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BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).
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Coagulantes , Fator VIII , Hemofilia A , Hemorragia , Humanos , Esquema de Medicação , Meia-Vida , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Fator de von Willebrand/administração & dosagem , Fator de von Willebrand/uso terapêutico , Quimioprevenção , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Coagulantes/administração & dosagem , Coagulantes/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
PUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).
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Hemofilia A , Proteínas Recombinantes de Fusão , Criança , Fator VIII , Meia-Vida , Hemofilia A/tratamento farmacológico , Hemorragia/induzido quimicamente , Humanos , Masculino , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do TratamentoRESUMO
INTRODUCTION: People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life. AIM: To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130). METHODS: PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety. RESULTS: There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed. CONCLUSIONS: Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies.
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Hemofilia A , Ansiedade/etiologia , Estudos Transversais , Depressão/complicações , Hemofilia A/complicações , Hemofilia A/terapia , Humanos , Dor/complicações , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Recombinant factor IX Fc fusion protein (rFIXFc) has demonstrated efficacy for treatment of haemophilia B in the Phase 3 B-LONG and Kids B-LONG studies. However, long-term rFIXFc safety and efficacy data have not yet been reported. AIM: To report long-term rFIXFc safety and efficacy in subjects with haemophilia B. METHODS: B-YOND (NCT01425723) was an open-label extension for eligibl previously treated subjects who completed B-LONG or Kids B-LONG. Subjects received ≥1 treatment regimen: weekly prophylaxis (WP), individualized interval prophylaxis (IP), modified prophylaxis or episodic treatment. Subjects could switch regimens at any time. The primary endpoint was inhibitor development. RESULTS: Ninety-three subjects from B-LONG and 27 from Kids B-LONG (aged 3-63 years) were enrolled. Most subjects received WP (B-LONG: n = 51; Kids B-LONG: n = 23). For subjects from B-LONG, median (range) treatment duration was 4.0 (0.3-5.4) years and median (range) number of exposure days (EDs) was 146 (8-462) EDs. Corresponding values for paediatric subjects were 2.6 (0.2-3.9) years and 132 (50-256) EDs. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-8.9) and the overall rFIXFc safety profile was consistent with prior studies. Annualized bleed rates remained low and extended-dosing intervals were maintained for most subjects. Median dosing interval for the IP group was approximately 14 days for adults and adolescents (n = 31) and 10 days for paediatric subjects (n = 5). CONCLUSIONS: B-YOND results confirm the long-term (up to 5 years, with cumulative duration up to 6.5 years) well-characterized safety and efficacy of rFIXFc treatment for haemophilia B.
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Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Fator IX/farmacologia , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/farmacologia , Fatores de Tempo , Adulto JovemRESUMO
INTRODUCTION: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study. AIM: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. METHODS: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. RESULTS: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respectively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. CONCLUSION: ASPIRE results, which include up to 5 years of follow-up data, confirm earlier reports on the consistent and well-characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A.
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Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Fator VIII/farmacologia , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Background: Pain is a common feature of hemophilia, but prevalence of depression and anxiety is less studied. Registry data on prescription drugs can provide an objective measure of the magnitude of these complications. Objectives: To identify treatment patterns of prescribed pain, antidepressant, and antianxiety medications compared with those of matched controls in 4 Nordic countries. Methods: The MIND study (NCT03276130) analyzed longitudinal individual-level national data during 2007-2017. People with hemophilia (PwH) were identified from National Health Data Registers by diagnosis or factor replacement treatment and compared with population controls. Three subgroups were defined by the use of factor concentrates and sex (moderate-to-high factor consumption (factor VIII [FVIII] use of ≥40 IU/kg/week or FIX use of ≥10 IU/kg/week), low factor consumption, and women including carriers). Results: Data of 3246 PwH, representing 30,184 person-years, were analyzed. PwH (including children and adults) used more pain, depression, and anxiety medications compared with controls. This was most accentuated in the moderate-to-high factor consumption group and notably also observed in men with low factor consumption and women including carriers, usually representing a milder phenotype. A higher opioid use was observed across all age groups: 4- to 6-fold higher in the moderate-to-high factor consumption group and 2- to 4-fold higher in the low factor consumption group. Conclusion: The consistent higher use of pain, depression, and anxiety medications among PwH compared with population controls, regardless of age, sex, or factor consumption, in broad national data suggests a need for improved bleed protection and hemophilia care for all severities including mild hemophilia.
