metastases have been found over a period of nearly 4 years on quarterly computed tomographic (CT) scanning of the chest and abdomen, and magnetic resonance imaging of the head. CONCLUSION: Active specific immunotherapy with cutaneous melanoma lysates has caused a clinically useful protracted regression of a primary choroidal melanoma in an elderly patient in whom surgery and radiation therapy were contraindicated. This may represent the first case of a primary choroidal melanoma, and perhaps the only primary tumor, successfully treated with systemic immunotherapy alone. A formal trial of active specific immunotherapy for primary choroidal melanoma in selected patients may be warranted.
Assuntos
Neoplasias da Coroide/terapia , Imunoterapia Ativa/métodos , Melanoma/terapia , Adjuvantes Imunológicos , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Coroide/diagnóstico , Humanos , Masculino , Melanoma/diagnósticoRESUMO
OBJECTIVE: The disparate occurrence of few cases of retinoblastoma in the same extended pedigree confronts us with the unsolved problem of a low-penetrant autosomal-dominant trait vs fortuitous familial aggregation of sporadic cases. Determination as to whether the disease arises from a common inherited mutation or sporadic mutations has important implications for genetic counseling. This is illustrated in this report of two presumed low-penetrant retinoblastoma pedigrees characterized by two distantly affected relatives connected through apparently healthy carriers. DESIGN: We mathematically modeled the inheritance patterns and calculated the a priori relative probabilities of heredity with low penetrance vs chance occurrence of independent mutations for each pedigree. The derived odds clearly show that the disease, which occurred twice in each family, most likely resulted from unrelated mutations. To prove this, extensive DNA testing was conducted, including determination of intragenic RB1 DNA sequence polymorphisms and screening for mutation using the polymerase chain reaction coupled with single-strand conformation polymorphism analysis. PATIENTS: All living key members from both pedigrees were included. RESULTS: Consistent with our initial expectation, there was no common intragenic haplotype or common germ-line mutation that segregated with the disease phenotype in either of these two families. CONCLUSIONS: We therefore conclude that collateral incidence of retinoblastoma in these two pedigrees occurred by chance and not according to autosomal-dominant inheritance with low penetrance. Furthermore, our data provide the first evidence, to our knowledge, that related individuals may have independent mutations involving an identical gene locus, giving rise to an artefactual inheritance pattern.
Assuntos
Neoplasias Oculares/genética , Mutação , Retinoblastoma/genética , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Genes do Retinoblastoma , Ligação Genética/genética , Humanos , Lactente , Masculino , Modelos Biológicos , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , ProbabilidadeRESUMO
The suppression of tumor formation, first demonstrated by somatic cell hybrid and microcell fusion experiments, suggests the existence of a class of genes that selectively suppress the growth of tumor cells but not normal cells. The reintroduction of these genes into tumor cells presumably renders the cells responsive to in vivo growth inhibitory environment. As the inheritance of a defective retinoblastoma gene (Rb-1) allele results in a predisposition to the development of various cancers, and since inactivation of both alleles are observed in tumor cells, the Rb gene has been suspected to have the ability to suppress tumor growth. Data presented here demonstrated that different types of normal cells, which have a limited life span, were also growth arrested by a transfected Rb gene. Cell lines which are resistant to the growth suppression effect of the Rb gene in vitro, retain the ability to form tumors in nude mice even in the presence of a stable and highly expressed wild type Rb protein. We conclude that while the Rb gene can suppress the growth of many tumor cell lines, its growth suppression effect is not tumor specific.
