RESUMO
Fibroblast growth factors (FGFs) act as proangiogenic and mitogenic cytokines in several cancers, including multiple myeloma (MM). Indeed, corrupted FGF autocrine and paracrine secretion induces an aberrant activation of the FGF receptor (FGFR) signaling sustaining cancer cell spreading and resistance to pharmacological treatments. Thus, FGF traps may represent a promising anti-cancer strategy to hamper the ligand-dependent activation of the FGF/FGFR system. We previously identified NSC12 as the first orally available small molecule FGF trap able to inhibit the growth and progression of several FGF-dependent tumor models. NSC12 is a pregnenolone derivative carrying a 1,1-bis-trifluoromethyl-1,3-propanediol chain in position 17 of the steroid nucleus. Investigation of structure-activity relationships (SARs) provided more potent and specific NSC12 steroid derivatives and highlighted that the C17-side chain is pivotal for the FGF trap activity. Here, a scaffold hopping approach allowed to obtain two FGF trap compounds (22 and 57) devoid of the steroid nucleus and able to efficiently bind FGF2 and to inhibit FGFR activation in MM cells. Accordingly, these compounds exert a potent anti-tumor activity on MM cell lines both in vitro and in vivo and on MM patient-derived primary cells, strongly affecting the survival of both proteasome-inhibitor sensitive and resistant MM cells. These results propose a new therapeutic option for relapsed/refractory MM patients and set the bases for the development of novel FGF traps prone to chemical diversification to be used in the clinic for the treatment of those tumors in which the FGF/FGFR system plays a pivotal role, including MM.
Assuntos
Antineoplásicos , Fatores de Crescimento de Fibroblastos , Mieloma Múltiplo , Receptores de Fatores de Crescimento de Fibroblastos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Linhagem Celular Tumoral , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade , Descoberta de Drogas , Camundongos , Fator 2 de Crescimento de Fibroblastos/metabolismoRESUMO
BACKGROUND: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment. MATERIALS AND METHODS: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR)3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients. RESULTS: A total of 215 patients in stable MR3.0/MR4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR3.0 loss was 27% vs. 46% (P = .005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR3.0 was 59% vs. 53%, respectively (P = .13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P = .03). CONCLUSIONS: The intensification of intermittent TKI therapy is associated with a higher incidence of MR3.0 loss, but those patients who maintain the MR3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Qualidade de Vida , Humanos , Idoso , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Feminino , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Itália , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
OBJECTIVES: Solitary plasmacytoma (SP) is characterized by a single mass of clonal plasma cells. Definitive RT can result in long-term local control of the SP. Due to the small number of patients and narrow range of doses, phase III randomized trials are lacking. The aim of this study is to further support the potential use of RT for the treatment of SP. METHODS: Clinical data of all patients treated for SP at our Institution between 1992 and 2018 were reviewed. A total of 42 consecutive patients were analyzed. RESULTS: The median follow-up was 84.8 months. Radiation dose did not differ significantly as a function of sex, type of SP (solitary bone plasmacytoma or as extramedullary plasmacytoma), tumor size; conversely differs significantly as a function of age (p = 0.04). The 5y-OS and 10y-OS were, respectively, 96 and 91%. Local recurrences developed in 21.4% of patients (9/42). 16 patients progressed to MM (38.1%). The 5y-progression to MM free survival (PMFS) and the 10y-PMFS were, respectively, 68.6 and 61.9%. CONCLUSIONS: Our data confirm that good results are achievable with RT to treat SP, but they don't allow defining a dose-effect correlation; therefore, it remains uncertain which is the most effective dose and whether lower doses can guarantee adequate disease control.
Assuntos
Plasmocitoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/radioterapia , Progressão da Doença , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/radioterapia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/radioterapia , Plasmocitoma/diagnóstico , Plasmocitoma/mortalidade , Plasmocitoma/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non-conventional drugs such as fludarabine are considered responsible for the increased risk of infections. METHODS: In this study, we retrospectively analysed the infections occurred in 224 newly diagnosed AML patients =65 yr, consecutively treated between 1997 and 2002 with an induction regimen including fludarabine, arabinosyl cytosine and idarubicin, with or without etoposide (FLAI/FLAIE), in the context of three multicentric prospective trials (AML97, AML99, AML02). RESULTS: During the induction phase, 146 (65%) patients experienced fever of undetermined origin (FUO), 30 (13%) and 47 (21%) patients had Gram-negative and positive bacteremias, respectively, and 10 (4%) patients developed a probable/proven invasive fungal infection (IFI). The fatality rate for Gram-negative, Gram-positive bacteremias and probable/proven IFI was 10%, 8% and 60% respectively. During consolidation, 75 (35%) patients had FUO, 43 (20%) and 40 (19%) patients had Gram-negative and positive bacteremias, respectively, and 5 (2%) patients developed a probable/proven IFI. The fatality rate for Gram-negative, Gram-positive bacteremias and probable/proven IFI was 14%, 5% and 80% respectively. Interestingly, the overall incidence of microbiologically documented infections during induction was 38% and the incidence of probable/proven IFIs during the induction/consolidation programme was 7%. No infections caused by viruses or opportunistic pathogens were observed neither during induction, nor during consolidation. CONCLUSIONS: These data, although retrospectively collected, suggest that fludarabine-based chemotherapy is not associated with an increased incidence of infections, in particular IFIs, compared to conventional regimens commonly used for AML induction.
