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BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Trifluridina/uso terapéutico , Uracilo/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Países Bajos , Neutropenia/inducido químicamente , Pronóstico , Pirrolidinas , Timina , Resultado del Tratamiento , Trifluridina/efectos adversos , Uracilo/efectos adversos , Uracilo/uso terapéuticoRESUMEN
Post-deposition annealing by ultra-short laser pulses can modify the optical properties of SnO2 thin films by means of thermal processing. Industrial grade SnO2 films exhibited improved optical properties after picosecond laser irradiation, at the expense of a slightly increased sheet resistance [Proc. SPIE 8826, 88260I (2013)]. The figure of merit Ï = T¹° / R(sh) was increased up to 59% after laser processing. In this paper we study and discuss the causes of this improvement at the atomic scale, which explain the observed decrease of conductivity as well as the observed changes in the refractive index n and extinction coefficient k. It was concluded that the absorbed laser energy affected the optoelectronic properties preferentially in the top 100-200 nm region of the films by several mechanisms, including the modification of the stoichiometry, a slight desorption of dopant atoms (F), adsorption of hydrogen atoms from the atmosphere and the introduction of laser-induced defects, which affect the strain of the film.
RESUMEN
BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.
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Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Implementación de Plan de Salud , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Calidad de Vida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Procedimientos Quirúrgicos del Sistema Biliar , Carcinoma Ductal Pancreático/epidemiología , Niño , Preescolar , Análisis por Conglomerados , Drenaje , Terapia de Reemplazo Enzimático , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Terapia Neoadyuvante , Países Bajos/epidemiología , Cuidados Paliativos , Neoplasias Pancreáticas/epidemiología , Pancreaticoduodenectomía , Cooperación del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Stents , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: An important class of dietary mutagens and carcinogens are the heterocyclic arylamine compounds that have been identified in a variety of cooked, protein-containing foods. Among these heterocyclic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) is potentially the most important carcinogen for human cancer risk. We have recently observed that PhIP-derived radioactivity is excreted into the breast milk of lactating rats administered [3H]PhIP. PURPOSE: To better assess the significance of breast milk as a route of exposure of the newborn to dietary heterocyclic amines, we examined the metabolites of PhIP in breast milk and in urine of nursing pups. METHODS: Lactating Fischer 344 rats with 5-day-old pups were given a single oral dose of 10 mg/kg of [3H]PhIP. We collected milk from the dams and urine from the pups and then analyzed the samples for metabolites of PhIP, using high-pressure liquid chromatography (HPLC). PhIP-DNA adduct levels in the tissues of the pups were determined by 32P-postlabeling analysis. RESULTS: Three radioactive peaks were observed by HPLC separation of milk samples: an unidentified early eluting peak, 4'-hydroxy-PhIP, and PhIP. Four metabolites and the parent compound were found in urine of the pups nursed by dams given radiolabeled PhIP: PhIP-4'-O-glucuronide, PhIP-4'-sulfate, 4'-hydroxy-PhIP, and N2-hydroxy-PhIP-N3-glucuronide. 4'-Hydroxy-PhIP and its conjugates contributed approximately 60% of the radioactivity found in the urine. By 32P-postlabeling analysis, PhIP-DNA adducts were detected in spleen, lung, heart, kidney, liver, and stomach of pups at mean levels ranging from 0.06 to 0.55 adducts/10(7) nucleotides. CONCLUSIONS: The large percentage of 4-hydroxy-PhIP and its conjugates in the urine indicates that 5-day-old pups detoxify PhIP and further metabolize 4'-hydroxy-PhIP obtained from the breast milk. The presence of the glucuronide conjugate of N-hydroxy-PhIP in the urine of pups and the lack of detectable conjugate or N-hydroxylamine itself in breast milk suggest that PhIP from breast milk undergoes metabolic activation via N-hydroxylation in 5-day-old rat pups. This conclusion was further supported by the observation that hepatic S9 fractions from the pups activated PhIP to a mutagen in the Ames Salmonella mutagenicity assay and by the presence of PhIP-DNA adducts in the tissues of the pups. IMPLICATIONS: The findings reported here may have carcinogenic and toxicologic implications for the offspring of women who breast-feed and consume a diet rich in cooked meat.
