RESUMEN
MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m(2), with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts Asunto(s)
Benzamidas/administración & dosificación
, Benzamidas/farmacocinética
, Inhibidores de Histona Desacetilasas
, Leucemia/tratamiento farmacológico
, Pirimidinas/administración & dosificación
, Pirimidinas/farmacocinética
, Administración Oral
, Adulto
, Anciano
, Anciano de 80 o más Años
, Benzamidas/toxicidad
, Células Cultivadas
, Relación Dosis-Respuesta a Droga
, Femenino
, Histona Desacetilasas/metabolismo
, Histonas/metabolismo
, Humanos
, Leucemia/complicaciones
, Leucemia Mieloide Aguda/complicaciones
, Leucemia Mieloide Aguda/tratamiento farmacológico
, Masculino
, Dosis Máxima Tolerada
, Persona de Mediana Edad
, Farmacocinética
, Pirimidinas/toxicidad
RESUMEN
MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC(50) (concentration lethal to 50%) of 0.23 micromol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0-12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3-4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pirimidinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Aberraciones Cromosómicas , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Histona Desacetilasas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Rituximab , Resultado del TratamientoRESUMEN
PURPOSE: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay. EXPERIMENTAL DESIGN: Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients. RESULTS: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheral WBC correlated with induction of histone acetylation in blood and in implanted tumors in mice. In cancer patients, sustained pharmacodynamic effect of MGCD0103 was visualized only by dose-dependent enzyme inhibition in peripheral WBC but not by histone acetylation analysis. CONCLUSIONS: This study shows that MGCD0103 has sustained pharmacodynamic effects that can be monitored both in vitro and in vivo with a cell-based HDAC enzyme assay.
Asunto(s)
Antineoplásicos/administración & dosificación , Benzamidas/administración & dosificación , Bioensayo/métodos , Histona Desacetilasas/análisis , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Línea Celular Tumoral , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.
Asunto(s)
Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/farmacología , Acetilación , Animales , Benzamidas/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Femenino , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Isoenzimas , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Pirimidinas/farmacocinética , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Células Tumorales Cultivadas , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Inhibidores de Histona Desacetilasas , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Antineoplásicos/química , Benzamidas/química , Benzamidas/farmacología , Dominio Catalítico , Línea Celular , Histona Desacetilasa 1 , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Modelos Moleculares , NADH NADPH Oxidorreductasas/química , NADH NADPH Oxidorreductasas/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. We have designed and synthesized novel nonhydroxamate sulfonamide anilides that can inhibit human HDAC enzymes and can induce hyperacetylation of histones in human cancer cells. These compounds selectively inhibit proliferation and cause cell cycle blocks in various human cancer cells but not in normal cells. The growth inhibitory activity of sulfonamide anilides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. One of these compounds (Compound 2) can significantly reduce tumor growth of implanted human colon tumors in nude mice. Unlike another anilide-based HDAC inhibitor, MS-275, which decreases both red and white blood counts and reduces spleen weights in mice, Compound 2 does not exhibit noticeable toxicity. By using cDNA array analysis, we have identified downstream genes whose expression is altered by Compound 2 in human cancer cells. In correlation with its antitumor activity both in vitro and in vivo, Compound 2 induces expression of p21(WAF1/Cip1), gelsolin, and keratin 19, while down-regulating expression of cyclin A and cyclin B1 in human cancer cells in a dose-dependent manner. Our results suggest that sulfonamide anilides are novel HDAC inhibitors and may be useful as antiproliferative agents in cancer chemotherapy.
Asunto(s)
Anilidas/farmacología , Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas , Sulfonamidas/farmacología , Acetilación/efectos de los fármacos , Anilidas/toxicidad , Animales , Antineoplásicos/toxicidad , Benzamidas/farmacología , Benzamidas/toxicidad , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ciclina A/biosíntesis , Ciclina B/biosíntesis , Ciclina B1 , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Femenino , Fase G2/efectos de los fármacos , Histonas/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitosis/efectos de los fármacos , Piridinas/farmacología , Piridinas/toxicidad , Sulfonamidas/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Histone deacetylases (HDACs) constitute a family of enzymes that deacetylate histones and other cellular proteins. They are major regulators of transcription and are also important in other cellular processes. OBJECTIVE: The review provides an updated summary of HDAC pharmacological inhibition in clinical oncology, as well as in preclinical studies on inflammation and neurodegenerative diseases. RESULTS/CONCLUSION: HDAC inhibition is a validated approach in cancer therapy, as evidenced by the approval of vorinostat and by encouraging clinical data from various HDAC inhibitors. Moreover, preclinical proof-of-concept studies are emerging from animal models for non-oncologic diseases, including inflammatory and neurodegenerative diseases. The identification of the appropriate target spectrum and the development of class- or isotype-selective inhibitors will be central events in the future.