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OBJECTIVE: To describe the development of a web-based data collection tool to track the management and outcomes of uveal melanoma patients. DESIGN: Description of a clinical registry. PARTICIPANTS: Patients with uveal melanoma. METHODS: A panel of expert ocular oncologists, with input from other relevant specialties and individuals with expertise in registry development, collaborated to formulate a minimum data set to be collected to track patient centred, real-world outcomes in uveal melanoma. This data set was used to create the Fight Tumour Blindness! (FTB!) registry within Save Sight Registries. RESULTS: The data set to be collected includes patient demographics and medical history, baseline visit, follow-up visit including tumour treatment, metastatic staging and surveillance, pathology, and patient-reported questionnaires. The inbuilt mechanisms to ensure efficient and complete data collection are described. CONCLUSIONS: The FTB! registry can be used to monitor outcomes for patients with uveal melanoma. It allows benchmarking of outcomes and comparisons between different clinics and countries.
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PURPOSE: To investigate clinical manifestations and prognoses in pediatric patients (≤12 years old) with ocular melanoma. METHODS: This was a retrospective, multicenter cohort study with individual participant data (IPD) meta-analysis pooling available published cases, and unpublished cases from an international collaboration of seven ocular oncology centers. RESULTS: There were 133 eyes of 133 pediatric patients with choroidal or ciliary body (n = 66 [50%]), iris (n = 33 [25%]), conjunctival (n = 26 [19%]), and eyelid (n = 8 [6%]) melanoma. Overall, the mean patient age at presentation was 7 years (median, 8; range, 1-12 years), with 63 males (49%). The mean age by tumor site was 6.50 ± 3.90, 7.44 ± 3.57, 9.12 ± 2.61, and 5.63 ± 2.38 years, for choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively (P = 0.001). Association with ocular melanocytosis was seen in 15%, 11%, 4%, and 0%, respectively (P = 0.01). Frequency of ocular melanoma family history did not vary by tumor site (7%, 17%, 9% and 12%, resp. [P = 0.26]). After mean follow-up of 74, 85, 50, and 105 months (P = 0.65), metastasis was seen in 12%, 9%, 19%, and 13% of choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively. Death was reported in 5%, 3%, 8%, and 0%, respectively, with survival analysis indicating higher mortality in choroidal/ciliary body and conjunctival melanoma patients. CONCLUSIONS: Ocular melanoma in the pediatric population is rare, with unique clinical features and outcomes. Iris melanoma accounts for about one-third of pediatric uveal melanoma cases.
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Neoplasias Oculares , Neoplasias Palpebrais , Melanoma , Neoplasias Uveais , Masculino , Humanos , Criança , Melanoma/patologia , Estudos Retrospectivos , Estudos de Coortes , Neoplasias Uveais/patologia , Neoplasias Uveais/secundário , Neoplasias Oculares/complicações , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Prognostic cytological and molecular features of uveal melanoma have been well researched and are essential in management. Samples can be obtained in vivo through fine needle aspirate biopsy, vitrector cutter, forceps or post-enucleation for off-site testing. This study aims to examine cytological and chromosome microarray yields of these samples. METHODS: A retrospective cohort analysis of 119 uveal melanoma biopsies submitted to our laboratory. Samples included those taken in vivo (n = 57) and post-enucleation (n = 62). Patient and tumour features were collected including age, sex, primary tumour location, basal diameter and tumour height. Prognostic outcomes measured include cell morphology, chromosomal status and immunohistochemistry. RESULTS: Post-enucleation biopsies accounted for just over half of our samples (52%). Post-enucleation samples had a more successful genetic yield than in vivo biopsies (77% vs. 50%, p = 0.04) though there was no difference for cytological yields. There was no difference in cytological or microarray yields between instruments. The vitrector biopsy group had the smallest tumour thickness (5 mm vs. 10 mm [fine-needle aspirate biopsy], p = 0.003). There was a strong correlation between monosomy 3, BAP1 aberrancy and epithelioid cell type in post-enucleation samples (Tb = 0.742, p = 0.005). However, epithelioid morphology was not associated with either monosomy 3 (p = 0.07) or BAP1 aberrancy (p = 0.24) for in vivo biopsies. CONCLUSIONS: All three biopsy instruments provide similar cytological yields as post-enucleation sampling, although post-enucleation samples had a more successful chromosome microarray yield. Epithelioid cytomorphology alone is insufficient for prognostication in in vivo biopsies, immunohistochemistry would be a useful surrogate test.