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Animales Lactantes/orina , Carcinógenos/metabolismo , Imidazoles/metabolismo , Lactancia/metabolismo , Leche/metabolismo , Animales , Femenino , Imidazoles/orina , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
The death of a newborn infant is an extremely emotional event for relatives. Many hospitals provide the parents with support, and in some cases a mourning protocol is available. Some hospitals offer parents photographs of infants which have died around birth. The photographs are often taken by a nurse or doctor on the maternity or paediatric ward. It is advisable to draw up a mourning protocol which allows professional studio photographs to be taken. As a photograph is often the only concrete memento that parents have of their baby, it is important for it to be of good quality. The parents decide what they would prefer, but it is important to point out to them that their wishes and needs immediately following the death may differ to those in the longer term.
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Aflicción , Muerte Fetal , Padres/psicología , Fotograbar , Humanos , Recién NacidoRESUMEN
The mutagenic heterocyclic amine 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) is carcinogenic in the Fischer-344 rat, affecting the liver and small and large intestines, as well as several other organs. In male animals the incidences of tumors in the liver, small intestine, and large intestine were reported to be 67.5, 30.0, and 62.5%, respectively. Using 32P-postlabeling assays, the formation and persistence of IQ-DNA adducts in the liver and small and large intestines were studied in male Fischer-344 rats. Young, adult animals were either given a single p.o. dose (5, 25, or 50 mg/kg) of IQ and were killed 24 h later or were given a single p.o. or i.p. dose (50 mg/kg) of IQ and were killed at different time points, from 6 h to 31 days after p.o. treatment and from 6 h to 6 days after i.p. treatment, to follow adduct persistence. Up to five specific adducts could be isolated, and adduct formation was dose related in all three organs. Adduct 1, previously shown to be N-(hydroxyguanosin-8-yl)-IQ, was the major adduct in all cases, comprising up to 78% of the total. After p.o. administration (6-24 h) adduct levels in the liver were 3- to 4-fold higher than after i.p. administration, while levels in the intestines during this time period were independent of the route of administration. At 24 h after p.o. administration total adduct levels in the liver were 13.5-41.4 and 9.2-18.4 times higher than those in the small intestine and large intestine, respectively. Maximum adduct levels were observed between 6 and 24 h after administration, and from 1 to 6 days later, rates of removal from the liver were 7-fold and 2-fold slower, respectively, than from the small and large intestine. Rates of adduct removal from the intestines after i.p. administration were similar to those after p.o. administration. Beyond day 15 adduct levels in all organs constituted less than 12% of those on day 1, and low levels of adducts persisted for up to 31 days. In all cases there was no preferential loss or persistence of any of the adducts. It is concluded that total adduct levels and persistence in target organs may, in part, be related to susceptibility to IQ-induced carcinogenesis in the Fischer-344 rat.
