RESUMO
BACKGROUND: Lead is classified as a probable human carcinogen. However, its role in renal cell cancer (RCC) has not been established. Calcium and vitamin D may off-set toxicity in vivo. METHODS: In this nested case-control study, whole blood lead, total serum calcium, and serum 25-hydroxyvitamin D levels were measured in blood drawn prior to diagnosis among male smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Single-nucleotide polymorphisms (SNP) in five genes (CALB1, TRPV5, TRPV6, VDR, and ALAD) related to lead toxicity or calcium transport were genotyped. Logistic and linear regressions were used to determine RCC risk and time to diagnosis (respectively), adjusting for other risk factors. RESULTS: Among 154 newly diagnosed cases and 308 matched controls, RCC was associated with higher whole blood lead [OR = 2.0; 95% confidence interval (CI), 1.0-3.9; quartile 4 (Q4) vs. Q1, P(trend) = 0.022] and CALB1 rs1800645 (P(trend) = 0.025, minor 'T' allele frequency = 0.34). Higher total serum calcium (P(trend) ≤ 0.001) was associated with reduced RCC risk. Total serum calcium and 25-hydroxyvitamin D levels did not alter the association observed with lead. Time from enrollment to RCC diagnosis was positively associated with serum calcium (P(trend) = 0.002) and 25-hydroxyvitamin D (P(trend) = 0.054) among cases. CONCLUSIONS: Higher blood lead concentrations, below the 10 µg/dL level of concern, were associated with RCC, independent from serum calcium and CALB1 promoter polymorphism. IMPACT: Increased risk of RCC is associated with lower serum calcium and higher whole blood lead in smokers. The clinical prognostic value of serum calcium and vitamin D in RCC should be further investigated.
Assuntos
Cálcio/sangue , Carcinoma de Células Renais/sangue , Neoplasias Renais/sangue , Intoxicação por Chumbo/sangue , Chumbo/sangue , Fumar/sangue , Idoso , Calbindina 1 , Calbindinas , Cálcio/farmacocinética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Finlândia , Genótipo , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Chumbo/farmacocinética , Intoxicação por Chumbo/genética , Intoxicação por Chumbo/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Proteína G de Ligação ao Cálcio S100/genética , Fumar/genética , Fumar/metabolismo , Vitamina D/sangueRESUMO
Carcinomatosis from peritoneal surface malignancies, such as mesothelioma, appendiceal carcinoma or ovarian metastases, significantly decreases survival and quality of life. Given a 60-80% locoregional recurrence rate after surgical debulking for mesothelioma, the current study explores the use of polymeric nanoparticles, specifically engineered to expand and locally deliver chemotherapeutic agents at endosomal pH, for the prevention of progressive carcinomatosis. Anti-tumor efficacy of paclitaxel-loaded pH-responsive expansile nanoparticles (Pax-eNP) was evaluated in vitro and in in vivo murine models of malignant peritoneal mesothelioma. Pax-eNP inhibited mesothelioma growth in vitro, markedly decreased tumor growth and disease severity in vivo, prevented initial intraperitoneal tumor implants, and significantly prolonged survival compared to other intraperitoneal drug delivery methods. These outcomes suggest that the mechanism of pH-triggered drug delivery and tumor affinity associated with eNP may effectively improve the local control of residual microscopic disease following surgical debulking of locoregionally aggressive malignancies.