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Neoplasias Uveais , Biópsia por Agulha Fina , Humanos , Melanoma , Monossomia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismoRESUMO
BACKGROUND/PURPOSE: To report the largest case series to date of uveitis occurring in association with immunomodulatory therapy for malignant melanoma. METHODS: A retrospective multicenter case review. Twenty-two patients with uveitis occurring in association with either immunotherapy or targeted immune therapy for malignant melanoma were identified. RESULTS: Of 22 patients, 11 had anterior uveitis in isolation. The remainder showed a variety of clinical features including panuveitis, ocular hypotony, papillitis, cystoid macular edema, and melanoma-associated retinopathy. Most patients responded well to treatment. CONCLUSION: We report the largest case series to date of patients with uveitis secondary to drug treatment for malignant melanoma. These cases are likely to increase in number in the future as newer immunomodulatory therapies for cancers are developed and the indications for these drugs increase. A dilemma arises when patients respond well to these drugs but develop vision-threatening side effects.
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Imunoterapia , Melanoma , Uveíte , Humanos , Imunoterapia/efeitos adversos , Melanoma/terapia , Estudos Retrospectivos , Uveíte/etiologiaRESUMO
Uveal melanoma (UM) is the commonest primary intraocular malignancy in adults. There is limited published data on lipid production in UM. Here, we describe the clinical, histological, immunohistochemical, and molecular findings in a ciliochoroidal melanoma with lipid production and expression of the enzyme HMG-CoA reductase. This case highlights an unusual UM tumour phenotype with a high-risk molecular metastatic profile and discusses tumour lipogenesis and activation of the mevalonate pathway as a potential therapeutic target in managing lipidised ciliochoroidal UM.
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BACKGROUND: Conjunctival melanoma is rare in adults and rarer in children. We systematically reviewed the presentation, diagnostic and management strategies as well as outcomes for conjunctival melanoma in children and adolescents. METHODS: The following databases were searched: Medline, Embase, Web of Science and Scopus for cases of conjunctival melanoma occurring in children and adolescents < 18 years of age. RESULTS: Seventeen studies with 32 patients (18 males) were identified. The median age at presentation was 11 years (range 4-18 years). Most patients were white. Most patients presented with a conjunctival mass or naevus with a recent history of growth or change. Excision biopsy provided diagnosis and management for all cases. Adjuvant chemotherapy and radiotherapy were also used. One patient had metastatic disease at diagnosis and 3 developed metastatic disease (range 1-10 months). Two patients died from disease and one was alive with metastatic disease. Two patients had disease recurrence. Outcomes were observed to be better where diagnosis was made earlier and "no-touch" excision biopsy was performed in an appropriate specialist setting. CONCLUSIONS: Conjunctival melanoma occurs rarely in children and adolescents. Surgery is the mainstay of management. The prognosis is guarded in metastatic disease due to the small sample size and limited follow-up.
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Research is currently underway worldwide into the development of receptor-specific radiopharmaceuticals for the imaging and treatment of cancer. The successful clinical development of radiolabeled somatostatin analogs for imaging and treatment of cancers overexpressing somatostatin receptors has catalyzed further preclinical investigation of other radiolabeled peptides for molecular imaging and peptide-receptor radiotherapy, including such well-studied peptide vectors as cholecystokinin, neurotensin, bombesin and RGD peptides. Within this larger context, this article will focus on the current status of two more recent additions to the list of molecular imaging targets - guanylate cyclase C, a specific marker for colorectal cancer, and the urokinase plasminogen activator receptor, a cell-surface receptor overexpressed in diverse cancer types.