Assuntos
Antineoplásicos/efeitos adversos , Infecções por Bactérias Gram-Negativas/mortalidade , Infecções por Bactérias Gram-Positivas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Micoses/mortalidade , Vidarabina/análogos & derivados , Adulto , Antineoplásicos/administração & dosagem , Bacteriemia/induzido quimicamente , Bacteriemia/mortalidade , Feminino , Febre/induzido quimicamente , Febre/mortalidade , Infecções por Bactérias Gram-Negativas/induzido quimicamente , Infecções por Bactérias Gram-Positivas/induzido quimicamente , Humanos , Incidência , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Micoses/induzido quimicamente , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/efeitos adversosRESUMO
One hundred and six patients aged =60 years with newly diagnosed acute myeloid leukaemia (AML) treated with fludarabine-based regimens (cases) were matched with 106 AML patients treated with conventional non-fludarabine-based regimens (controls). The cases and controls were matched by expression of the multidrug resistance P-glycoprotein (MDR-Pgp), measured by flow cytometry as mean fluorescence index (MFI), cytogenetics, and age. The complete remission (CR) rate of the cases was 61% among the MDR-Pgp-positive (pos(ve)) patients (MFI >/= 6) vs. 75% among the MDR-Pgp-negative (neg(ve)) ones (MFI < 6) (P = 0.16). Conversely, in the controls, the CR rate was 44% among the MDR-Pgp-pos(ve) patients vs. 67% among the MDR-Pgp-neg(ve) ones (P = 0.02). The 4-year disease-free survival (DFS) and overall survival (OS) of MDR-Pgp-pos(ve) cases were significantly longer than those of MDR-Pgp-pos(ve) controls (DFS, 28.1% vs. 6.5%, P = 0.004; OS, 33.5% vs. 9.6%, P = 0.01). This difference was not found among the MDR-Pgp-neg(ve) patients. By univariate (P = 0.007) and multivariate (P = 0.007) analysis, the MDR-Pgp-pos(ve) phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine-based induction treatments as a promising strategy for MDR-Pgp-pos(ve) AML patients. In this setting of patients, large prospective randomised studies should be planned.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistência a Múltiplos Medicamentos , Leucemia Mieloide/tratamento farmacológico , Vidarabina/análogos & derivados , Doença Aguda , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Humanos , Cariotipagem , Leucemia Mieloide/mortalidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Indução de Remissão , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do Tratamento , Vidarabina/uso terapêuticoRESUMO
Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.
Assuntos
Ácidos Borônicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/farmacologia , Inibidores da Angiogênese/farmacologia , Angiopoietina-1/biossíntese , Angiopoietina-1/genética , Angiopoietina-2/biossíntese , Angiopoietina-2/genética , Animais , Antineoplásicos/farmacologia , Bortezomib , Processos de Crescimento Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/biossíntese , Fator de Crescimento Insulin-Like I/genética , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-6/metabolismo , Mieloma Múltiplo/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Thymidine phosphorylase (TP), also known as platelet derived endothelial cell growth factor (PD-ECGF), is an enzyme involved in thymidine synthesis and degradation and exerts an angiogenic activity, whereas N4 pentyloxy-carbonyl- 5'-deoxy-5-fluorocytidine, commonly called capecitabine (CAP), is a TP-activated oral fluorpyrimidine, which generates 5-fluorouracil (5-FU) within tumours. In addition to its classic antitumour activity, recent studies suggest that CAP may act as an antiangiogenetic molecule. Assessment of tumour microvessel density as expressed by endothelial cell TP positivity may identify the most vascularized and hence CAP-sensitive tumours. This review summarizes: (i) the biochemical and tissue expression of TP; (ii) the pharmacological profile of CAP as an anti-cancer compound and the central role of TP in its activation; (iii) the potential antiangiogenetic role of TP-activated CAP in tumours.
Assuntos
Inibidores da Angiogênese/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Timidina Fosforilase/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Capecitabina , Ensaios Clínicos como Assunto , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Neoplasias/irrigação sanguínea , Patentes como Assunto , Radioterapia/efeitos adversos , Fluxo Sanguíneo Regional , Timidina Fosforilase/biossíntese , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/efeitos da radiaçãoRESUMO
Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.