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Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.
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Hemofilia A , Hemofilia B , Humanos , Fator IX/efeitos adversos , Fator IX/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Hemofilia B/complicações , Hemorragia/induzido quimicamente , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia. Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 µg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22). Findings: Forty-two participants received TransCon CNP at doses of 6 µg (n = 10; 7 female), 20 µg (n = 11; 3 female), 50 µg (n = 10; 3 female), or 100 µg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 µg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 µg CNP/kg/week. Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 µg CNP/kg/week in the ongoing pivotal trial. Funding: Ascendis Pharma, A/S.
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PUPs B-LONG evaluated the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) in previously untreated patients (PUPs) with hemophilia B. In this open-label, phase 3 study, male PUPs (age <18 years) with hemophilia B (≤2 IU/dL of endogenous factor IX [FIX]) were to receive treatment with rFIXFc. Primary end point was occurrence of inhibitor development, with a secondary end point of annualized bleed rate (ABR). Of 33 patients who received ≥1 dose of rFIXFc, 26 (79%) were age <1 year at study entry and 6 (18%) had a family history of inhibitors. Twenty-eight patients (85%) received prophylaxis; median dosing interval was 7 days, with an average weekly dose of 58 IU/kg. Twenty-seven patients (82%) completed the study. Twenty-one (64%), 26 (79%), and 28 patients (85%) had ≥50, ≥20, and ≥10 exposure days (EDs) to rFIXFc, respectively. One patient (3.03%; 95% confidence interval, 0.08% to 15.76%) developed a low-titer inhibitor after 11 EDs; no high-titer inhibitors were detected. Twenty-three patients (70%) had 58 treatment-emergent serious adverse events; 2 were assessed as related (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal). Median ABR was 1.24 (interquartile range, 0.00-2.49) for patients receiving prophylaxis. Most (>85%) bleeding episodes required only 1 infusion for bleed resolution. In this first study reporting results with rFIXFc in pediatric PUPs with hemophilia B, rFIXFc was well tolerated, with the adverse event profile as expected in a pediatric hemophilia population. rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes. This trial was registered at www.clinicaltrials.gov as #NCT02234310.
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Hemofilia A , Hemofilia B , Adolescente , Testes de Coagulação Sanguínea , Criança , Hemofilia B/tratamento farmacológico , Hemorragia , Humanos , MasculinoRESUMO
INTRODUCTION: Haemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8-12 hours typically administered every 2-3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use. METHODS AND ANALYSIS: A-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect. ETHICS AND DISSEMINATION: Study approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT02976753, Pre-results.
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Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Assistência Perioperatória/métodos , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Criança , Relação Dose-Resposta a Droga , Fator VIII/farmacocinética , Meia-Vida , Hemofilia A/sangue , Hemorragia/prevenção & controle , Humanos , Masculino , Pontuação de Propensão , Estudos Prospectivos , Proteínas Recombinantes de Fusão/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: In the phase 3 B-LONG study (NCT01027364), prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) every 7 to >14 days was associated with low annualized bleed rates (ABRs) in males aged ≥12 years with severe hemophilia B. The long-term safety and efficacy of rFIXFc prophylaxis was confirmed in the B-YOND study (NCT01425723), an extension of the B-LONG clinical trial. OBJECTIVE: The aim of this post-hoc analysis was to evaluate the efficacy of a ≥14-day rFIXFc dosing interval in patients treated prophylactically during B-LONG or B-YOND. METHODS: The analysis included 22 patients aged ≥12 years who received prophylactic rFIXFc with a ≥14-day dosing interval at any time during B-LONG or B-YOND up until the second interim analysis of B-YOND (September 2015). RESULTS: The median (interquartile range [IQR]) rFIXFc exposure on the ≥14-day dosing interval was 3.4 (1.8-4) years. Patients treated with a ≥14-day dosing interval were well controlled with a median (IQR) overall ABR of 1.6 (0.6-2.7) and a median (IQR) spontaneous ABR of 0.7 (0.3-1.1) in 18 evaluable patients. A rFIXFc dosing interval of ≥14 days was well tolerated, with no new safety concerns identified. CONCLUSION: Most patients on rFIXFc prophylaxis, with a dosing interval of ≥14 days, remained well controlled; ABRs were consistent with those reported in the overall study population. A ≥14-day dosing interval can be utilized in some well controlled individuals and reduces the burden imposed by frequent prophylactic injections while maintaining adequate bleed suppression.
