RESUMO
OBJECTIVES: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials. STUDY DESIGN: The two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings. RESULTS: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment. CONCLUSIONS: E4/DRSP is associated with a favorable tolerability and safety profile. IMPLICATIONS STATEMENT: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.
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Estetrol , Tromboembolia Venosa , Humanos , Gravidez , Feminino , Estetrol/efeitos adversos , Anticoncepcionais Orais Combinados/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Androstenos/efeitos adversos , Estrogênios , Etinilestradiol/efeitos adversosRESUMO
OBJECTIVE: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen. STUDY DESIGN: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors. RESULTS: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m2, 25 to 29.9 kg/m2, and ≥30 kg/m2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception. CONCLUSION: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable. IMPLICATIONS STATEMENT: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure.
Assuntos
Estetrol , Humanos , Gravidez , Feminino , Estados Unidos , Adolescente , Adulto Jovem , Adulto , Estetrol/efeitos adversos , Androstenos/uso terapêutico , Anticoncepcionais Orais Combinados , Anticoncepção/métodos , EstrogêniosRESUMO
OBJECTIVE: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. STUDY DESIGN: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. RESULTS: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event. CONCLUSION: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. IMPLICATIONS STATEMENT: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.
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Estetrol , Metrorragia , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Anticoncepcionais Orais Combinados/efeitos adversos , Androstenos/efeitos adversos , Estrogênios , Metrorragia/induzido quimicamente , Hemorragia Uterina/induzido quimicamenteRESUMO
INTRODUCTION: Estrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. AREAS COVERED: This narrative review discusses E4's pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. EXPERT OPINION: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.
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Estetrol , Anticoncepção , Anticoncepcionais Orais Combinados , Estetrol/efeitos adversos , Estrogênios/efeitos adversos , Feminino , Humanos , MenopausaRESUMO
OBJECTIVE: To evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function. STUDY DESIGN: Single-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study. RESULTS: None of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated. CONCLUSIONS: E4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP. IMPLICATIONS STATEMENT: Treatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.
Assuntos
Estetrol , Androstenos , Anticoncepcionais Orais Combinados , Estradiol , Estrogênios , Etinilestradiol , Feminino , HumanosRESUMO
OBJECTIVES: To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). STUDY DESIGN: Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. RESULTS: At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism. CONCLUSIONS: E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. IMPLICATIONS STATEMENT: Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
Assuntos
Estetrol , Androstenos , Anticoncepcionais Orais Combinados , Estrogênios , Etinilestradiol , Feminino , Humanos , Levanogestrel , Globulina de Ligação a Hormônio SexualRESUMO
OBJECTIVE: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC). STUDY DESIGN: In this randomized, single centre, open-label, exploratory study, healthy women received either 15â¯mg estetrol/3 mg drospirenone (E4/DRSP) (nâ¯=â¯39), 30â¯mcg ethinylestradiol/150â¯mcg levonorgestrel (EE/LNG) (nâ¯=â¯30), or 20â¯mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (nâ¯=â¯32) for six 28-day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG). RESULTS: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value <0.05 vs E4/DRSP), and +219% for EE/DRSP (p-value <0.05 vs E4/DRSP). Changes to prothrombin fragment 1â¯+â¯2 and SHBG for E4/DRSP, EE/LNG, and EE/DRSP were +23%, +71%, and +64% (p-value <0.05 vs E4/DRSP); and +55%, +74% and +251% (p-value <0.05 vs E4/DRSP), respectively. At cycle 6, changes to other hemostasis parameters for E4/DRSP were similar or smaller than for EE/LNG or EE/DRSP. CONCLUSIONS: In this study, changes in hemostasis parameters after treatment with 6 cycles of E4/DRSP were smaller or similar to those observed for EE/LNG. Similar, but more pronounced changes were also observed versus EE/DRSP, which supports the hypothesis that the effect of COCs on hemostasis parameters is mainly mediated by the estrogenic component. Further studies are needed to provide more insight into the venous thromboembolic risk of E4/DRSP. IMPLICATIONS STATEMENT: This study reports that the effects on hemostasis parameters of a COC containing 15â¯mg E4/3 mg DRSP are less or similar to those for EE/LNG or EE/DRSP. It also demonstrates that the choice of estrogen modulates the effects of COCs on hemostasis parameters.
