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1.
Oncologist ; 27(8): 615-620, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35791894

RESUMO

Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Síndromes Neoplásicas Hereditárias , Adolescente , Antineoplásicos/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Gestão de Riscos
2.
Anticancer Res ; 35(11): 5857-65, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26504008

RESUMO

Microcystin-LR (MC-LR) is a cyanobacterial cyclopeptide, known for its unique ability to cause acute liver injury. Its cellular uptake is facilitated by specific transmembrane organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and 1B3. The objective of the present study was to investigate the expression of OATPs 1A2, 1B1 and 1B3 in pancreatic cancer cell lines BxPC-3 and MIA PACA-2 and assess their role in MC-LR-mediated cytotoxicity by using the novel xCELLigence system and flow cytometry. OATP1B1 and 1B3 were found to be expressed in both cell lines at both the mRNA and protein levels. The cytotoxic effects of MC-LR were proportionally related to the expression of these transporters. Moreover the cytotoxic potency of MC-LR was found superior to gemcitabine. Based on the expression of the organic anion transporting polypeptides 1B1 and 1B3 in pancreatic carcinoma tissue and cell lines and the potent cytotoxicity induced by MC-LR in vitro, we propose that this molecule could be held as structural basis for the development of novel targeted-compounds against pancreatic cancer.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Microcistinas/farmacologia , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Neoplasias Pancreáticas/patologia , Sequência de Aminoácidos , Transporte Biológico , Western Blotting , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Transportador 1 de Ânion Orgânico Específico do Fígado , Toxinas Marinhas , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/química , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Fosfoproteínas Fosfatases/antagonistas & inibidores , Conformação Proteica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Células Tumorais Cultivadas
3.
J Drug Deliv ; 2013: 863539, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23431456

RESUMO

Members of the organic anion transporter family (OATP) mediate the transmembrane uptake of clinical important drugs and hormones thereby affecting drug disposition and tissue penetration. Particularly OATP subfamily 1 is known to mediate the cellular uptake of anticancer drugs (e.g., methotrexate, derivatives of taxol and camptothecin, flavopiridol, and imatinib). Tissue-specific expression was shown for OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis, while other OATPs, for example, OATP4A1, are expressed in multiple cells and organs. Many different tumor entities show an altered expression of OATPs. OATP1B1/OATP1B3 are downregulated in liver tumors, but highly expressed in cancers in the gastrointestinal tract, breast, prostate, and lung. Similarly, testis-specific OATP6A1 is expressed in cancers in the lung, brain, and bladder. Due to their presence in various cancer tissues and their limited expression in normal tissues, OATP1B1, OATP1B3, and OATP6A1 could be a target for tumor immunotherapy. Otherwise, high levels of ubiquitous expressed OATP4A1 are found in colorectal cancers and their metastases. Therefore, this OATP might serve as biomarkers for these tumors. Expression of OATP is regulated by nuclear receptors, inflammatory cytokines, tissue factors, and also posttranslational modifications of the proteins. Through these processes, the distribution of the transporter in the tissue will be altered, and a shift from the plasma membrane to cytoplasmic compartments is possible. It will modify OATP uptake properties and, subsequently, change intracellular concentrations of drugs, hormones, and various other OATP substrates. Therefore, screening tumors for OATP expression before therapy should lead to an OATP-targeted therapy with higher efficacy and decreased side effects.

