RESUMEN
Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.
Asunto(s)
Everolimus/uso terapéutico , Indoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/uso terapéutico , Pirrolidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Inhibidores mTOR/farmacología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Receptores del Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The myelosuppression patterns from phase I, II, and III clinical trials were analyzed to evaluate the degree of hematologic toxicity and to determine risk factors predictive of myelosuppression. Additionally, recent publications of alternative topotecan doses and schedules were examined. Extent of prior therapy, prior platinum therapy (particularly carboplatin), advanced age, impaired renal function, and prior radiation therapy were identified as potential risk factors for greater hematologic toxicity after topotecan therapy. Reducing the starting topotecan dose to 1.0 or 1.25 mg/m2/day is recommended to reduce the incidence of severe myelosuppression in high-risk individuals receiving topotecan for 5 consecutive days. Hematopoietic growth factors, transfusion therapy, and schedule adjustments may also help manage myelosuppression. Alternative schedules of 3-day or weekly dosing appear to have less myelotoxicity and are currently under evaluation. The clinical aspects of topotecan-related myelosuppression and results from clinical trials indicate that the dose, and possibly the dosing schedule, of topotecan can be modified to reduce hematologic toxicity and improve tolerance without compromising efficacy. Prospective individualization of topotecan dosing may prevent or minimize dose-limiting myelosuppression and allow patients to achieve the maximum topotecan benefit by improving their ability to complete therapy with fewer treatment delays. Ongoing clinical trials evaluating alternative dosing schedules with superior hematologic tolerability may facilitate the inclusion of topotecan in combination regimens for patients with ovarian cancer. Proposed topotecan dosing guidelines to reduce and manage myelosuppression are outlined.
Asunto(s)
Antineoplásicos/administración & dosificación , Enfermedades Hematológicas/prevención & control , Neoplasias Ováricas/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Topotecan/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Esquema de Medicación , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Incidencia , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Recurrencia , Factores de Riesgo , Topotecan/efectos adversos , Topotecan/uso terapéuticoRESUMEN
A number of randomized trials have recently been completed evaluating the effect of hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor) as adjuncts to the treatment of patients with acute myeloid leukemia. Most studies used the growth factors to decrease the duration of neutropenia with the hope of reducing infectious morbidity and mortality. The results of these trials are generally quite consistent. Virtually all trials showed a modest reduction in the duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and the duration of hospitalization. There was no consistent benefit in terms of improvements in complete response rate, complete response duration, or overall survival. However, it is important that there does not appear to be an increase in the incidence of drug-resistant leukemia in trials in which the growth factor was begun after completion of the chemotherapy. Other trials administered growth factors either before or simultaneous with the chemotherapy in an attempt to enhance chemosensitivity and decrease drug resistance. None of these trials, whether conducted as part of initial induction therapy or in relapse, showed improvements in response rate or survival. Lastly, some anecdotal reports have suggested that occasional patients who receive growth factors as the only therapy for overt leukemia can achieve remission, possibly through a differentiating effect of the growth factor. However, there are very few such reports, and growth factor use in this situation is potentially dangerous and should be performed only in the context of a clinical trial. In summary, there appears to be no role at this time for priming of leukemia cells by growth factors to enhance the effect of chemotherapy, and more in vitro studies should be performed before further clinical trials of this approach. It is clear that growth factors administered after induction and possibly consolidation chemotherapy can shorten the duration of neutropenia, without a significant effect on treatment outcome. It is as yet unclear whether the use of growth factors in this fashion is cost effective.
