RESUMEN
Carboxylesterase 1c (CES1c) is responsible for linker-drug instability and poor pharmacokinetics (PK) of several antibody-drug conjugates (ADC) in mice, but not in monkeys or humans. Preclinical development of these ADCs could be improved if the PK in mice would more closely resemble that of humans and is not affected by an enzyme that is irrelevant for humans. SYD985, a HER2-targeting ADC based on trastuzumab and linker-drug vc-seco-DUBA, is also sensitive to CES1c. In the present studies, we first focused on the interaction between CES1c and SYD985 by size- exclusion chromatography, Western blotting, and LC/MS-MS analysis, using recombinant CES1c and plasma samples. Intriguingly, CES1c activity not only results in release of the active toxin DUBA but also in formation of a covalent bond between CES1c and the linker of vc-seco-DUBA. Mass spectrometric studies enabled identification of the CES1c cleavage site on the linker-drug and the structure of the CES1c adduct. To assess the in vivo impact, CES1c-/- SCID mice were generated that showed stable PK for SYD985, comparable to that in monkeys and humans. Patient-derived xenograft (PDX) studies in these mice showed enhanced efficacy compared with PDX studies in CES1c+/+ mice and provided a more accurate prediction of clinical efficacy of SYD985, hence delivering better quality data. It seems reasonable to assume that CES1c-/- SCID mice can increase quality in ADC development much broader for all ADCs that carry linker-drugs susceptible to CES1c, without the need of chemically modifying the linker-drug to specifically increase PK in mice. Mol Cancer Ther; 17(11); 2389-98. ©2018 AACR.
Asunto(s)
Carboxilesterasa/deficiencia , Inmunoconjugados/farmacología , Inmunoconjugados/farmacocinética , Animales , Carboxilesterasa/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Femenino , Humanos , Inmunoconjugados/química , Ratones Noqueados , Ratones SCID , Péptidos/química , Ratas Wistar , Trastuzumab/química , Resultado del TratamientoRESUMEN
Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model. Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99mTc-HYNIC-Annexin V, and a cell proliferation assay. 99mTc-HYNIC-Annexin V SPECT and [18F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells. Results: Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [18F]-FDG uptake when measured during treatment. Conclusions: This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.
Asunto(s)
Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Imagen Multimodal/métodos , Radiofármacos/química , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Femenino , Xenoinjertos , Humanos , Imagen por Resonancia Magnética/métodos , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/farmacología , Tomografía Computarizada de Emisión de Fotón Único , Investigación Biomédica Traslacional , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.
Asunto(s)
Antineoplásicos/farmacología , Oligopéptidos/sangre , Oligopéptidos/farmacología , Animales , Antineoplásicos/sangre , Proteínas Sanguíneas , Línea Celular Tumoral/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Perros , Descubrimiento de Drogas , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Semivida , Humanos , Ratones Endogámicos BALB C , Péptidos/química , Péptidos/farmacología , RatasRESUMEN
Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor (VEGFR) tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for cancer treatment. In the present study, we show that a quinoline-urea derivative, KRN951, is a novel tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities. KRN951 potently inhibited VEGF-induced VEGFR-2 phosphorylation in endothelial cells at in vitro subnanomolar IC50 values (IC50 = 0.16 nmol/L). It also inhibited ligand-induced phosphorylation of platelet-derived growth factor receptor-beta (PDGFR-beta) and c-Kit (IC50 = 1.72 and 1.63 nmol/L, respectively). KRN951 blocked VEGF-dependent, but not VEGF-independent, activation of mitogen-activated protein kinases and proliferation of endothelial cells. In addition, it inhibited VEGF-mediated migration of human umbilical vein endothelial cells. Following p.o. administration to athymic rats, KRN951 decreased the microvessel density within tumor xenografts and attenuated VEGFR-2 phosphorylation levels in tumor endothelium. It also displayed antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer. Furthermore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis revealed that a significant reduction in tumor vascular hyperpermeability was closely associated with the antitumor activity of KRN951. These findings suggest that KRN951 is a highly potent, p.o. active antiangiogenesis and antitumor agent and that DCE-MRI would be useful in detecting early responses to KRN951 in a clinical setting. KRN951 is currently in phase I clinical development for the treatment of patients with advanced cancer.
Asunto(s)
Antineoplásicos/farmacología , Isoxazoles/farmacología , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Permeabilidad Capilar/efectos de los fármacos , Línea Celular Tumoral , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Humanos , Isoxazoles/farmacocinética , Imagen por Resonancia Magnética , Ratones , Células 3T3 NIH , Neoplasias/enzimología , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Compuestos de Fenilurea/farmacocinética , Fosforilación , Inhibidores de Proteínas Quinasas/farmacocinética , Distribución Aleatoria , Ratas , Ratas Desnudas , Transducción de Señal/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The relative distribution of gefitinib-related material in nude mice bearing s.c. human tumor xenografts and in an orthotopic rat lung tumor model was investigated following oral administration (50 mg/kg) of [14C]-gefitinib. Selected tissue samples were monitored for radioactivity by liquid scintillation counting, whereas plasma and tumor extracts were assayed for gefitinib and its major metabolites (M523595 and M537194) by high-performance liquid chromatography with tandem mass spectrometric detection. Tissue distribution was also determined by whole body autoradiography. Gefitinib was extensively distributed into the tissues of tumor-bearing mice and unchanged gefitinib was shown to account for most of the tumor radioactivity. Concentrations of gefitinib in mouse s.c. tumor xenografts were similar to skin concentrations and substantially greater (up to 12-fold based on area under the concentration-time curve) than plasma. Concentrations of gefitinib-related material in an orthotopic rat lung tumor were similar to those in healthy lung tissue and were much higher than corresponding blood levels. Following treatment of breast cancer patients with oral gefitinib (Iressa) 250 mg/d for > or = 14 days, gefitinib concentrations (mean, 7.5 microg/g, 16.7 micromol/L) in breast tumor tissue were 42 times higher than plasma, confirming the preferential distribution of gefitinib from blood into tumor tissue in the clinical situation. These gefitinib tumor concentrations are considerably higher than those reportedly required in vitro to achieve complete inhibition of epidermal growth factor receptor autophosphorylation in both epidermal growth factor receptor mutant (0.2 micromol/L) and wild-type cells (2 micromol/L).
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Quinazolinas/farmacocinética , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Modelos Químicos , Mutación , Trasplante de Neoplasias , Quinazolinas/farmacología , Ratas , Ratas Desnudas , Conteo por Cintilación , Transducción de Señal , Factores de Tiempo , Distribución TisularRESUMEN
By decreasing drug drainage through the peritoneal and tumoral vascular networks, epinephrine increases the penetration of cisplatin and oxaliplatin into the metastatic peritoneal tumor nodules. This improved drug penetration increases their antitumor efficacy, allowing the cure of millimetric-sized peritoneal tumor nodules that could not be obtained with cisplatin or oxaliplatin used alone. However, limited drug diffusion into supramillimetric nodules did not result in curing advanced peritoneal carcinomatosis, unless complete resection of macroscopic localized tumor nodules is performed before intraperitoneal chemotherapy. In our opinion, the intraperitoneal epinephrine-cisplatin combination should be clinically assessed in completely or almost completely surgically resected peritoneal carcinomatosis with the objective of preventing recurrent tumors. Due to its reduced toxicity, repeated courses of intraperitoneal oxaliplatin associated with epinephrine could be an interesting alternative to cisplatin for the unresectable disease.