Assuntos
Resistência à Proteína C Ativada/induzido quimicamente , Androstenos/farmacologia , Anticoncepcionais Orais Combinados/farmacologia , Estetrol/farmacologia , Estrogênios/farmacologia , Etinilestradiol/farmacologia , Hemostasia/efeitos dos fármacos , Adolescente , Adulto , Androstenos/administração & dosagem , Androstenos/efeitos adversos , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/efeitos adversos , Estetrol/administração & dosagem , Estetrol/efeitos adversos , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Feminino , Humanos , Ciclo Menstrual/efeitos dos fármacos , Pessoa de Meia-Idade , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (nâ=â257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15âmg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. RESULTS: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15âmg E4 versus placebo at both W4 (-66% vs -49%, Pâ=â0.032) and W12 (-82% vs -65%, Pâ=â0.022). The decrease in severity of HFs was significantly more pronounced for 15âmg E4 than for placebo at both W4 (-0.59 vs -0.33, Pâ=â0.049) and W12 (-1.04 vs -0.66, Pâ=â0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. CONCLUSIONS: Estetrol 15âmg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. : Video Summary:http://links.lww.com/MENO/A591.
Video Summary:http://links.lww.com/MENO/A591.
Assuntos
Hiperplasia Endometrial , Estetrol , Adulto , Idoso , Método Duplo-Cego , Estrogênios , Feminino , Fogachos/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Resultado do TratamentoRESUMO
OBJECTIVES: The primary objective was to evaluate the safety and local tolerance of a topical 2% (w/w) cidofovir gel, applied directly to the cervices of women with high-grade cervical intraepithelial neoplasia (CIN 2+). The secondary objective was to evaluate the pharmacokinetics of cidofovir during the treatment. MATERIALS AND METHODS: Nine women with CIN 2+, were treated with a course of 3 g of cidofovir gel, applied locally once per week for 3 weeks in total (9 g). The treatment was administered in a cervical cap, applied to the cervix for 5 or 10 hours (n = 6 and 3 patients, respectively). Follow-up included a structured questionnaire, a gynecological examination, blood analysis for hematology, C-reactive protein (CRP), and renal function assessment plus pharmacokinetic analyses of cidofovir after each treatment and at the end of the full course. RESULTS: No clinically significant hematological/biochemical abnormalities or serious adverse events (SAE) were reported, although 6 mild to moderate adverse events (AE) occurred in relation to the study drug: 1 flu-like syndrome and 5 local AEs. Plasma concentrations of cidofovir were very low (mean Cmax of 103.0 and 99.2 ng/mL after 5 and 10 hours of exposure, respectively). CONCLUSION: Cidofovir, directly applied on CIN 2+, is reasonably well tolerated and the systemic exposure following topical application is much lower than that seen with intravenous administration, at the approved dose.â©.
Assuntos
Antivirais/administração & dosagem , Proteína C-Reativa/metabolismo , Citosina/análogos & derivados , Organofosfonatos/administração & dosagem , Displasia do Colo do Útero/tratamento farmacológico , Administração Tópica , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Cidofovir , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/farmacocinética , Feminino , Seguimentos , Géis , Humanos , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Inquéritos e Questionários , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVES: The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women. METHODS: This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 µg levonorgestrel; or 20 µg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. RESULTS: A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. CONCLUSIONS: Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.
Assuntos
Androstenos/administração & dosagem , Anticoncepcionais Orais Combinados/administração & dosagem , Estetrol/administração & dosagem , Levanogestrel/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Inibição da Ovulação , Adolescente , Adulto , Androstenos/efeitos adversos , Anticoncepcionais Orais Combinados/efeitos adversos , Relação Dose-Resposta a Droga , Endométrio/diagnóstico por imagem , Estetrol/efeitos adversos , Estradiol/sangue , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Levanogestrel/efeitos adversos , Hormônio Luteinizante/sangue , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Folículo Ovariano/diagnóstico por imagem , Ovulação/efeitos dos fármacos , Projetos Piloto , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , Progesterona/sangue , Ultrassonografia , Adulto JovemRESUMO
The increasing diversity in both substrates and functions of matrix metalloproteinases (MMPs) makes these enzymes central regulators in the complex tumor ecosystem composed of cancer cells and their microenvironment. In the majority of cancers, membrane-associated and extracellular proteases are mainly produced by host cells including inflammatory cells, endothelial cells, pericytes and fibroblasts. Recent data based on in vitro and in vivo studies have demonstrated the relevance of these enzymes in multiple processes controlling cancer growth, angiogenesis and metastatic dissemination. This review will present the emerging MMP-related features of cancer cells and host cells.