Assuntos
Divisão Celular/fisiologia , Genes do Retinoblastoma/fisiologia , Células 3T3 , Animais , Sequência de Bases , Células Cultivadas/citologia , Fibrossarcoma/química , Fibrossarcoma/genética , Fibrossarcoma/patologia , Genes do Retinoblastoma/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Transplante de Neoplasias , Osteossarcoma/química , Osteossarcoma/genética , Osteossarcoma/patologia , Neoplasias da Próstata/química , Neoplasias da Próstata/patologia , Proteína do Retinoblastoma/análise , Transfecção , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
The presence of melanocytic hamartomas on the iris, known eponymously as Lisch nodules, is highly characteristic of neurofibromatosis type 1 (NF1). Early recognition of NF1 is vital for optimal detection of associated tumours and for genetic counselling of family members. Although the iris nodules are probably not visible at birth, their prevalence in patients with NF1 gradually increases from birth to about 50% of 5-year-olds, 75% of 15-year-olds and 95-100% of adults over the age of 30. Iris hamartomas in NF1 are elevated, pale brown lesions that vary in appearance depending on the underlying colour of the iris. Colour illustrations are shown in this article, enabling the clinician readily to differentiate hamartomas from other iris lesions.
Assuntos
Hamartoma/patologia , Neoplasias da Íris/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cor de Olho , Hamartoma/epidemiologia , Humanos , Lactente , Neoplasias da Íris/epidemiologia , Pessoa de Meia-Idade , Neurofibromatose 1/patologia , PrevalênciaRESUMO
Although chloral hydrate sedation has been proposed as an alternative to evaluation under anesthesia for pediatric patients who are unable to cooperate with routine test procedures, a careful study of the drug's safety and effectiveness is lacking. This study reports the effectiveness and safety of high-dose chloral hydrate for ophthalmic examination in 302 patients between the ages of 1 month and 5 years. The patients had nothing to eat or drink for 4 hours prior to drug administration. The patients were monitored during sedation and until fully awake. Eighty-eight percent of the patients (266/302) were successfully sedated without a supplemental dose. There were no reports of any complications including emesis, respiratory distress or depression, behavioral problems, changes in vital signs, patient injury, or hospital admission. The high-dose chloral hydrate protocol described, results in safe and generally successful sedation of pediatric patients for ophthalmic examination.
Assuntos
Hidrato de Cloral/administração & dosagem , Testes Visuais , Pré-Escolar , Hidrato de Cloral/efeitos adversos , Relação Dose-Resposta a Droga , Eletrofisiologia , Oftalmopatias/diagnóstico , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , SuturasRESUMO
The origins of the initial mutations in sporadic retinoblastoma were explored using polymorphic markers from chromosome 13q. The paternal chromosome was maintained in 3 of 3 informative bilateral tumors which had undergone reduction to homozygosity for regions of this chromosome. The paternal chromosome was maintained in 7 of 8 informative unilateral tumors which likewise demonstrated a reduction of homozygosity. These data are in contrast to previously published studies of chromosome retention in unilateral retinoblastoma [Dryja, T. P., Mukai, S., Petersen, R., Rapaport, J. M., Walton, D., and Yandel, D. W. Nature (Lond.), 339: 556-558, 1989; Zhu, Z., Dunn, J. M., Phillips, R. A., Goddard, A. D., Paton, K. E., Becker, A., and Gallie, B. L. Nature (Lond.), 340: 312-313, 1989] and provide the first evidence that genomic imprinting may play a role in this disease.
Assuntos
Retinoblastoma/genética , Alelos , Southern Blotting , Cromossomos Humanos Par 13 , Heterozigoto , Humanos , Paternidade , Polimorfismo de Fragmento de RestriçãoRESUMO
The human retinoblastoma gene (RB1) encodes a protein (Rb) of 105 kilodaltons that can be phosphorylated. Analysis of Rb metabolism has shown that the protein has a half-life of more than 10 hours and is synthesized at all phases of the cell cycle. Newly synthesized Rb is not extensively phosphorylated (it is "underphosphorylated") in cells in the G0 and G1 phases but is phosphorylated at multiple sites at the G1/S boundary and in S phase. HL-60 cells that were induced to terminally differentiate by various chemicals lost their ability to phosphorylate newly synthesized Rb at multiple sites when cell growth was arrested. These findings suggest that underphosphorylated Rb may restrict cell proliferation.