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Guanilato Ciclase/antagonistas & inibidores , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Fragmentos de Peptídeos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Animais , Ensaios Clínicos como Assunto , Humanos , Prognóstico , RadiografiaRESUMO
Analogues of the E. coli heat-stable enterotoxin (STh) are currently under study as both imaging and therapeutic agents for colorectal cancer. Studies have shown that the guanylate cyclase C (GC-C) receptor is commonly expressed in colorectal cancers. It has also been shown that STh peptides inhibit the growth of tumor cells expressing GC-C. The ability to determine GC-C status of tumor tissue using in vivo molecular imaging techniques would provide a useful tool for the optimization of GC-C-targeted therapeutics. In this work, we have compared receptor binding affinities, internalization/efflux rates, and in vivo biodistribution patterns of an STh analogue linked to N-terminal DOTA, TETA, and NOTA chelating moieties and radiolabeled with Cu-64. The peptide F(19)-STh(2-19) was N-terminally labeled with three different chelating groups via NHS ester activation and characterized by RP-HPLC, ESI-MS, and GC-C receptor binding assays. The purified conjugates were radiolabeled with Cu-64 and used for in vitro internalization/efflux, in vivo biodistribution, and in vivo PET imaging studies. In vivo experiments were carried out using SCID mice bearing T84 human colorectal cancer tumor xenografts. Incorporation of DOTA-, TETA-, and NOTA-chelators at the N-terminus of the peptide F(19)-STh(2-19) resulted in IC(50)s between 1.2 and 3.2 nM. In vivo, tumor localization was similar for all three compounds, with 1.2-1.3%ID/g at 1 h pi and 0.58-0.83%ID/g at 4 h pi. The principal difference between the three compounds related to uptake in nontarget tissues, principally kidney and liver. At 1 h pi, (64)Cu-NOTA-F(19)-STh(2-19) demonstrated significantly (p < 0.05) lower uptake in liver than (64)Cu-DOTA-F(19)-STh(2-19) (0.36 +/- 0.13 vs 1.21 +/- 0.65%ID/g) and significantly (p < 0.05) lower uptake in kidney than (64)Cu-TETA-F(19)-STh(2-19) (3.67 +/- 1.60 vs 11.36 +/- 2.85%ID/g). Use of the NOTA chelator for coordination of Cu-64 in the context of E. coli heat-stable enterotoxin analogues results in higher tumor/nontarget tissue ratios at 1 h pi than either DOTA or TETA macrocycles. Heat-stable enterotoxin-based radiopharmaceuticals such as these provide a means of noninvasively determining GC-C receptor status in colorectal cancers by PET.
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Toxinas Bacterianas/química , Neoplasias Colorretais/diagnóstico , Radioisótopos de Cobre/química , Enterotoxinas/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Proteínas de Escherichia coli , Feminino , Humanos , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Transplante de Neoplasias , Coloração e RotulagemRESUMO
BACKGROUND: Uroguanylin is an endogenous peptide agonist that binds to the guanylate cyclase C receptor (GC-C). GC-C is overexpressed in human colorectal cancer (CRC), and exposure of GC-C-expressing cells to GC-C agonists results in cell cycle arrest and/or apoptosis, highlighting the therapeutic potential of such compounds. This study describes the first use of radiolabeled uroguanylin analogs for in vivo detection of CRC. MATERIALS AND METHODS: The peptides uroguanylin and E(3)-uroguanylin were N-terminally labeled with the DOTA chelating group via NHS ester activation and characterized by RP-HPLC, ESI-MS, and GC-C receptor binding assays. The purified conjugates were radiolabeled with In-111 and used for in vivo biodistribution and SPECT imaging studies. In vivo experiments were carried out using SCID mice bearing T84 human colorectal cancer tumor xenografts. RESULTS: Alteration of the position 3 aspartate residue to glutamate resulted in increased affinity for GC-C, with IC(50) values of 5.0+/-0.3 and 9.6+/-2.9 nM for E(3)-uroguanylin and DOTA-E(3)-uroguanylin, respectively. In vivo, (111)In-DOTA-E(3)-uroguanylin demonstrated tumor uptake of 1.17+/-0.23 and 0.61+/-0.07% ID/g at 1 and 4 h post injection, respectively. The specificity of tumor localization was demonstrated by coinjection of 3 mg/kg unlabeled E(3)-uroguanylin, which reduced tumor uptake by 69%. Uptake in kidney, however, was dramatically higher for the uroguanylin peptides than for previously characterized radiolabeled E. coli heat-stable enterotoxin (STh) analogs targeting GC-C, and was also inhibited by coinjection of unlabeled peptide in a fashion not previously observed. CONCLUSION: Use of uroguanylin-targeting vectors for in vivo imaging of colorectal cancers expressing GC-C resulted in tumor uptake that paralleled that of higher affinity heat-stable enterotoxin peptides, but also resulted in increased kidney uptake in vivo.
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Neoplasias Colorretais/diagnóstico por imagem , Radioisótopos de Índio , Peptídeos Natriuréticos , Compostos Radiofarmacêuticos , Sequência de Aminoácidos , Animais , Neoplasias Colorretais/metabolismo , Feminino , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Humanos , Radioisótopos de Índio/química , Radioisótopos de Índio/farmacocinética , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Dados de Sequência Molecular , Peptídeos Natriuréticos/química , Peptídeos Natriuréticos/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Transplante HeterólogoRESUMO
This study describes the synthesis and preliminary biologic evaluation of an (111)In-labeled peptide antagonist of the urokinase-type plasminogen activator receptor (uPAR) as a potential probe for assessing metastatic potential of human breast cancer in vivo. The peptide (NAc-dD-CHA-F-dS-dR-Y-L-W-S-betaAla)(2)-K-K(DOTA)-NH(2) was synthesized and conjugated with the DOTA chelating moiety via conventional solid-phase peptide synthesis (SPPS), purified by reversed-phase HPLC, and characterized by MALDI-TOF MS and receptor binding assay. In vitro receptor binding studies demonstrated an IC(50) of 240 +/- 125 nM for the peptide, compared with IC(50) values of 0.44 +/- 0.02 and 0.75 +/- 0.01 nM for the amino terminal fragment (ATF) of the urokinase-type plasminogen activator (uPA) and full-length uPA, respectively. In vivo biodistribution studies were carried out using SCID mice bearing MDA-MB-231 human breast cancer xenografts. Biodistribution data was collected at 1, 4, and 24 h postinjection of (111)In-DOTA-peptide, and compared with data obtained using a scrambled control peptide as well as with data obtained using wild-type ATF radiolabeled with I-125. Biodistribution studies showed rapid elimination of the (111)-labeled peptide from the blood pool, with 0.12 +/- 0.06% ID/g remaining in blood at 4 h pi. Elimination was seen primarily via the renal/urinary route, with 83.9 +/- 2.2% ID in the urine at the same time point. Tumor uptake at this time was 0.53 +/- 0.11% ID/g, resulting in tumor/blood and tumor/muscle ratios of 4.2 and 9.4, respectively. Uptake in tumor was significantly higher than that obtained using a scrambled control peptide that showed no specific binding to uPAR (p < 0.05). In vitro and ex vivo results both suggested that the magnitude of tumor-specific binding was reduced in this model by endogenous expression of uPA. The results indicate that radiolabeled peptide uPAR antagonists may find application in the imaging and therapy of uPAR-expressing breast cancers in vivo.
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Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Radioisótopos de Índio/química , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Sequência de Aminoácidos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Imagem Molecular , Dados de Sequência Molecular , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/farmacologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/química , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
BACKGROUND: With recent advances in the diagnosis and management of ocular and periocular melanoma, many of which are based on results from randomized control trials, there is an increasing need for an evidence-based review of the literature for the Australasian population. The Australian Cancer Network has recently redeveloped the evidence-based Clinical Practice Guidelines for the Management of Melanoma, including a chapter on ocular melanoma. These are the first evidence-based guidelines on ocular melanoma to be created by the Australian Cancer Network. METHODS: The primary research questions were formed and a detailed literature search was undertaken. Each relevant article was assessed and graded I-IV according to the level of evidence. Articles were grouped into bodies of evidence which were then assessed. RESULTS: A total of 107 relevant articles were identified and grouped into 12 bodies of evidence. Guidelines based on this analysis were formulated and graded. These are presented below. CONCLUSIONS: The management of ocular melanoma has benefited from recent advances in imaging, molecular biology and cytogenetics, and tumours today are detected earlier and with greater accuracy than 25 years ago. With improved treatment ocular and periocular melanomas can be controlled locally, with good preservation of vision in many patients. However, there remains no cure for metastatic disease.