Assuntos
Comunicação Celular/fisiologia , Metaloproteinases da Matriz/fisiologia , Neoplasias/enzimologia , Neoplasias/patologia , Adipócitos/enzimologia , Adipócitos/metabolismo , Adipócitos/fisiologia , Animais , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Humanos , Macrófagos/enzimologia , Macrófagos/metabolismo , Macrófagos/fisiologia , Mastócitos/enzimologia , Mastócitos/metabolismo , Mastócitos/fisiologia , Metaloproteinases da Matriz/metabolismo , Modelos Biológicos , Invasividade Neoplásica , Células-Tronco Neoplásicas/enzimologia , Neutrófilos/enzimologia , Neutrófilos/metabolismo , Neutrófilos/fisiologiaRESUMO
An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis.
Assuntos
Células da Medula Óssea/fisiologia , Carcinoma/irrigação sanguínea , Neovascularização de Coroide/etiologia , Neovascularização Patológica/etiologia , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Neoplasias Cutâneas/irrigação sanguínea , Animais , Transplante de Medula Óssea , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Queratinócitos/patologia , Queratinócitos/transplante , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidor 1 de Ativador de Plasminogênio/genéticaRESUMO
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients. The more aggressive exudative form is characterized by abnormal blood-vessel development that occurs beneath the retina as a result of choroidal neovascularization (CNV). Vascular endothelial growth factor (VEGF) has emerged as the key mediator of CNV formation; this has led to intensive research on VEGF and the recent approval of anti-VEGF compounds by the US Food and Drug Administration. Despite this successful introduction of anti-angiogenic therapies into the clinical setting, there is still a lack of treatments that definitively reverse damaged vision. Here, we consider the importance of putative molecular targets other than VEGF that might have been underestimated. Emerging cellular mechanisms offer additional opportunities for innovative therapeutic approaches.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Degeneração Macular/tratamento farmacológico , Envelhecimento , Animais , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Humanos , InflamaçãoRESUMO
Among matrix metalloproteinases (MMP), MMP-19 displays unique structural features and tissue distribution. In contrast to most MMPs, MMP-19 is expressed in normal human epidermis and down-regulated during malignant transformation and dedifferentiation. The contribution of MMP-19 during tumor angiogenesis is presently unknown. In an attempt to give new insights into MMP-19 in vivo functions, angiogenic response of mutant mice lacking MMP-19 was analyzed after transplantation of murine malignant PDVA keratinocytes and after injection of Matrigel supplemented with basic fibroblast growth factor. In situ hybridization and immunohistochemical analysis revealed that MMP-19 is produced by host mesenchymal cells but not by endothelial capillary cells or CD11b-positive inflammatory cells. Based on a new computer-assisted method of quantification, we provide evidence that host MMP-19 deficiency was associated with an increased early angiogenic response. In addition, increased tumor invasion was observed in MMP-19-/- mice. We conclude that, in contrast to most MMPs that promote tumor progression, MMP-19 is a negative regulator of early steps of tumor angiogenesis and invasion. These data highlight the requirement to understand the individual functions of each MMP to improve anticancer strategies.
