RESUMEN
Multiple clinical trials using bevacizumab, ziv-aflibercept, and regorafenib have recently demonstrated efficacy for patients with metastatic colorectal cancer. While the net clinical benefit of each of these therapies in the second-line and refractory disease setting appears to be similar, important distinctions exist between the agents at the pharmacodynamic, tumor microenvironment, and clinical levels. The purpose of this review is to survey the preclinical evidence regarding the mechanisms of action of these novel antiangiogenic agents and provide an overview of their respective clinical activity, while highlighting distinctions between therapies. Fundamental understanding of these distinctions may aid in clinical decisions and choice of antiangiogenic therapies.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/patología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Microambiente Tumoral/efectos de los fármacosRESUMEN
We have characterized the alpha-bungarotoxin receptors (BgtRs) found on the cell surface of undifferentiated pheochromocytoma (PC12) cells. The PC12 cells express a homogeneous population of alpha7-containing receptors that bind alpha-Bgt with high affinity (Kd = 94 pM). The BgtRs mediate most of the response elicited by nicotine, because the BgtR-specific antagonists methyllycaconitine and alpha-Bgt block approximately 90% of the whole-cell current. The binding of nicotinic agonists to cell-surface BgtRs was highly cooperative with four different agonists showing Hill coefficients in the range of 2.3-2.4. A similar agonist binding cooperativity was observed for BgtR homomers formed from chimeric alpha7/5HT3 subunits expressed in tsA 201 cells. Two classes of agonist binding sites, in the ratio of 4:1 for PC12 cell BgtRs and 3:1 for alpha7/5HT3 BgtRs, were revealed by bromoacetylcholine alkylation of the reduced sites on both PC12 BgtRs and alpha7/5HT3 BgtRs. We conclude from this data that PC12 BgtRs and alpha7/5HT3 homomers contain at least three distinguishable agonist binding sites and thus are different from other nicotinic receptors.