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ADN/metabolismo , Mutágenos/metabolismo , Quinolinas/metabolismo , Animales , Intestino Grueso/metabolismo , Intestino Delgado/metabolismo , Hígado/metabolismo , Masculino , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are heterocyclic amine mutagens/carcinogens formed from the cooking of meat. Here we used the pSP189 shuttle vector developed by Parris and Seidman (Gene, 117: 1-5, 1992) to study and compare the mutation spectra induced by these compounds. pSP189 was adducted by reaction with the N-acetoxy derivatives of IQ or PhIP. 32P-Postlabeling analysis was used to measure the C8-guanine adduct level and the total adduct levels formed in the plasmid. Plasmids were replicated and mutagenized in repair-proficient [GM0637(SV40)] or repair-deficient [XP12Be(SV40)] human fibroblasts. Resulting inactivation mutations in the supF gene were determined by the formation of white or light blue colonies on indicator bacteria (carrying a lacZ amber mutation) and cycle sequencing. With both compounds in either cell line, 85-93% of the mutations induced were base substitutions and the remainder of the mutations were base deletions. The majority of the substitution mutations involved a single base, and nearly all base substitution mutations (> 97%) were at guanine. This latter finding is consistent with the results from 32P-postlabeling showing that both compounds adduct to the guanine base with the major adduct being formed at the C8-guanine position. The predominant mutation found with IQ and PhIP in either cell line was G:C to T:A transversion, followed by G:C to A:T transition, and then G:C to C:G transversion; these mutations accounted for 59-72%, 19-27%, and 6-14% of total base substitution mutations, respectively. There was a preference seen with both compounds to induce mutations at a guanine base having a neighboring guanine or cytosine (i.e., GG and GC sites). However, despite the striking similarity in the kinds of base substitution mutations induced by IQ and PhIP, their mutation spectra were distinct. For example, in repair-proficient cells, 26% of the mutations induced with PhIP, but not with IQ, also involved a GA site, containing the 5-base pair sequence 5'-GCAGA-3'. Mutation spectra for IQ and PhIP were also different between repair-deficient and repair-proficient cells. The findings shown here may serve to be predictive of the kinds of mutations induced by the adducts of IQ and PhIP in oncogenes and tumor suppressor genes altered during heterocyclic amine-induced carcinogenesis.
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Genes Supresores , Vectores Genéticos , Imidazoles/toxicidad , Mutágenos/toxicidad , Quinolinas/toxicidad , Secuencia de Bases , Línea Celular , ADN/metabolismo , Humanos , Imidazoles/metabolismo , Datos de Secuencia Molecular , Mutación , Plásmidos , Quinolinas/metabolismoRESUMEN
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a mutagenic and carcinogenic heterocyclic amine found in cooked meat. Hepatic DNA adduct formation, in vivo mutagenicity, and hepatocarcinogenicity of MeIQx were examined in mice harboring the lacZ mutation reporter gene (Muta mice) and bitransgenic mice overexpressing the c-myc oncogene. C57Bl/lambda lacZ and bitransgenic c-myc (albumin promoter)/lambda lacZ mice were bred and weaned onto an American Institute of Nutrition-76-based diet containing 0.06% (w/w) MeIQx or onto control diet. After 30 weeks on diet, only male bitransgenic mice on MeIQx developed hepatocellular carcinoma (100% incidence). By 40 weeks, hepatic tumor incidence was 100%/75% (17%/0%) and 44%/17% (0%/0%) in male c-myc/lambda lacZ and C57Bl/lambda lacZ mice who were given MeIQx (or control) diet, respectively, supporting a synergism between MeIQx and c-myc overexpression in hepatocarcinogenesis. At either time point, mutant frequency in the lacZ gene was at least 40-fold higher in MeIQx-treated mice than in control mice of either strain. These findings suggest that MeIQx-induced hepatocarcinogenesis is associated with MeIQx-induced mutations. Elevated mutant frequency in MeIQx-treated mice also occurred concomitant with the formation of MeIQx-guanine adducts, as detected by the 32P-postlabeling assay. Irrespective of strain or diet, sequence analysis of the lacZ mutants from male mouse liver showed that the principal sequence alterations were base substitutions at guanine bases. Adenine mutations, however, were detected only in animals on control diet. MeIQx-fed mice harboring the c-myc oncogene showed a 1.4-2.6-fold higher mutant frequency in the lacZ gene than mice not carrying the transgene. Although there was a trend toward higher adduct levels in c-myc mice, MeIQx-DNA adduct levels were not significantly different between c-myc/lambda lacZ and C57Bl/lambda lacZ mice after 30 weeks on diet. Thus, it seemed that factors in addition to MeIQx-DNA adduct levels, such as the enhanced rate of proliferation associated with c-myc overexpression, may have accounted for a higher mutant frequency in c-myc mice. In the control diet groups, the lacZ mutant frequency was significantly higher in c-myc/lambda lacZ mice than in C57Bl/lambda lacZ mice. The findings are consistent with the notion that c-myc overexpression is associated with an increase in mutagenesis. The mechanism for the synergistic effects of c-myc overexpression on MeIQx hepatocarcinogenicity seems to involve an enhanced expression of MeIQx-induced mutations.