Assuntos
Metaloendopeptidases/deficiência , Neoplasias Cutâneas/irrigação sanguínea , Animais , Colágeno , Combinação de Medicamentos , Feminino , Laminina , Masculino , Metaloproteinases da Matriz Secretadas , Metaloendopeptidases/biossíntese , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Neovascularização Patológica/enzimologia , Neovascularização Patológica/patologia , Proteoglicanas , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Células Estromais/enzimologiaRESUMO
Angiogenesis and tumor expansion are associated with extracellular matrix remodeling and involve various proteases such as the plasminogen (Plg)/plasminogen activator (PA) system. Recently, several experimental data have implicated the plasminogen activator inhibitor-1 (PAI-1) in tumor angiogenesis in murine systems. However, little is known about PAI-1 functions in human skin carcinoma progression. By generating immunodeficient mice (in Rag-1-/- or nude background) deleted for PAI-1 gene (PAI-1-/-), we have evaluated the impact of host PAI-1 deficiency on the tumorigenicity of two malignant human skin keratinocyte cell lines HaCaT II-4 and HaCaT A5-RT3 forming low-grade and high-grade carcinomas, respectively. When using the surface transplantation model, angiogenesis and tumor invasion of these two cell lines are strongly reduced in PAI-1-deficient mice as compared to the wild-type control animals. After subcutaneous injection in PAI-1-/- mice, the tumor incidence is reduced for HaCaT II-4 cells, but not for those formed by HaCaT A5-RT3 cells. These data indicate that PAI-1 produced by host cells is an important contributor to earlier stages of human skin carcinoma progression. It exerts its tumor-promoting effect in a tumor stage-dependent manner, but PAI-1 deficiency is not sufficient to prevent neoplastic growth of aggressive tumors of the human skin.
Assuntos
Neovascularização Patológica/metabolismo , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Neoplasias Cutâneas/patologia , Animais , Progressão da Doença , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Inibidor 1 de Ativador de Plasminogênio/genética , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/etiologia , Células Tumorais Cultivadas/química , Células Tumorais Cultivadas/transplanteRESUMO
The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti- or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively). MMP-9 was predominantly expressed by neutrophils in tumor transplants, whereas MMP-2 and MMP-3 were stromal. Neither the single deficiency of MMP-2, MMP-3, or MMP-9, nor the combined absence of MMP-9 and MMP-3 did impair tumor invasion and vascularization in vivo. However, there was a striking cooperative effect in double MMP-2:MMP-9-deficient mice as demonstrated by the absence of tumor vascularization and invasion. In contrast, the combined lack of MMP-2 and MMP-9 did not impair the in vitro capillary outgrowth from aortic rings. These results point to the importance of a cross talk between several host cells for the in vivo tumor promoting and angiogenic effects of MMP-2 and MMP-9. Our data demonstrate for the first time in an experimental model that MMP-2 and MMP-9 cooperate in promoting the in vivo invasive and angiogenic phenotype of malignant keratinocytes.
Assuntos
Queratinócitos/patologia , Metaloproteinase 2 da Matriz/fisiologia , Metaloproteinase 9 da Matriz/fisiologia , Neoplasias/irrigação sanguínea , Neoplasias/enzimologia , Neovascularização Patológica/enzimologia , Animais , Linhagem Celular Tumoral , Queratinócitos/química , Queratinócitos/metabolismo , Metaloproteinase 2 da Matriz/deficiência , Metaloproteinase 3 da Matriz/deficiência , Metaloproteinase 3 da Matriz/fisiologia , Metaloproteinase 9 da Matriz/deficiência , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos , Camundongos Mutantes , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transplante de Neoplasias/métodos , Transplante de Neoplasias/patologia , Neoplasias/genética , Neoplasias/patologia , Regiões Promotoras Genéticas/genéticaRESUMO
Plasminogen activator inhibitor type 1 (PAI-1) plays a key role in tumor progression and is believed to control proteolytic activity and cell migration during angiogenesis. We report here that host PAI-1, at physiological concentration, promotes in vivo tumor invasion and angiogenesis. In sharp contrast, inhibition of tumor vascularization was observed when PAI-1 was produced at supraphysiologic levels, either by host cells (transgenic mice overexpressing PAI-1) or by tumor cells (after transfection with murine PAI-1 cDNA). This study provides for the first time in vivo evidence for a dose-dependent effect of PAI-1 on tumor angiogenesis. Of great interest is the finding that PAI-1 produced by tumor cells, even at high concentration, did not overcome the absence of PAI-1 in the host, emphasizing the importance of the cellular source of PAI-1.
Assuntos
Neoplasias Experimentais/irrigação sanguínea , Neovascularização Patológica/etiologia , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Animais , Queratinócitos/patologia , Camundongos , Invasividade Neoplásica , Neoplasias Experimentais/patologia , Inibidor 1 de Ativador de Plasminogênio/análiseRESUMO
Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization.