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1.
Cancer Chemother Pharmacol ; 87(4): 525-532, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33423090

RESUMEN

BACKGROUND: Fenretinide is a synthetic retinoid that can induce cytotoxicity by several mechanisms. Achieving effective systemic exposure with oral formulations has been challenging. An intravenous lipid emulsion fenretinide formulation was developed to overcome this barrier. We conducted a study to establish the maximum tolerated dose (MTD), preliminary efficacy, and pharmacokinetics of intravenous lipid emulsion fenretinide in patients with advanced solid tumors. METHODS: Twenty-three patients with advanced solid tumors refractory to standard treatments received fenretinide as a continuous infusion for five consecutive days in 21-day cycles. Five different dose cohorts were evaluated between doses of 905 mg/m2 and 1414 mg/m2 per day using a 3 + 3 dose escalation design. A priming dose of 600 mg/m2 on day 1 was introduced in an attempt to address the asymptomatic serum triglyceride elevations related to the lipid emulsion. RESULTS: The treatment-related adverse events occurring in ≥ 20% of patients were anemia, hypertriglyceridemia, fatigue, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase, thrombocytopenia, bilirubin increase, and dry skin. Five evaluable patients had stable disease as best response, and no patients had objective responses. Plasma steady-state concentrations of the active metabolite were significantly higher than with previous capsule formulations. CONCLUSION: Fenretinide emulsion intravenous infusion had a manageable safety profile and achieved higher plasma steady-state concentrations of the active metabolite compared to previous capsule formulations. Single-agent activity was minimal but combinatorial approaches are under evaluation.


Asunto(s)
Fenretinida/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fenretinida/efectos adversos , Fenretinida/farmacocinética , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad
2.
Cochrane Database Syst Rev ; 12: CD013154, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33331670

RESUMEN

BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.


Asunto(s)
Fenretinida/uso terapéutico , Atrofia Geográfica/tratamiento farmacológico , Atrofia Geográfica/prevención & control , Degeneración Macular/complicaciones , Éteres Fenílicos/uso terapéutico , Propanolaminas/uso terapéutico , Espera Vigilante , Anciano , Anciano de 80 o más Años , Neovascularización Coroidal/epidemiología , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Fenretinida/efectos adversos , Atrofia Geográfica/etiología , Humanos , Incidencia , Éteres Fenílicos/efectos adversos , Placebos/uso terapéutico , Propanolaminas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Agudeza Visual/efectos de los fármacos
3.
Cancer Prev Res (Phila) ; 11(12): 811-818, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30352838

RESUMEN

Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/prevención & control , Fenretinida/administración & dosificación , Calidad de Vida , Tamoxifeno/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Mama/diagnóstico por imagen , Mama/efectos de los fármacos , Densidad de la Mama/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fenretinida/efectos adversos , Estudios de Seguimiento , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Persona de Mediana Edad , Placebos/administración & dosificación , Placebos/efectos adversos , Premenopausia/efectos de los fármacos , Encuestas y Cuestionarios/estadística & datos numéricos , Tamoxifeno/efectos adversos , Resultado del Tratamiento
4.
Exp Biol Med (Maywood) ; 242(11): 1178-1184, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28429653

RESUMEN

Fenretinide (4-HPR) is a synthetic retinoid that has cytotoxic activity against cancer cells. Despite substantial in vitro cytotoxicity, response rates in early clinical trials with 4-HPR have been less than anticipated, likely due to the low bioavailability of the initial oral capsule formulation. Several clinical studies have shown that the oral capsule formulation at maximum tolerated dose (MTD) achieved <10 µmol/L concentrations in patients. To improve bioavailability of 4-HPR, new oral powder (LYM-X-SORB®, LXS) and intravenous lipid emulsion (ILE) formulations are being tested in early-phase clinical trials. ILE 4-HPR administered as five-day continuous infusion achieved over 50 µmol/L at MTD with minimal systemic toxicities; multiple complete and partial responses were observed in peripheral T cell lymphomas. The LXS oral powder 4-HPR formulation increased plasma levels approximately two-fold at MTD in children without dose-limiting toxicities and demonstrated multiple complete responses in recurrent neuroblastoma. The clinical activity observed with new 4-HPR formulations is attributed to increased bioavailability. Phase I and II clinical trials of both LXS 4-HPR and ILE 4-HPR are in progress as a single agent or in combination with other drugs. Impact statement One of the critical components in drug development is understanding pharmacology (especially pharmacokinetics) of the drugs being developed. Often the pharmacokinetic properties, such as poor solubility leading to poor bioavailability, of the drug can limit further development of the drug. The development of numerous drugs has often halted at clinical testing stages, and several of them were due to the pharmacological properties of the agents, resulting in increased drug development cost. The current review provides an example of how improved clinical activity can be achieved by changing the formulations of a drug with poor bioavailability. Thus, it emphasizes the importance of understanding pharmacologic characteristics of the drug in drug development.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Fenretinida/farmacología , Fenretinida/farmacocinética , Linfoma de Células T/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Fenretinida/administración & dosificación , Fenretinida/efectos adversos , Humanos , Infusiones Intravenosas , Resultado del Tratamiento
5.
Cancer Prev Res (Phila) ; 10(1): 76-88, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27756753

RESUMEN

Over one third of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long-term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives, that is, the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins, and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic), and the humanized mAb to the IL6R receptor tocilizumab (TOC, reduces IL6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high-affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally delivered TOC, TOC+4-HPR, and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents use diverse mechanisms to disrupt tumorigenesis at multiple venues, that is, intracellular, tumor cell-ECM, and tumor microenvironment; beneficial qualities for secondary chemopreventives. Cancer Prev Res; 10(1); 76-88. ©2016 AACR.


Asunto(s)
Anticarcinógenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinogénesis/efectos de los fármacos , Carcinoma de Células Escamosas/prevención & control , Neoplasias de la Boca/prevención & control , Recurrencia Local de Neoplasia/prevención & control , 2-Metoxiestradiol , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticarcinógenos/administración & dosificación , Anticarcinógenos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Estradiol/administración & dosificación , Estradiol/efectos adversos , Estradiol/análogos & derivados , Estradiol/uso terapéutico , Fenretinida/administración & dosificación , Fenretinida/efectos adversos , Fenretinida/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Invasividad Neoplásica , Fenotipo , Fosforilación , Receptores de Interleucina-6/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Pediatr Blood Cancer ; 63(11): 2050-3, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27399265

RESUMEN

Retinoid therapy has contributed to improved outcomes in neuroblastoma. Clinical trials of fenretinide report favorable toxicity and disease stabilization in patients with high risk (HR) neuroblastoma. Skeletal effects have been described with other retinoids, but not with fenretinide to date. Two patients with HR, metastatic, refractory neuroblastoma received protracted courses of oral fenretinide for more than 5 years' duration. Both developed premature long bone physeal closure, causing limb length discrepancies; their neuroblastoma remains in remission. The radiographic and clinical findings reported suggest these skeletal abnormalities may be a consequence of treatment with 13-cis-retinoic acid (13cisRA) followed by prolonged oral fenretinide exposure.


Asunto(s)
Antineoplásicos/efectos adversos , Fenretinida/efectos adversos , Placa de Crecimiento/efectos de los fármacos , Isotretinoína/efectos adversos , Neuroblastoma/tratamiento farmacológico , Niño , Preescolar , Femenino , Humanos , Masculino
7.
BMC Res Notes ; 7: 256, 2014 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-24755475

RESUMEN

BACKGROUND: Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study. CASE PRESENTATION: On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 µM. Over the next three days, although blood cultures remained negative, the patient's condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity. CONCLUSIONS: After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.


Asunto(s)
Acetaminofén/efectos adversos , Ceftriaxona/efectos adversos , Fenretinida/efectos adversos , Neuroblastoma/tratamiento farmacológico , Acetaminofén/administración & dosificación , Acetaminofén/uso terapéutico , Ceftriaxona/administración & dosificación , Ceftriaxona/uso terapéutico , Niño , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Resultado Fatal , Fenretinida/administración & dosificación , Fenretinida/uso terapéutico , Humanos , Inyecciones Intravenosas , Masculino , Neuroblastoma/diagnóstico por imagen , Radiografía
8.
Pediatr Blood Cancer ; 60(11): 1801-8, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23813912

RESUMEN

BACKGROUND: A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. PROCEDURE: 4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design. RESULTS: Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10-46 courses). 4-HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 µM. An MTD was not reached. CONCLUSIONS: 4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course.