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PURPOSE: Breast cancer frequently leads to incurable bone metastasis. Essential requirements for the development of bone metastasis are cell-cell and cell-matrix interactions, release of bioactive growth factors and cytokines, and removal of large amounts of bone matrix. Matrix metalloproteinases (MMPs) play an important role in all of these processes, but the possibility of using synthetic MMP inhibitors to decrease bone metastasis has received little attention. EXPERIMENTAL DESIGN: In the present study, we tested two general MMP inhibitors, BB-94 and GM6001, in a mouse model of breast cancer-induced bone metastasis. RESULTS: In a simulation of intervention therapy, mice were inoculated with breast cancer cells, and at the time of diagnosis of osteolytic lesions, the mice were treated for 10 or 15 consecutive days with BB-94 or GM6001, respectively. Both inhibitors reduced the growth of osteolytic lesions by >55% compared with control mice. Next, we simulated prevention therapy by initiating treatment with GM6001 at time of inoculation with cancer cells or 3 days earlier. Assessment of osteolytic lesions 28 days after inoculation showed that, in both cases, the treatment reduced the size of the osteolytic lesions by 60%, compared with that of control mice. Importantly, MMP inhibition also resulted in extension of symptom-free survival in the mice, whether the treatment was initiated at the time of diagnosis of osteolytic lesions or of cancer cell inoculation. CONCLUSIONS: The present study suggests the potential of synthetic MMP inhibitors as intervention or prevention treatments of breast cancer-induced osteolysis.
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Antineoplásicos/farmacologia , Neoplasias Ósseas/prevenção & controle , Neoplasias da Mama/prevenção & controle , Dipeptídeos/farmacologia , Inibidores de Metaloproteinases de Matriz , Osteólise/prevenção & controle , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Inibidores de Proteases/farmacologia , Tiofenos/farmacologia , Animais , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Sobrevivência Celular/efeitos dos fármacos , Feminino , Terapia Genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Transfecção , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The effect of 17-beta-estradiol (E2) on the induction of osteolytic lesions by estrogen receptor (ER)-negative breast cancer cells was investigated in 4-week-old female nude mice. Exposure to exogenous E2 was found to increase osteolytic areas on radiographs up to 5.3 times in mice inoculated intracardially with MDA-231 human breast cancer cells. The MDA-231 cells were ER-negative, both before inoculation, and after isolation from osteolytic lesions, and the corresponding cell cultures were insensitive to E2. The induction of skeletal lesions by E2 in this mouse model was mainly effectuated at the early development of bone metastases, since exposure to E2 for 8 days around MDA-231 inoculation increased osteolysis to the same level, as did E2 given throughout the entire 31-day experimental period, and because E2-exposure for just the final 14 days had no effect. Independently of exposure to E2, histology revealed cancer cells in hind limp long bones of approximately 80% of the mice, and tumors were absent in non-skeletal organs. In vitro studies showed that the number and activity of osteoclasts generated from mouse bone marrow cells were increased 5-6 times when co-cultured with MDA-231 cells. Addition of 0.1-10 nM E2 further dose-dependently increased the osteoclastogenesis and associated bone resorption in these co-cultures. In conclusion, E2 was found to increase the morbidity in mice inoculated with ER-negative MDA-231 cells, and to stimulate osteoclast formation and bone resorption in co-cultures of bone marrow cells and MDA-231, suggesting that the progression of osteolytic metastases by ER-negative breast cancer cells can be induced by E2 due to stimulation of osteoclastogenesis.