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Carcinógenos/metabolismo , Aductos de ADN/metabolismo , Mutágenos/metabolismo , Quinoxalinas/metabolismo , Animales , Carcinógenos/toxicidad , Aductos de ADN/toxicidad , Femenino , Operón Lac , Neoplasias Hepáticas Experimentales/inducido químicamente , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Transgénicos , Mutágenos/toxicidad , Quinoxalinas/toxicidad , Análisis de Secuencia de ADN , Factores SexualesRESUMEN
We have confirmed previous results which suggest that transplacental exposure of fetal mice to carcinogens does not cause an increase in tumor incidence as they mature unless treatment occurs after midorganogenesis. In C3HeB/FeJ mice we found a negligible increase in tumor incidence and multiplicity following transplacental exposure to the direct-acting carcinogen ethylnitrosourea (ENU) on gestation day 10, but significant increases in lung and liver tumor incidence following exposure on days 13 or 15 or in adults. To explore the possibility that this observed difference is due to differences in the biodistribution of the carcinogen or its interaction with cellular macromolecules, the level of covalent binding between ENU and fetal and maternal DNA following an i.p. injection of a dose of 50 mg/kg of tritium-labeled ENU was measured 30 min after its injection into pregnant females on days 10, 13, and 15 of gestation. The DNA from fetal and maternal lung, liver, and brain was isolated and the amount of covalent binding estimated from the dpm/mg DNA recovered. Samples of DNA were hydrolyzed and chromatographed to determine that the bound tritium was associated with ENU-DNA adducts and not as a product of DNA synthesis. The level of binding of ENU to fetal DNA was equivalent at all gestation days studied but was significantly less than maternal tissues. Binding to the DNA of maternal liver was 4-fold greater than to fetal DNA while maternal lung and brain DNA were bound at intermediate levels. We conclude that the lack of carcinogenic response to ENU documented here, in fetal mice exposed early in gestation (day 10), is not due to differences in ENU binding to fetal DNA during development.
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Daño del ADN , Etilnitrosourea , Neoplasias Experimentales/inducido químicamente , Adenoma/inducido químicamente , Animales , ADN/efectos de los fármacos , Etilnitrosourea/metabolismo , Femenino , Edad Gestacional , Neoplasias Hepáticas/inducido químicamente , Neoplasias Pulmonares/inducido químicamente , Masculino , Intercambio Materno-Fetal , Ratones , Embarazo , Distribución TisularRESUMEN
In our previous experiments, multiple injections with the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were used to induce intestinal tumors in C57BL/6J-multiple intestinal neoplasia (Min)/+ mice. To define the period of highest susceptibility to PhIP perinatally, we first determined the effect of a single s.c. injection. Ten or 50 mg/kg PhIP increased the number and diameter of small intestinal tumors dose-dependently in 3-day-old Min/+ mice. In the colon, only 50 mg/kg PhIP increased the incidence and number of tumors. The number of dysplastic aberrant crypt foci decreased from weeks 7 to 11. In the same period, an increase in the number of tumors was seen, indicating that over time the dysplastic aberrant crypt foci develop into tumors. Min/+ mice were then exposed in utero through their dams being given one s.c. injection of 50 mg/kg PhIP 3 days before giving birth or were exposed directly to the same dose on day 3, 12, or 36 after birth. Remarkably, the most susceptible period for tumorigenesis in the small intestine was between days 3-12 after birth, whereas in the colon it was from day 3 before to day 3 after birth. Furthermore, we examined whether the formation of DNA adducts determined after 24 h could explain the observed time-dependent and regional susceptibility to PhIP. A higher level of PhIP-DNA adducts was found after exposure on day 12 after birth, compared with day 36 after birth, in all parts of the small intestine but not in the colon, which was in close accordance with the numbers of tumors present. The levels of PhIP-DNA adducts along the intestines were highest in the middle and distal parts of the small intestine, where tumor numbers were also the highest. In conclusion, Min/+ mice are most susceptible to intestinal tumor induction by PhIP from day 3 before to day 12 after birth, and this susceptibility could at least partly be explained by the formation of PhIP-DNA adducts.