Asunto(s)
Antineoplásicos/administración & dosificación , Fenretinida/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Niño , Preescolar , Femenino , Fenretinida/efectos adversos , Fenretinida/farmacocinética , Humanos , Masculino , Dosis Máxima Tolerada , Adulto Joven
9.
Retina ; 33(3): 498-507, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23023528

RESUMEN

BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol-binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy. METHODS: The efficacy of fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States. RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of ≤ 1 µM (≤ 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of fenretinide, which have been observed in other disease states. CONCLUSION: The findings of this study and the established safety profile of fenretinide in chronic dosing regimens warrant further study of fenretinide in the treatment of geographic atrophy.


Asunto(s)
Antineoplásicos/uso terapéutico , Fenretinida/uso terapéutico , Atrofia Geográfica/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Sensibilidad de Contraste/fisiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Fenretinida/efectos adversos , Atrofia Geográfica/sangre , Atrofia Geográfica/patología , Humanos , Masculino , Persona de Mediana Edad , Proteínas Plasmáticas de Unión al Retinol/antagonistas & inhibidores , Encuestas y Cuestionarios , Resultado del Tratamiento , Agudeza Visual/fisiología , Vitamina A/sangre
10.
Cell Biol Int ; 36(12): 1281-6, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22953972

RESUMEN

The borderline between necrosis and apoptosis is indistinct, but that between types of cell death is important because necrosis may lead to local inflammation, whereas apoptosis usually does not. In certain autoimmune disorders, inhibition of cell death is crucial, since macromolecules released from the dead cells may accelerate the autoimmune processes. We have used various cell death inhibitors to block cell death induced by 4HPR [N-(4-hydroxyphenil)-retinamide] the BL41 and U937 cell lines. VD-FMK, a general caspase inhibitor, inhibited DNA fragmentation induced by 4HPR, but not PI (propidium iodide) uptake and necrosis. Interestingly heparin, a serine-protease inhibitor, lowered the PI fluorescence of the dead cell population and increased the sub-G1 population as measured by flow cytometry. Regarding these changes, we found that heparin failed to increase DNA fragmentation, but merely liberated high molecular mass DNA fragments from dead cells. The exact mechanism is unclear, but heparin during secondary necrosis might enter the cells, bind RNPs (ribonucleoproteins), and pull them out with the attached DNA, where they would be sensitive to enzymatic degradation. Thus, the results suggest that heparin treatment helps in the clearance of cell debris and decreases the immunogenity of secondary necrotic cells.


Asunto(s)
Fragmentación del ADN/efectos de los fármacos , Fenretinida/efectos adversos , Heparina/farmacología , Necrosis/inducido químicamente , Inhibidores de Serina Proteinasa/farmacología , Clorometilcetonas de Aminoácidos/farmacología , Línea Celular , ADN/genética , Humanos , Necrosis/tratamiento farmacológico , Necrosis/genética , Propidio/efectos adversos , Células U937
11.
Clin Cancer Res ; 17(21): 6858-66, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-21908574

RESUMEN

PURPOSE: To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. EXPERIMENTAL DESIGN: Patients received 7 days of fenretinide: 2,475 mg/m(2)/d divided TID (<18 years) or 1,800 mg/m(2)/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only). RESULTS: Sixty-two eligible patients, median age 5 years (range 0.6-19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17-506) for stratum 1 and 48 days (range 17-892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 µmol/L (coefficient of variation 40-56%) at day 7 course 1. Toxicities were mild and reversible. CONCLUSIONS: Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies.