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Medicina Baseada em Evidências , Neoplasias Oculares/terapia , Melanoma/terapia , Guias de Prática Clínica como Assunto , Austrália , Neoplasias Oculares/cirurgia , Humanos , Melanoma/cirurgiaRESUMO
Developing seeds of Brassica napus contain significant levels of ABA and products of oxidation at the 7'- and 9'-methyl groups of ABA, 7'- and 9'-hydroxy ABA, as well stable products of oxidation of the 8'-methyl group, phaseic acid and dihydrophaseic acid. To probe the biological roles of the initially formed hydroxylated compounds, we have compared the effects of supplied ABA and the hydroxylated metabolites in regulating oil synthesis in microspore-derived embryos of B. napus, cv Hero that accumulate long chain fatty acids. Uptake into the embryos and metabolism of each of the hormone metabolites was studied by using deuterium labeled analogs. Supplied ABA, which was rapidly metabolized, induced expression of oleosin and fatty acid elongase genes and increased the accumulation of triacylglycerols and very long chain fatty acids. The metabolites 7'- and 9'-hydroxy ABA had similar effects, with the 9'-hydroxy ABA having even greater activity than ABA. The principal catabolite of ABA, 8'-hydroxy ABA, also had hormonal activity and led to increased oil synthesis but induced the genes weakly. These results indicate that all compounds tested could be involved in lipid synthesis in B. napus, and may have hormonal roles in other ABA-regulated processes.
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Ácido Abscísico/metabolismo , Brassica napus/metabolismo , Hormônios/metabolismo , Óleos/metabolismo , Sementes/metabolismo , Esporos/metabolismo , Ácido Abscísico/farmacologia , Acetiltransferases/metabolismo , Brassica napus/embriologia , Brassica napus/genética , Elongases de Ácidos Graxos , Ácidos Graxos Monoinsaturados/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Hormônios/farmacologia , Proteínas de Plantas/genética , Sementes/embriologia , Sementes/genética , Triglicerídeos/metabolismoRESUMO
BACKGROUND: To report the 31-year experience of outcomes in retinoblastoma from a single centre. METHODS: A retrospective analysis of consecutive cases of retinoblastoma diagnosed and treated at the Westmead Children's Hospital, Sydney between 1974 and 2005 was performed. The subjects were analysed as two groups: those diagnosed between 1974 and 1989 (series alpha) and those diagnosed between 1990 and 2005 (series beta). RESULTS: There were a total of 142 patients included in the study, with a median follow up of 72 months. There were 84 patients with unilateral disease and 58 patients (116 eyes) with bilateral disease. The total enucleation rate remained high throughout both series for those with unilateral disease: 89% (series alpha) and 95% (series beta). There was a reduction in enucleations performed for those with bilateral disease from 68.4% (series alpha) to 43.6% (series beta) (P < 0.025). There were no bilateral enucleations performed after 1995. Actuarial Kaplan-Meier curves showed that 56% of all preserved eyes had not recurred at a median follow up of 95 months and 78.1% had avoided enucleation. Overall 43% of preserved eyes attained a visual acuity better than or equal to 6/12 and 55% achieved a visual acuity better than 6/60. There were four deaths due to retinoblastoma. Five patients were diagnosed with a second non-ocular malignancy. The most common treatment-related complications were cataracts, facial deformity, sepsis and febrile neutropaenia. CONCLUSIONS: The introduction of newer globe-preserving treatments for retinoblastoma was associated with equivalent visual outcomes, stable mortality rate and a greater number of short-term complications but avoided the late side-effects associated with external beam radiotherapy.