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Carcinógenos/toxicidad , Aductos de ADN/metabolismo , Imidazoles/toxicidad , Neoplasias Intestinales/inducido químicamente , Neoplasias Intestinales/metabolismo , Administración Oral , Factores de Edad , Animales , Animales Recién Nacidos , Carcinógenos/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/administración & dosificación , Inyecciones Subcutáneas , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Because of the potential for human exposure to mutagenic and carcinogenic heterocyclic arylamines in the diet, the carcinogenicity of three HAAs, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, is being evaluated in nonhuman primates, especially cynomolgus monkeys. Concomitant with the carcinogenicity studies, the metabolic processing, disposition, and DNA-adduct formation of these compounds are being examined in these monkeys. This report highlights the results from studies in monkeys and from in vitro models examining metabolic activation and genotoxicity of HAAs. The extent of in vivo activation of HAAs in monkeys was assessed by measuring DNA adducts in various tissues. Both 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine form high levels of DNA adducts in a number of organs, particularly the liver, kidney, and heart. The implications of metabolic activation and DNA-adduct formation to the carcinogenicity of HAAs are discussed.
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ADN/metabolismo , Compuestos Heterocíclicos/farmacocinética , Imidazoles/farmacocinética , Quinolinas/farmacocinética , Quinoxalinas/farmacocinética , Animales , Biotransformación , Sistema Enzimático del Citocromo P-450/metabolismo , Compuestos Heterocíclicos/toxicidad , Imidazoles/toxicidad , Ratones , Ratones Endogámicos C57BL , Pruebas de Mutagenicidad , Dibenzodioxinas Policloradas , Quinolinas/toxicidad , Quinoxalinas/toxicidad , Salmonella/efectos de los fármacosRESUMEN
Heterocyclic amines, suspected as cancer initiators, require metabolic activation to exert genotoxicity. The food carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) undergoes activation via N-hydroxylation by cytochrome P450 1A2, followed by O-esterification by N-acetyltransferase. We examined the effects of the Ah locus and acetylator polymorphisms (implicated in human colon and bladder cancer risk) on levels of 32P-postlabeled IQ-DNA adducts in C57BL/6 mice congenic for slow acetylation and/or Ah nonresponsiveness. Some were pretreated with beta-naphthoflavone (beta NF), an inducer of cytochromes P450 1A. Guanine adducts were detected in all organs, the predominant one corresponding to N2-(deoxyguanosine-8-yl)-IQ. In the kidney, beta NF pretreatment reduced total adducts by 50% in Ah-responsive animals (P = 0.021); the Ah or acetylator phenotype did not otherwise affect total adducts. In the colon of Ah-nonresponsive animals, rapid acetylators had 3-fold more adducts than slow acetylators (P = 0.0001, vehicle-pretreated; P = 0.0031, beta NF-pretreated). In Ah-responsive mice of either acetylator phenotype, beta NF pretreatment reduced total adducts in the colon by 70% (P = 0.0003). A significant interaction of phenotypes occurred in the bladder; beta NF-pretreatment caused a 2.5-fold increase in adducts but only in the Ah-responsive, rapid acetylator mice. In sum, these polymorphisms influenced the level of IQ-DNA adducts in the kidney, urinary bladder, and colon in complex ways.