Asunto(s)
Antineoplásicos/administración & dosificación , Fenretinida/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , 3-Yodobencilguanidina/farmacocinética , Administración Oral , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Cápsulas , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Fenretinida/efectos adversos , Fenretinida/sangre , Fenretinida/farmacocinética , Humanos , Lactante , Radioisótopos de Yodo , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/sangre , Neuroblastoma/sangre , Neuroblastoma/patología , Radiofármacos/farmacocinética , Tasa de Supervivencia , Tomografía Computarizada por Rayos X , Adulto Joven
12.
Anticancer Res ; 31(3): 961-6, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21498721

RESUMEN

BACKGROUND: The synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR) has shown promising anticancer activity in preclinical studies, but its limited oral bioavailability has hindered clinical assessment. A novel lipid matrix, Lym-X-Sorb (LXS), was evaluated to improve fenretinide bioavailability and attain higher plasma concentrations. PATIENTS AND METHODS: Adults with refractory malignancies were administered fenretinide/LXS oral powder in 2 divided doses over 24 h for 7 consecutive days every 21 days in a standard phase I dose-escalation study with pharmacokinetic analysis. RESULTS: The principal toxicities observed were diarrhea, reversible night blindness, and allergic reaction. The maximum tolerated dose regimens were 1,000 mg/m(2)/day divided into 2 daily doses for 7 days, every 21 days, and 800 mg/m(2)/day divided into 3 daily doses for 7 consecutive days, every 21 days. CONCLUSION: Better fenretinide formulations are needed to improve adult patient acceptability and compliance and to achieve the consistent systemic exposures associated with activity in preclinical models.


Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Fenretinida/administración & dosificación , Fenretinida/uso terapéutico , Lípidos/química , Linfoma/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Fenretinida/efectos adversos , Fenretinida/farmacocinética , Humanos , Linfoma/sangre , Masculino , Persona de Mediana Edad , Polvos
13.
Med Oncol ; 28 Suppl 1: S39-47, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20878269

RESUMEN

Fenretinide and tamoxifen have additive antitumor effects preclinically. We performed a randomized, placebo-controlled, double-blind adjuvant trial in breast cancer patients treated for 5 years with tamoxifen, with or without fenretinide. Between October 1995 and October 1999, 426 postmenopausal women with hormone receptor-positive breast cancer were randomized. Patients were monitored for efficacy and toxicity. Four hundred and nineteen patients were evaluable. The study was terminated early due to slow accrual. There were no significant differences between treatment groups in DFS, TTR or survival. More patients stopped treatment early on the fenretinide arm than on placebo (P = 0.02). Grade 3/4 toxicities, including visual problems and musculoskeletal complaints were more common in patients receiving fenretinide (P = 0.007). A Night Blindness Questionnaire was used to monitor nyctalopia, which was slightly, but not significantly, more common on fenretinide. In this underpowered study, no significant difference was observed in efficacy between treatment groups. This trial provides important toxicity information about fenretinide, a retinoid that has been used in the prevention setting, because it is the only placebo-controlled, double-blind randomized study ever performed.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Receptores de Estrógenos , Receptores de Progesterona , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante/métodos , Método Doble Ciego , Femenino , Fenretinida/administración & dosificación , Fenretinida/efectos adversos , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Ceguera Nocturna/inducido químicamente , Estudios Prospectivos , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversos
14.
Ophthalmic Surg Lasers Imaging ; 41 Suppl: S89-92, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21117610

RESUMEN

Intravenous fenretinide (4-HPR), a cytotoxic retinoid, is being evaluated as part of a phase I clinical trial for patients with hematologic malignancies. In its orally administered form, it is also being evaluated for the treatment of various malignancies and geographic atrophy in subjects with the dry form of age-related macular degeneration. The authors report a case of acute large subretinal and intraretinal hemorrhage noted immediately after initiation of intravenous fenretinide therapy in a patient with hairy cell leukemia. This case highlights the importance of considering multilayered retinal hemorrhage as a possible side effect of fenretinide therapy, especially in patients with underlying hematologic abnormalities.