Asunto(s)
Factores de Crecimiento de Célula Hematopoyética/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Neutropenia/prevención & control , Enfermedad Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Diferenciación Celular/efectos de los fármacos , Esquema de Medicación , Factores de Crecimiento de Célula Hematopoyética/administración & dosificación , Factores de Crecimiento de Célula Hematopoyética/efectos adversos , Factores de Crecimiento de Célula Hematopoyética/farmacología , Humanos , Leucemia Mieloide/sangre , Leucemia Mieloide/mortalidad , Estudios Multicéntricos como Asunto , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Neutropenia/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Inducción de Remisión , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Hematopoyesis/fisiología , Factores de Crecimiento de Célula Hematopoyética/fisiología , Receptores del Factor Estimulante de Colonias/fisiología , Secuencia de Aminoácidos , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Factores de Crecimiento de Célula Hematopoyética/farmacología , Humanos , Ratones , Modelos Biológicos , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores del Factor Estimulante de Colonias/clasificación , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The human c-kit receptor ligand, rhSCF, is the only cytokine known to be active on human mast cells, but its intracellular signal transduction pathway is still unknown. We compared the effect of rhSCF on intracellular Ca2+ levels in purified (> 70% pure) adult skin mast cells with two other immunologic stimuli, namely, anti-IgE and substance P. Both rhSCF (1 microgram/mL) and anti-IgE (3 micrograms/mL) induced a rapid (< 20 sec) and sustained (T1/2 for decay > 10 min) increase in free cytosolic Ca2+ concentration. In contrast, substance P (5 microM) elicited a very rapid (< 1 sec) and transient (T1/2 for decay congruent to 5 sec) rise in intracellular Ca2+ levels. Intracellular cAMP levels were then increased by pharmacologic means to examine the role of the cyclic nucleotide in controlling the Ca2+ response in skin mast cells. A combination of the general phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) (200 microM) and the adenylate cyclase activator, forskolin (30 microM) was effective in inhibiting the Ca2+ response induced by rhSCF or anti-IgE (82 and 68% inhibition, respectively), while IBMX and forskolin alone were much less effective. The phosphodiesterase isozyme IV inhibitor, rolipram (10 microM), variably affected the increase in Ca2+ levels induced by anti-IgE, but it exerted a significant inhibitory activity on anti-IgE- or rhSCF-induced response in the presence of forskolin (30 micrograms/mL) (33 and 67%, respectively). Two different protein kinase C (PKC) activators TPA (200 nM) and bryostatin 1 (200 nM) similarly inhibited rhSCF- (22 and 32%, respectively) and anti-IgE-induced (24 and 32%) Ca2+ response. Finally, the kinase inhibitor genistein (30 micrograms/mL) was a somewhat more effective inhibitor of the rise in intracellular Ca2+ induced by rhSCF (100%) than that activated by anti-IgE (54%) (P < 0.05). These data indicate that rhSCF and anti-IgE may act on human mast cells through a common pathway to increase free cytosolic Ca2+ levels and this effect is similarly modulated by various drugs.
Asunto(s)
Anticuerpos Antiidiotipos/farmacología , Calcio/análisis , Factores de Crecimiento de Célula Hematopoyética/farmacología , Mastocitos/metabolismo , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Piel/metabolismo , AMP Cíclico/análisis , Genisteína , Humanos , Isoflavonas/farmacología , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-kit , Proteínas Recombinantes/farmacología , Factor de Células Madre , Sustancia P/farmacología , Factores de TiempoRESUMEN
The receptor tyrosine kinase Kit and its cognate ligand KL/steel factor are encoded at the white spotting (W) and Steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl loci affect hematopoiesis including the stem cell hierarchy, erythropoiesis, and mast cells, as well as gametogenesis and melanogenesis. In addition, mutant mice display an increased sensitivity to lethal doses of irradiation. The role of KL/c-kit in cell proliferation and survival under conditions of growth factor-deprivation and gamma-irradiation was studied by using bone marrow-derived mast cells (BMMC) as a model. Whereas apoptosis induced by growth factor deprivation in BMMC is a stochastic process and follows zero order kinetics, gamma-irradiation-induced apoptosis is an inductive process and follows higher order kinetics. In agreement with these results, gamma-irradiation-induced apoptosis in BMMC was shown to be dependent on p53 whereas apoptosis induced by deprivation is partly dependent on p53, implying that there are other mechanisms mediating apoptosis in KL-deprived BMMC. In the presence and in the absence of serum, KL stimulated proliferation by promoting cell cycle progression. The presence of KL was required only during the early part of the G1 phase for entry into the S phase. At concentrations lower than those required for proliferation, KL suppressed apoptosis induced by both growth factor-deprivation and gamma-irradiation, and internucleosomal DNA fragmentation characteristic of apoptosis. The ability of KL to suppress apoptosis was independent of the phase of the cell cycle in which the cells were irradiated and suppression of apoptosis was a prerequisite for subsequent cell cycle progression. Moreover, addition of KL to gamma-irradiated and growth factor-deprived cells could be delayed for up to 1 h after irradiation or removal of growth factors when cells became irreversibly committed to apoptosis. KL and IL-3 induce suppression of apoptosis in mast cells by different mechanisms based on the observations of induction of bcl-2 gene expression by IL-3 but not by KL. It is proposed that the increased sensitivity of W and Sl mutant mice to lethal irradiation results from paucity of the apoptosis suppressing and proliferative effects of KL.