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Arilamina N-Acetiltransferasa/genética , Carcinógenos/metabolismo , Carcinógenos/toxicidad , Colon/efectos de los fármacos , Colon/metabolismo , Aductos de ADN/biosíntesis , ADN/efectos de los fármacos , ADN/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Quinolinas/metabolismo , Quinolinas/toxicidad , Receptores de Hidrocarburo de Aril/genética , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Acetilación , Animales , Arilamina N-Acetiltransferasa/metabolismo , Citocromo P-450 CYP1A2 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Genotipo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Fenotipo , Polimorfismo GenéticoRESUMEN
2-Amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) is known to induce colon tumors in male Fischer-344 rats. Using 32P-postlabeling assays, we have examined PhIP-DNA adduct formation in various organs and white blood cells (WBCs) of the male Fischer-344 rat 24 h after a single oral dose of 0, 0.5, 5 or 50 mg PhIP/kg. Three PhIP-DNA adducts were detected in WBCs and in all organs, except in the liver and stomach which had only two adducts. The extent of adduct formation was dose-related, but at 0.5 mg/kg no adducts could be detected in any of the organs. At 50 mg/kg, adduct levels, expressed as relative adduct labeling values (RAL x 10(7), or adducts per 10(7) nucleotides assuming complete labeling) were highest in the large intestine (5.66), followed by WBCs (5.04), stomach (1.44), small intestine (1.32), kidney (1.16), liver (0.67) and lungs (0.52). It is concluded that orally administered PhIP forms high levels of specific DNA adducts in the large intestine, the target organ in PhIP carcinogenesis in the male Fischer-344 rat, and that the high level of adducts in WBCs indicates that significant amounts of the ultimate carcinogenic form of PhIP are present in the circulation.
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ADN/efectos de los fármacos , Imidazoles/toxicidad , Mutágenos/toxicidad , Animales , Neoplasias del Colon/etiología , ADN/aislamiento & purificación , Masculino , Radioisótopos de Fósforo , Ratas , Ratas Endogámicas F344RESUMEN
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), a potent bacterial mutagen present in broiled sardines, cooked beef and beef extract, is a carcinogen in the F-344 rat, affecting mainly the liver and small and large intestines. Using 32P-postlabeling assays, the formation of IQ-DNA adducts was examined in male F-344 rats. Twenty-four hours after i.p. doses (5-50 mg IQ/kg) the liver, small and large intestine each showed the presence of 5 adducts, the liver and large intestine having an average of 18.1 and 2.4 times as many adducts, respectively, as the small intestine. None of these adducts could be detected in vehicle-treated animals. It is concluded that IQ forms specific DNA adducts in target tissues of the F-344 rat.
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Carcinógenos/metabolismo , ADN/metabolismo , Mutágenos/metabolismo , Quinolinas/metabolismo , Animales , Biotransformación , Neoplasias Intestinales/inducido químicamente , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
In vivo and in vitro covalent DNA binding was investigated in an attempt to explain the higher susceptibility of A/J mouse lung and Fischer-344 rat trachea to 7,12-dimethylbenz[a]anthracene (DMBA) as compared to benzo[a]pyrene (BP), and to evaluate the relative susceptibility of the human respiratory tract to these compounds. After in vivo administration of either BP or DMBA to A/J mice covalent DNA binding was higher in the liver than in the lungs. Forty-eight hours after administration, but not before, binding of DMBA was higher than that of BP in both organs. In vitro studies using cultured explants of both human and A/J mouse peripheral lung, as well as human bronchus and Fischer-344 rat trachea, revealed that covalent DNA binding of DMBA to mouse lung and rat trachea were similar and that both were significantly higher than that of BP to these organs. Binding of BP and DMBA was similar in both human tissues and did not differ from BP binding in the animal tissues. Enzymatic hydrolysis and HPLC separation of the DNA-hydrocarbon adducts revealed that patterns of adducts in human and mouse peripheral lung were similar and qualitatively resembled known patterns in other target and non-target tissues. It is concluded that the higher susceptibility of the mouse lung and rat trachea to DMBA as compared to BP may be related to the higher covalent DNA binding of the former and that the relative carcinogenic risk of the human respiratory tract after exposure to DMBA may be the same as that after BP exposure.