Asunto(s)
Antineoplásicos/efectos adversos , Fenretinida/efectos adversos , Leucemia de Células Pilosas/tratamiento farmacológico , Hemorragia Retiniana/inducido químicamente , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Hemorragia Retiniana/diagnóstico , Tomografía de Coherencia Óptica
15.
Cancer Chemother Pharmacol ; 66(5): 845-50, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20082080

RESUMEN

PURPOSE: Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer. METHODS: Eligibility criteria included hormone refractory prostate cancer with a rising PSA at least 6 weeks after peripheral anti-androgen withdrawal, ECOG performance status (PS) 0-1, and no prior chemotherapy. Fenretinide was administered orally at 900 mg m(-2) twice daily for 7 of every 21 days. PSA was measured before each cycle. The primary endpoint was a > or =50% reduction in PSA maintained for at least 3 weeks; secondary endpoints included duration of PSA response, time to treatment failure (TTF: treatment stopped for progression or toxicity) and adverse events (AE). RESULTS: Twenty seven pts were recruited from 7 centres over 27 months. Median age was 74 (range 49-86), median baseline PSA was 129 (range 19-1,000), and 70% had a PS of 0. The median number of cycles received was 2 (range 0-11) and 20 pts completed at least 1 cycle. One pt (4%) achieved a 50% reduction in PSA lasting 39 days and 15 pts (56%) had not progressed within 6 weeks of starting fenretinide. The median TTF was 54 days (IQR 19-73): 22 (81%) failed with tumour progression, 3 (11%) failed with toxicity and 2 (7%) never commenced the drug. Grade 3 rash occurred in 1 patient, all other AE were grade 1 or 2. The most common AE were nausea (40%), hot flushes (36%), constipation (32%) and nyctalopia (32%). CONCLUSION: High-dose fenretinide had limited anti-tumour activity in patients with advanced hormone refractory prostate cancer: further evaluation in this setting is not warranted.


Asunto(s)
Antineoplásicos/uso terapéutico , Fenretinida/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Fenretinida/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Insuficiencia del Tratamiento
17.
J Clin Oncol ; 27(23): 3749-56, 2009 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-19597031

RESUMEN

PURPOSE: Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. PATIENTS AND METHODS: A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. RESULTS: During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. CONCLUSION: Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.


Asunto(s)
Anticarcinógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/prevención & control , Fenretinida/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Mamografía , Premenopausia , Tamoxifeno/uso terapéutico , Adulto , Anticarcinógenos/administración & dosificación , Anticarcinógenos/efectos adversos , Anticarcinógenos/sangre , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico por imagen , Carcinoma Intraductal no Infiltrante/prevención & control , Carcinoma Lobular/prevención & control , Método Doble Ciego , Esquema de Medicación , Sinergismo Farmacológico , Femenino , Fenretinida/administración & dosificación , Fenretinida/efectos adversos , Fenretinida/sangre , Humanos , Incidencia , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Premenopausia/sangre , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversos , Tamoxifeno/análogos & derivados , Tamoxifeno/sangre , Resultado del Tratamiento , Vitamina A/sangre
19.
Invest New Drugs ; 27(6): 571-8, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19225720

RESUMEN

BACKGROUND: Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. METHODS: Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). RESULTS: Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 µg/ml (7.40 +/- 4.25 muM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 µg/ml and 0.05 +/- 0.07 µg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 µg/ml, with no correlation between salivary and plasma drug levels. CONCLUSIONS: Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.


Asunto(s)
Fenretinida/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Fenretinida/efectos adversos , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Vitamina A/uso terapéutico
20.
Cancer Prev Res (Phila) ; 2(1): 22-6, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19139014

RESUMEN

We previously showed that low-dose fenretinide (200 mg/d) had limited activity in retinoid-resistant oral leukoplakia (34% response rate) possibly because serum drug levels were insufficient to induce retinoid receptor-independent apoptosis. Therefore, we designed the single-arm phase II trial reported here to investigate whether higher-dose fenretinide would improve leukoplakia response over that of our previous study. Leukoplakia patients received fenretinide (900 mg/m(2) twice daily) in four 3-week cycles (1 week on drug followed by 2 weeks off). At week 12, clinical responses were determined and blood samples were collected for serum drug level assessments. A planned interim futility analysis led to early trial closure after the initial 15 (of 25 planned) patients because only 3 (20%) had a partial response (stopping rule:

Asunto(s)
Antineoplásicos/administración & dosificación , Fenretinida/administración & dosificación , Leucoplasia Bucal/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fenretinida/efectos adversos , Humanos , Masculino , Persona de Mediana Edad
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