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Hospitais Pediátricos/estatística & dados numéricos , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Braquiterapia , Crioterapia , Intervalo Livre de Doença , Enucleação Ocular/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Hipertermia Induzida , Lactente , Fotocoagulação a Laser , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , New South Wales/epidemiologia , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Acuidade VisualRESUMO
Diffuse iris melanoma is an uncommon variant of anterior uveal melanoma. It is characterized by heterochromia and unilateral glaucoma secondary to angle invasion, and can be difficult to diagnose. We present a patient who had been managed for left-sided raised intraocular pressure with latanoprost eye drops for 12-months and pigmentary changes were subsequently noted. On referral to the Ocular Oncology Unit, Sydney, iris melanoma was suspected and confirmed on iridectomy, and the eye was eventually enucleated.
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Ocular melanoma is a rare neoplasm with a poorly understood etiology, especially concerning its link with ultraviolet-light exposure. Studying the risk of second primary cancers may help to formulate causal hypotheses. We used data from 13 cancer registries, including 10,396 first occurring ocular melanoma cases, and 404 second occurring cases. To compare the second cancer incidence in ocular melanoma patients to that in noncancer population, we calculated standardized incidence ratios (SIRs) of 32 types of cancer. We also calculated SIRs of second ocular melanoma after other primaries. Ocular melanoma patients had significantly increased risk of cutaneous melanoma (SIR = 2.38, 95% CI 1.77-3.14), multiple myeloma (SIR = 2.00, 1.29-2.95), and of liver (SIR = 3.89, 2.66-5.49), kidney (SIR = 1.70, 1.22-2.31), pancreas (SIR = 1.58, 1.16-2.11), prostate (SIR = 1.31, 1.11-1.54), and stomach (SIR = 1.33, 1.03-1.68) cancers. Risks of cutaneous melanoma were highly variable between registries and were mainly increased in females, in younger patients, in first years following diagnosis, and for patients diagnosed after 1980. The risk of ocular melanoma was significantly increased only after prostate cancer (SIR = 1.41, 1.08-1.82). Risk of cutaneous melanoma after ocular melanoma had epidemiological patterns, similar to cutaneous melanoma screening in the general population. The increased risk of cutaneous melanoma would be largely due to greater skin cancer surveillance in ocular melanoma patients, and not to common etiological factors. The high SIR found for liver cancer may be explained by misclassification bias. Common etiological factors may be involved in ocular and prostate cancers.
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Neoplasias Oculares/epidemiologia , Melanoma/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Agências Internacionais , Neoplasias Renais/epidemiologia , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Vigilância da População , Neoplasias da Próstata/epidemiologia , Sistema de Registros , Medição de Risco , Fatores de Risco , Neoplasias Cutâneas/epidemiologiaRESUMO
BACKGROUND: Radiolabeled analogs of the E. coli heat-stable enterotoxin (ST(h)) are currently under study as imaging and therapeutic agents for colorectal cancer. The aim of these studies is to compare in vitro and in vivo characteristics of two novel ST(h) analogs with appended DOTA chelating moieties. MATERIALS AND METHODS: ST(h) analogs were synthesized with pendant N-terminal DOTA moieties and radiolabeled with indium-111. In vitro cell binding was studied using cultured T-84 human colorectal cancer cells, and in vivo biodistribution studies were carried out using T-84 human colorectal tumor xenografts in SCID mice. RESULTS: Competitive radioligand binding assays employing T-84 human colon cancer cells demonstrated similar IC50 values for the F19-ST(h)(2-19) and F9-ST(h)(6-19) analogs. Addition of DOTA to the N-terminus of these peptides elicited distinctly different effects on binding affinities in vitro, effects that were largely unchanged by metallation with nonradioactive (nat)In. In vivo pharmacokinetic studies in SCID mice bearing T-84 human colon cancer-derived tumor xenografts demonstrated tumor uptake of 0.74 +/- 0.1% ID/g at 4 h post-injection (p.i.) for the 111In-DOTA-F19-ST(h)(2-19) analog, and significantly reduced tumor localization (0.27 + 0.08 % ID/g) for the 111In-DOTA-F9-ST(h)(6-19) analog. CONCLUSION: These results demonstrate that placement of a DOTA moiety immediately adjacent to Cys 6 in ST(h) significantly inhibits receptor binding in vitro and in vivo, highlighting the need for intervening spacer residues between the pharmacophore and the DOTA chelating moiety in effective ST(h)-based radiopharmaceutical constructs.