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9,10-Dimetil-1,2-benzantraceno/metabolismo , Benzo(a)pireno/metabolismo , ADN/metabolismo , Sistema Respiratorio/metabolismo , Animales , Bronquios/metabolismo , Humanos , Hígado/metabolismo , Pulmón/metabolismo , Ratones , Neoplasias Experimentales/inducido químicamente , Ratas , Tráquea/metabolismoRESUMEN
The binding to DNA of 4,4'-methylene-bis(2-chloroaniline) (MOCA) in explant cultures of human and dog bladder was compared. The DNA binding of MOCA in both human and dog bladder explants increased with the concentration of MOCA in the medium. In both species, there appeared to be a population with high DNA binding activity and another with low DNA binding activity. Furthermore, the binding of MOCA to human bladder DNA appeared to be higher than to dog bladder DNA. The results indicate the potential of MOCA to induce genetic damage in human bladder and suggest caution in the occupational exposure of humans to this chemical.
Asunto(s)
Compuestos de Bencidrilo/metabolismo , ADN/metabolismo , Metilenobis (cloroanilina)/metabolismo , Vejiga Urinaria/metabolismo , Animales , Perros , Humanos , Leucina/metabolismo , Metilenobis (cloroanilina)/toxicidad , Técnicas de Cultivo de Órganos , Especificidad de la Especie , Timidina/metabolismo , Neoplasias de la Vejiga Urinaria/inducido químicamenteRESUMEN
We investigated the ability of the mammary gland to metabolically activate 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Although mammary gland microsomes had almost no capacity to metabolically activate the parent compounds, mammary gland cytosol was able to esterify the N-hydroxylamines. Acetyltransferase was the primary enzyme responsible for the phase II activation of the N-hydroxylamines. The level of acetyl CoA-stimulated binding when N-hydroxy PhIP served as the substrate was approximately 3- and 17-fold higher than when IQ and MeIQx served as substrates, respectively. N-Hydroxy-IQ and N-hydroxy PhIP can also be activated by tRNA synthetase and phosphatase, but not by sulfotransferase. However, the levels of proline- and ATP-enhanced DNA binding was approximately 30- and 60-fold lower than the acetyl CoA-enhanced DNA binding of IQ and PhIP, respectively. Differences observed in the phase II activation of the various heterocyclic amines in the mammary gland may explain why the mammary gland is a target organ for PhIP-induced carcinogenicity but not for IQ- or MeIQx-induced carcinogenicity in Fischer 344 rats.
Asunto(s)
Aminas/farmacocinética , Compuestos Heterocíclicos/farmacocinética , Lactancia , Glándulas Mamarias Animales/metabolismo , Mutágenos/farmacocinética , Acetil-CoA C-Acetiltransferasa/metabolismo , Aminoacil-ARNt Sintetasas/metabolismo , Animales , Autorradiografía , Biotransformación , ADN/metabolismo , Femenino , Alimentos , Imidazoles/farmacocinética , Hígado/enzimología , Hígado/metabolismo , Glándulas Mamarias Animales/enzimología , Microsomas/metabolismo , Pruebas de Mutagenicidad , Quinolinas/farmacocinética , Ratas , Ratas Endogámicas F344RESUMEN
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine (HCA) found in cooked meats, causes colon and prostate tumors in male rats. Polymorphic N-acetyltransferase metabolizes N-hydroxy-PhIP to a DNA-reactive form. Liver, colon, and prostate PhIP-DNA adduct levels were compared in male rapid-acetylator Fischer 344 (F344) and slow-acetylator Wistar-Kyoto (WKY) rats fed 0.01 or 0.04% PhIP. Liver PhIP-DNA adduct levels at both PhIP doses, and colon PhIP-DNA adduct levels at the 0.01% PhIP dose were unaffected by acetylator genotype. However, in rats fed 0.04% PhIP, colon PhIP-DNA adduct levels were higher in rapid acetylator F344 rats (P < 0.05). Similarly, prostate PhIP-DNA adduct levels were higher in rapid acetylator F344 rats at both PhIP doses (P < 0.05). The combination of the high-PhIP dose and rapid-acetylator genotype resulted in the highest level of PhIP-DNA adducts in rat colon and prostate.
