RESUMO
PURPOSE: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. EXPERIMENTAL DESIGN: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors. RESULTS: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. CONCLUSIONS: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.
Assuntos
Antineoplásicos/farmacologia , Compostos Azabicíclicos/farmacologia , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Cloridrato de Erlotinib , Feminino , Gefitinibe , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Camundongos SCID , Mutação , Fosforilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Higher bone mass in blacks than in whites has been related to greater calcium utilization efficiency. Dietary calcium requirements for maximal skeletal calcium accretion during puberty may differ between the races. OBJECTIVE: This study compared the relation between calcium intake and calcium retention in black and white adolescent girls. DESIGN: A range of controlled calcium intakes (760-1981 mg Ca/d) were used in 3-wk controlled balance studies. Some subjects were studied more than once; a total of 182 observations from 55 black girls and 66 white girls were analyzed. RESULTS: Blacks had 185 +/- 32 mg/d greater mean skeletal calcium retention than did whites (P < 0.0001) at all calcium intakes as a result of significantly greater net calcium absorption (P < 0.001) and lower calcium excretion (P < 0.0001). CONCLUSIONS: Dietary calcium requirements did not differ with race. Higher calcium retention at all calcium intakes during adolescence may underlie the higher bone mineral content of adult blacks than of adult whites.
Assuntos
População Negra , Densidade Óssea , Osso e Ossos/metabolismo , Cálcio/metabolismo , População Branca , Absorção , Adolescente , Biomarcadores/sangue , Osso e Ossos/química , Cálcio/administração & dosagem , Cálcio/análise , Cálcio da Dieta/administração & dosagem , Suplementos Nutricionais , Feminino , HumanosRESUMO
BACKGROUND: Sodium is an important determinant of urinary calcium excretion, and race is an important determinant of calcium retention. The effect of dietary sodium on calcium retention and the influence of race have not been studied in adolescence, the life stage during which peak bone mass is accrued. OBJECTIVE: The study reported here was undertaken to compare racial differences in calcium retention as a function of dietary salt intake. DESIGN: A total of 35 adolescent girls (22 black and 13 white) participated in two 20-d metabolic summer camps, separated by 2 wk, that simulated a free-living environment. The effect of changes in dietary sodium on calcium retention was tested in a randomized-order, crossover design with 2 concentrations of sodium-1.30 g/d (57 mmol/d) and 3.86 g/d (168 mmol/d)-and a constant calcium intake of 815 mg/d (20 mmol/d). RESULTS: Both race and sodium intake significantly affected calcium retention (P < 0.01). Calcium retention was significantly greater in black girls than in white girls, regardless of dietary sodium intake (P < 0.001). The high-sodium diet significantly reduced calcium retention in both whites and blacks (P < 0.01), primarily through a decrease in net calcium absorption. Black girls excreted significantly less calcium in the urine than did white girls, regardless of diet (P < 0.05). CONCLUSIONS: Calcium retention is significantly greater in black girls than in white girls but is significantly reduced in girls of both races in response to salt loading.
Assuntos
População Negra , Osso e Ossos/efeitos dos fármacos , Cálcio/metabolismo , Sódio na Dieta/farmacologia , População Branca , Adolescente , Osso e Ossos/metabolismo , Cálcio/urina , Feminino , Humanos , Sódio na Dieta/administração & dosagem , Sódio na Dieta/metabolismoRESUMO
Increased sodium (Na(+)) retention in blacks could be related to the high prevalence of hypertension in adult blacks. Na(+) retention in response to controlled dietary Na(+) has not been rigorously compared in the different race groups. The present study assessed Na(+) retention in 22 black and 14 white girls, 11-15 yr old, during 3 wk on a low (1.3 g, 57 mmol)- and during 3 wk on a high (4 g, 172 mmol)-Na(+) diet in a randomized order, crossover design. Subjects were matched by postmenarcheal age and weight. After a 1-wk equilibration period, the mean daily Na(+) retention was 357 +/- 69 mg (15.5 +/- 3.0 mmol) in blacks and 239 +/- 37 mg (10.4 +/- 1.6 mmol) in whites on the low-Na(+) diet and 991 +/- 138 mg (43.1 +/- 6.0 mmol) in blacks vs. 334 +/- 90 mg (14.5 +/- 3.9 mmol) in whites (P < 0.001) on the high-Na(+) diet. The greater Na(+) retention in blacks was not accompanied by an increase in fecal or sweat Na(+) excretion. Blood pressure and weight did not increase despite the Na(+) retention, and thus, the retained Na(+) appeared to reside in a nonextracellular compartment that we speculate to be bone. In summary, black girls showed greater Na(+) retention compared with white girls. The difference in Na(+) handling may contribute to underlying racial differences in susceptibility to hypertension.
Assuntos
População Negra , Sódio na Dieta/administração & dosagem , Sódio/farmacocinética , População Branca , Adolescente , Diurese/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Energia , Fezes/química , Feminino , Humanos , Sódio/análiseRESUMO
BACKGROUND AND OBJECTIVES: Patients with advanced chronic kidney disease (CKD) are in positive phosphorus balance, but phosphorus levels are maintained in the normal range through phosphaturia induced by increases in fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). This provides the rationale for recommendations to restrict dietary phosphate intake to 800 mg/d. However, the protein source of the phosphate may also be important. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a crossover trial in nine patients with a mean estimated GFR of 32 ml/min to directly compare vegetarian and meat diets with equivalent nutrients prepared by clinical research staff. During the last 24 hours of each 7-day diet period, subjects were hospitalized in a research center and urine and blood were frequently monitored. RESULTS: The results indicated that 1 week of a vegetarian diet led to lower serum phosphorus levels and decreased FGF23 levels. The inpatient stay demonstrated similar diurnal variation for blood phosphorus, calcium, PTH, and urine fractional excretion of phosphorus but significant differences between the vegetarian and meat diets. Finally, the 24-hour fractional excretion of phosphorus was highly correlated to a 2-hour fasting urine collection for the vegetarian diet but not the meat diet. CONCLUSIONS: In summary, this study demonstrates that the source of protein has a significant effect on phosphorus homeostasis in patients with CKD. Therefore, dietary counseling of patients with CKD must include information on not only the amount of phosphate but also the source of protein from which the phosphate derives.