Interacciones en la ruta de metabolización de los fármacos anti-diana oncológicos, como estrategia para reducir su dosis y coste total: sunitinb y ketocozanol

Objetivo Evaluar la farmacocinética (PK) y seguridad de diferentes dosis de sunitinib (25mg y 37,5mg) cuando se administran en combinación con ketoconazol (200mg y 400mg) y seleccionar la pauta cuyos parámetros PK sean similares a los obtenidos tras la administración de sunitinib 50mg en dosis única. Material y Métodos Ensayo clínico en fase I, piloto, abierto, aleatorizado, paralelo y cruzado posteriormente, de interacción. Se reclutaron 12 voluntarios sanos varones que fueron divididos en dos grupos. Los voluntarios del grupo 1 recibieron de manera aleatoria, con un periodo de lavado de 28 días, sunitinib 50mg, sunitinib 37,5mg + ketoconazol 200mg ó sunitinib 37,5mg + ketoconazol 400mg. Los voluntarios del grupo 2 recibieron los mismos tratamientos pero la dosis de sunitinib fue de 25mg en vez de 37,5mg. Las concentraciones plasmáticas de sunitinib fueron determinadas de forma ciega mediante cromatografía líquida con detección espectrofotométrica de masas en tándem. Para el análisis estadístico se empleó el análisis de la varianza de los parámetros cinéticos AUC0-72 y Cmax transformados logarítmicamente y la aplicación de los intervalos de confianza (IC) para el 90%. Resultados En el grupo 1 para la pauta de sunitinib 37,5mg + ketoconazol 200mg vs sunitinib 50mg el ratio para AUC0-72 fue 113,89 IC90 (105,66-122,76) y para Cmax fue 101,13 IC90 (93,33- 109,58) y con ketoconazol 400mg vs sunitinib 50mg el ratio para Cmax fué 104,12 IC90 (96.09- 112.83) pero para AUC0-72 fue 124,87 IC90 (115,85-134,60). En el grupo 2 tanto las concentraciones plasmáticas como los parámetros cinéticos obtenidos con las pautas de combinación fueron inferiores respecto sunitinib 50mg. Al comparar en cada grupo los resultados obtenidos con ketoconazol 200mg y ketoconazol 400mg, los límites del IC90 para AUC0-72 y Cmax siempre estuvieron comprendidos entre 80-125. No se observaron efectos adversos graves. Conclusiones De todas las pautas de combinación estudiadas, sólo con sunitinib 37,5mg + ketoconazol 200mg se obtuvieron resultados bioequivalentes, que deben confirmarse en un estudio con un mínimo de 12 voluntarios según las guías de la Agencia Europea del Medicamento (EMA). Ambas dosis de ketoconazol inhibieron el citocromo p450 de forma similar. La coadministración de Sunitinib y Ketoconazol resultó ser bien tolerada

Sunitinib-induced asthenia: from molecular basis to clinical relief

[Abstract] Asthenia-fatigue syndrome (AFS) is defined as a persistent, subjective sense of tiredness related to cancer or its treatment and greatly impacts quality of life among cancer patients. All tyrosine kinase inhibitors, but especially sunitinib, may induce AFS. The reason for sunitinib-induced AFS is not yet well understood. Adverse events caused by sunitinib associated with AFS may include anemia, hypothyroidism, nausea and vomiting. However, AFS is also reported when active treatment with sunitinib is ongoing, and no other relevant adverse event can justify it. The molecular mechanisms by which sunitinib triggers AFS remain elusive. Sunitinib displays multiple off-target tyrosine-kinase interactions and competitively inhibits multiple proteins through the blockade of their ATP-binding sites. The broad spectrum of kinases inhibited may play a key role not only in terms of activity but also in terms of toxicity induced by sunitinib. This study considered different clinical observations and current metabolic and pharmacological knowledge, leading to hypotheses regarding which molecular mechanisms may be involved in sunitinib-induced AFS in cancer patients. Deeper knowledge of the molecular mode of action of sunitinib may lead to improved optimization of its clinical use

Final Report of the First Refractory Germ Cell Tumor Treated with Sunitinib Malate

Patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy, but the outcome remains unsatisfactory for patients with relapsed disease, including those patients with refractory disease after bone marrow transplantation. Targeted therapies have changed the standard of care for many advanced solid tumors. We have identified, in the literature, potential targets for the treatment of refractory germ cell tumors, and applied to a patient with a refractory disease. We chose sunitinib for this purpose. To our knowledge, this is the first case to be treated with sunitinib, and we have found a promising activity

Potential Role of Sugar Transporters in Cancer and Their Relationship with Anticancer Therapy

Sugars, primarily glucose and fructose, are the main energy source of cells. Because of their hydrophilic nature, cells use a number of transporter proteins to introduce sugars through their plasma membrane. Cancer cells are well known to display an enhanced sugar uptake and consumption. In fact, sugar transporters are deregulated in cancer cells so they incorporate higher amounts of sugar than normal cells. In this paper, we compile the most significant data available about biochemical and biological properties of sugar transporters in normal tissues and we review the available information about sugar carrier expression in different types of cancer. Moreover, we describe the possible pharmacological interactions between drugs currently used in anticancer therapy and the expression or function of facilitative sugar transporters. Finally, we also go into the insights about the future design of drugs targeted against sugar utilization in cancer cells

Notch signalling in cancer stem cells

[Abstract] A new theory about the development of solid tumours is emerging from the idea that solid tumours, like normal adult tissues, contain stem cells (called cancer stem cells) and arise from them. Genetic mutations encoding for proteins involved in critical signalling pathways for stem cells such as BMP, Notch, Hedgehog and Wnt would allow stem cells to undergo uncontrolled proliferation and form tumours. Taking into account that cancer stem cells (CSCs) would represent the real driving force behind tumour growth and that they may be drug resistant, new agents that target the above signalling pathways could be more effective than current anti-solid tumour therapies. In the present paper we will review the molecular basis of the Notch signalling pathway. Additionally, we will pay attention to their role in adult stem cell self-renewal, and cell fate specification and differentiation, and we will also review evidence that supports their implication in cancer

Crossing paths in Human Renal Cell Carcinoma (hRCC)

[Abstract] Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways

Biology of BMP signalling and cancer

[Abstract] In recent years, it has been proposed that tumours are not homogeneous but composed of several cellular types like normal tissues. A cellular subtype, which is though to be the origin of tumours as well as their malignant properties (i.e., capacity for regrowth and metastasis), are the cancer stem cells (CSCs). CSCs, like normal stem cells, have a nearly unlimited capacity to self-renew and to proliferate so that are responsible, besides their same auto-perpetuation giving rise to the features previously depicted, also for the generation of the bulk of more differentiated cells in tumour. The altered behaviour of CSCs may be caused by the malfunction of a number of signalling pathways involved in normal embryonic development and in tissue homeostasis in adulthood. Among these signalling pathways are Wnt, Hedgehog, Notch and BMP pathways. In this review, we will focus on the study of molecular aspects of BMP signalling as well as its involvement in cancer

New insights into molecular mechanisms of sunitinib-associated side effects

Review[Abstract] The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events

Old and New Insights in the Treatment of Thyroid Carcinoma

Thyroid cancer is the endocrine tumor that bears the highest incidence with 33 550 new cases per year. It bears an excellent prognosis with a mortality of 1530 patients per year (Jemal et al.; 2007). We have been treating patients with thyroid carcinoma during many years without many innovations. Recently, we have assisted to the development of new agents for the treatment of this disease with unexpected good results. Here we present a review with the old and new methods for the treatment of this disease