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Carcinógenos/administración & dosificación , Colon/metabolismo , Aductos de ADN/metabolismo , Imidazoles/administración & dosificación , Próstata/metabolismo , Animales , Neoplasias del Colon/etiología , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Aductos de ADN/genética , Predisposición Genética a la Enfermedad , Masculino , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas WKY , Especificidad de la EspecieRESUMEN
The elimination and metabolism of a single dose (100 mg/kg) of 2,4-dinitrotoluene (2,4-DNT) in A/J mice were examined. After intraperitoneal administration, elimination was rapid, with 70% of the dose appearing in the urine within 4 hr. Four hours after oral administration, only 28.5% of the dose was excreted in the urine, which increased to 66% after 8 hr. Elimination via the feces was minimal (less than 2.1% of the dose) in both cases. From 0.5 to 4 hr after intraperitoneal administration, 3.6 to 8.8% of the urinary metabolites was unconjugated while 2.4 to 8.8% was present in the glucuronide fraction. After oral administration these amounts were 5.5 to 6.8% and 20.5 to 28.2% respectively. After both intraperitoneal and oral administration, no unchanged 2,4-DNT could be detected in the urine, and 2,4-dinitrobenzyl alcohol (2,4-DNBAlc) represented the most abundant identifiable neutral metabolite. Small amounts of 2,4-diaminotoluene, 2-amino-4-nitrobenzyl alcohol, 2-(N-acetyl)amino-4-nitrotoluene, 4-amino-2-nitrotoluene (4A2NT), and 2-amino-4-nitrotoluene (2A4NT) were also present. In almost all cases the largest proportion of metabolites represented unknowns, some of which exhibited the chromatographic properties of carboxylic acid metabolites. Metabolism of 2,4-DNT by liver and lung microsomes yielded mainly 2,4-DNBAlc with lower amounts of 4A2NT and 2A4NT, and their formation was dependent on the presence of oxygen and NADPH. Pretreatment of the animals with 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in increased yields of all three metabolites. Aerobic metabolism of 2,4-DNT by explants of the small intestine, large intestine, or by cecal contents yielded 2,4-DNBAlc, 2A4NT, 4A2NT and 4-(N-acetyl)amino-2-nitrotoluene (4Ac2NT). The proportion of reduced metabolites (2A4NT, 4A2NT, and 4Ac2NT) was much higher in these systems than with liver or lung microsomes and their formation by small intestine and cecal contents was enhanced several-fold under anaerobic conditions, while that of 2,4-DNBAlc was abolished. It is concluded that 2,4-DNT metabolism in the A/J mouse is rapid and complete and that the major neutral urinary metabolite is 2,4-DNBAlc. Minor amounts of reduced or partially reduced products appear to be formed mainly in the intestine, with a major role by its microflora.
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Carcinógenos/metabolismo , Dinitrobencenos/metabolismo , Nitrobencenos/metabolismo , Acetilación , Animales , Glucuronatos/metabolismo , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Oxidación-Reducción , Dibenzodioxinas Policloradas/farmacología , Especificidad de la EspecieRESUMEN
In numerous in vivo systems it has been shown that diets high in menhaden oil (a fish oil high in omega-3 fatty acids) can inhibit the carcinogenic process. In the present study, we have assessed the effects of a diet containing menhaden oil on 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA adduct formation in target tissues of the male Fischer 344 rat. Young adult male Fischer 344 rats were maintained on either a) an AIN-76A diet containing 5% corn oil, b) an isocaloric AIN-76A diet modified to contain 2% corn oil and 19% menhaden oil (MO diet), or c) a regular laboratory rodent diet (chow diet) for 6 weeks prior to receiving a single oral dose of 10 or 50 mg IQ/kg. Groups of four animals were killed 1 or 6 days after IQ administration. Using 32P-postlabeling assays, IQ-DNA adducts were isolated and quantitated in the liver, small intestine, and large intestine. Adduct patterns were similar in all cases. Adduct levels, expressed as relative adduct labeling values (RAL x 10(7)), were related to dose in all three tissues, with liver levels up to 10-fold higher than the large intestine and up to 20-fold higher than the small intestine. On day one, liver adduct levels in animals on the AIN-76A diet were similar to those in animals on the chow diet, but those in animals on the MO diet were approximately 2-fold lower.(ABSTRACT TRUNCATED AT 250 WORDS)