Asunto(s)
Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Factores de Crecimiento de Célula Hematopoyética/farmacología , Mastocitos/citología , Animales , Apoptosis/efectos de la radiación , Moléculas de Adhesión Celular/farmacología , Ciclo Celular/efectos de los fármacos , División Celular/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Citometría de Flujo , Rayos gamma , Cinética , Mastocitos/efectos de los fármacos , Mastocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-kit , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Receptores del Factor Estimulante de Colonias/metabolismo , Factor de Células MadreRESUMEN
The c-kit ligand or stem cell factor (SCF) and the c-kit ligand receptor (KR) are thought to play pivotal roles in the regulation of human hematopoiesis. When added to interleukin 3 (IL-3) and/or granulocyte-macrophage colony stimulating factor (GM-CSF), SCF has an especially profound effect on the in vitro proliferation of several classes of primitive hematopoietic progenitor cells including the burst forming unit megakaryocyte (BFU-MK), the high proliferative potential colony forming cell (HPP-CFC) and the long-term bone marrow culture-initiating cell (LTBMC-IC). These primitive hematopoietic progenitor cells are present in a CD34+HLA-DR- fraction of marrow which has in vivo marrow populating ability and thereby resembles the pluripotent hematopoietic stem cell. Furthermore, the CD34+HLA-DR- marrow subpopulation which expresses KR contains virtually all of the marrow BFU-MK, HPP-CFC and LTBMC-IC, indicating that the human stem cell is KR positive. The addition of SCF, IL-3 and GM-CSF to suspension cultures initiated with CD34+HLA-DR- cells results in an exponential expansion of the numbers of hematopoietic progenitor cells. Large numbers of such progenitor cells generated ex vivo may be useful as transfusion products for the treatment of chemotherapy induced cytopenias. The therapeutic potential of the in vivo administration of SCF has also been evaluated in a phase I trial of recombinant methionyl SCF. SCF administration led to an increase in both differentiated and primitive hematopoietic progenitor cells within the marrow. Such studies suggest that in vivo SCF administration may be useful for improving the quality of bone marrow grafts to be used either for autologous or allogeneic bone marrow transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hematopoyesis/efectos de los fármacos , Factores de Crecimiento de Célula Hematopoyética/farmacología , Neoplasias de la Mama/terapia , Ensayo de Unidades Formadoras de Colonias , Sinergismo Farmacológico , Eritropoyesis/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Factores Inmunológicos/uso terapéutico , Interleucina-3/farmacología , Megacariocitos/efectos de los fármacos , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-kit , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores del Factor Estimulante de Colonias/efectos de los fármacos , Receptores del Factor Estimulante de Colonias/fisiología , Proteínas Recombinantes/uso terapéutico , Factor de Células MadreRESUMEN
Tumor necrosis factor alpha (TNF-alpha) has been shown to both stimulate and inhibit the proliferation of hematopoietic progenitor cells (HPCs) in vitro, but its mechanisms of action are not known. We demonstrate that the direct effects of TNF-alpha on murine bone marrow progenitors are only inhibitory and mediated at least in part through downmodulation of colony-stimulating factor receptor (CSF-R) expression. The stimulatory effects of TNF-alpha are indirectly mediated through production of hematopoietic growth factors, which subsequently results in increased granulocyte-macrophage CSF and interleukin 3 receptor expression. In addition, the effects of TNF-alpha (stimulatory or inhibitory) are strictly dependent on the particular CSF stimulating growth as well as the concentration of TNF-alpha present in culture. A model is proposed to explain how TNF-alpha might directly and indirectly regulate HPC growth through modulation of CSF-R expression.