4.
Leuk Lymphoma ; 53(9): 1709-13, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22288719

RESUMO

BIK (bcl2-interacting killer) is the founding member of the BH3-only bcl-2 family of pro-apoptotic proteins, which is suppressed in various cancers. In multiple myeloma (MM), BIK has been shown to be epigenetically silenced in vitro, but there is a lack of clinical data. We investigated the CpG methylation status of the BIK promoter in a well-characterized clinical series of patients with MM and investigated its clinical relevance. Forty patients with MM (21 male, 19 female; mean age 66) were studied. According to the International Staging System (ISS) they were classified as 16 patients with stage I, 12 patients with stage II and 12 patients with stage III disease. Methylation in the BIK CpG island was assessed by methylation-specific polymerase chain reaction (MSP) assay. Logistic regression analysis was used to investigate associations between gene methylation and age, ISS stage, performance status, extramedullary disease, bone disease, anemia (hemoglobin ≤10 mg/dL), serum albumin, ß(2)-microglobulin level and relapsed/refractory disease. Methylation in the BIK CpG island was detected in 16 patients (40%), with a trend favoring male gender (odds ratio [OR] = 3.08, p = 0.09) and development of bone disease and extramedullary disease (OR = 1.6, p = 0.35 and OR = 3, p = 0.14, respectively). Patients with MM with methylated BIK CpG island had a statistically significant risk for disease evolution to relapsed/refractory disease (OR = 5.4, p = 0.03). This study provides clinical evidence that methylation-induced transcriptional silencing of the BIK pro-apoptotic gene may occur in MM, which might serve as a predictor of the development of relapsed/refractory MM. These findings warrant validation in larger cohorts of patients and suggest therapeutic utility for agents that enhance BIK expression.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Ilhas de CpG/genética , Metilação de DNA , Proteínas de Membrana/genética , Mieloma Múltiplo/genética , Idoso , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Modelos Logísticos , Masculino , Proteínas Mitocondriais , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Recidiva
5.
Onco Targets Ther ; 4: 27-32, 2011 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-21552413

RESUMO

BACKGROUND: Organic anion-transporting polypeptides (OATPs) are influx transporters that mediate intracellular uptake of selective endogenous and xenobiotic compounds. Identification of new molecular targets and discovery of novel targeted therapies is top priority for pancreatic cancer, which lacks any effective therapy. MATERIALS AND METHODS: We studied expression of OATP 1A2, 1B1, and 1B3 in pancreatic cancer tissue and in cell lines. Formalin-fixed paraffin-embedded biopsy material of 12 human pancreatic cancers was immunohistochemically assessed for protein expression of the three studied influx transporters. Immunohistochemistry was evaluated by experienced pathologists and quantified by use of an automated image analysis system. BxPC-3 and MIA PaCa-2 pancreatic cancer cell lines were used to quantify transcripts of OATP 1B1 and 1B3. RESULTS: OATP 1A2, 1B1, and 1B3 proteins were found ubiquitously expressed in all studied cases. Quantification performed by HistoQuest system revealed that mean intensity was 53 for 1A2, 45 for 1B1, and 167 for OATP 1B1/1B3 on a range scale 0-250 units. At mRNA level, 1B1 and 1B3 were overexpressed in both studied cancer cell lines but not in normal pancreatic tissue. CONCLUSION: OATPs 1A2, 1B1, and 1B3 are highly expressed in pancreatic adenocarcinoma. We suggest that expression of these transporters in pancreatic cancer justify research efforts towards discovery of novel therapeutics targeting OATPs.

6.
Mar Drugs ; 8(3): 629-57, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20411119

RESUMO

Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion-transporting polypeptides (OATP). Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). Interestingly, certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. In the era of targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters. Moreover, their structure offers opportunities for combinatorial engineering to enhance the therapeutic index and resolve organ-specific toxicity issues. In this article, we revisit cyanobacterial cyclopeptides as potential novel targets for anticancer drugs by summarizing existing biomedical evidence, presenting structure-activity data and discussing developmental perspectives.


Assuntos
Antineoplásicos/química , Cianobactérias/química , Peptídeos/química , Animais , Antineoplásicos/farmacologia , Toxinas Bacterianas/química , Toxinas Bacterianas/farmacologia , Proliferação de Células/efeitos dos fármacos , Toxinas de Cianobactérias , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Toxinas Marinhas/química , Toxinas Marinhas/farmacologia , Microcistinas/química , Microcistinas/farmacologia , Neoplasias/tratamento farmacológico , Peptídeos/farmacologia
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