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Toxinas Bacterianas/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Enterotoxinas/farmacocinética , Proteínas de Escherichia coli/farmacocinética , Temperatura Alta , Animais , Toxinas Bacterianas/uso terapêutico , Ligação Competitiva , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Enterotoxinas/química , Enterotoxinas/uso terapêutico , Proteínas de Escherichia coli/uso terapêutico , Feminino , Compostos Heterocíclicos com 1 Anel , Humanos , Radioisótopos de Índio/farmacocinética , Radioisótopos de Índio/uso terapêutico , Ligantes , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Ligação Proteica , Desnaturação Proteica , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Surgical excision with cryotherapy is a well-established treatment option for malignant melanoma or primary acquired melanosis (PAM) with atypia of the conjunctiva and cornea. Topical chemotherapeutic agents such as mitomycin C (MMC) however, are increasingly finding use in clinical practice. A search was performed of Medline and Pubmed databases for English language articles from 1980 to the present in this field. Relevant studies were reviewed with regards to treatment regimen, rates of recurrence and metastasis, side effect profile and length of follow up. A total of 22 and 16 unique cases of biopsy proven PAM with atypia and malignant melanoma, respectively, treated with topical MMC were identified. Topical MMC was well tolerated and shows considerable promise, particularly in the treatment of diffuse PAM with atypia. However, long-term data are lacking and further studies are required.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Túnica Conjuntiva/tratamento farmacológico , Doenças da Córnea/tratamento farmacológico , Neoplasias Oculares/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanose/tratamento farmacológico , Mitomicina/uso terapêutico , Administração Tópica , Bases de Dados Factuais , Humanos , Guias de Prática Clínica como AssuntoRESUMO
The human E. coli heat-stable enterotoxin (ST(h), amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. Analogs of ST(h) are currently being used as vectors targeting human colon cancers. Previous studies in our laboratory have focused on development of 111Indium-labeled ST(h) analogs for in vivo imaging applications. Here, we extend the scope of this work to include targeting of the therapeutic radionuclides 90Y and 177Lu. The peptide DOTA-F19-ST(h)(1-19) was synthesized using conventional Fmoc-based solid-phase techniques and refolded in dilute aqueous solution. The peptide was purified by RP-HPLC and characterized by MALDI-TOF MS and in vitro receptor binding assay. The DOTA-conjugate was metallated with nonradioactive Lu(III)Cl3 and Y(III)Cl3, and IC50 values of 2.6+/-0.1 and 4.2+/-0.9 nM were determined for the Lu- and Y-labeled peptides, respectively. 177Lu(III)Cl3 and 90Y(III)Cl3 labeling yielded tracer preparations that were inseparable by C18 RP-HPLC, indicating that putative differences between Lu-, Y- and In coordination spheres are not observed in the context of labeled ST(h) peptides. In vivo biodistribution studies of the 177Lu-labeled peptide in severe combined immunodeficient (SCID) mice bearing T-84 human cancer tumor xenografts showed rapid clearance from the bloodstream, with >90 %ID in the urine at 1 h pi. Localization of the tracer within tumor xenografts was 1.86+/-0.91 %ID/g at 1 h pi, a value higher than for all other tissues with the exception of kidney (2.74+/-0.24 %ID/g). At 24 h pi, >98 %ID was excreted into the urine, and 0.35+/-0.23 %ID/g remained in tumor, again higher than in all other tissues except kidney (0.91+/-0.46 %ID/g). Biodistribution results at 24 h pi for the 90Y-labeled peptide mirrored those for the 177Lu analog, in agreement with the identical behavior of the labeled analogs by C18 RP-HPLC. These results demonstrate the ability of 177Lu- and 90Y-labeled ST(h) molecules to specifically target GC-C receptors expressed on T-84 human colon cancer cells.