Showing papers on "Toxicity published in 2006"
Children's Hospital of Philadelphia1, University of Pennsylvania2, Stanford University3, University of Pittsburgh4, Royal Prince Alfred Hospital5, State University of Campinas6, University of Texas Health Science Center at Houston7, Christiana Care Health System8, Cornell University9, Wistar Institute10, Howard Hughes Medical Institute11
TL;DR: In this article, a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B.
Abstract: We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.
1,930 citations
TL;DR: It is concluded that human hepatotoxicity is highly concordant with in vitro cytotoxicity in this novel model and as detected by HCS.
Abstract: To develop and validate a practical, in vitro, cell-based model to assess human hepatotoxicity potential of drugs, we used the new technology of high content screening (HCS) and a novel combination of critical model features, including (1) use of live, human hepatocytes with drug metabolism capability, (2) preincubation of cells for 3 days with drugs at a range of concentrations up to at least 30 times the efficacious concentration or 100 μM, (3) measurement of multiple parameters that were (4) morphological and biochemical, (5) indicative of prelethal cytotoxic effects, (6) representative of different mechanisms of toxicity, (7) at the single cell level and (8) amenable to rapid throughput. HCS is based on automated epifluorescence microscopy and image analysis of cells in a microtiter plate format. The assay was applied to HepG2 human hepatocytes cultured in 96-well plates and loaded with four fluorescent dyes for: calcium (Fluo-4 AM), mitochondrial membrane potential (TMRM), DNA content (Hoechst 33342) to determine nuclear area and cell number and plasma membrane permeability (TOTO-3). Assay results were compared with those from 7 conventional, in vitro cytotoxicity assays that were applied to 611 compounds and shown to have low sensitivity (<25%), although high specificity (∼90%) for detection of toxic drugs. For 243 drugs with varying degrees of toxicity, the HCS, sublethal, cytotoxicity assay had a sensitivity of 93% and specificity of 98%. Drugs testing positive that did not cause hepatotoxicity produced other serious, human organ toxicities. For 201 positive assay results, 86% drugs affected cell number, 70% affected nuclear area and mitochondrial membrane potential and 45% affected membrane permeability and 41% intracellular calcium concentration. Cell number was the first parameter affected for 56% of these drugs, nuclear area for 34% and mitochondrial membrane potential for 29% and membrane permeability for 7% and intracellular calcium for 10%. Hormesis occurred for 48% of all drugs with positive response, for 26% of mitochondrial and 34% nuclear area changes and 12% of cell number changes. Pattern of change was dependent on the class of drug and mechanism of toxicity. The ratio of concentrations for in vitro cytotoxicity to maximal efficaciousness in humans was not different across groups (12±22). Human toxicity potential was detected with 80% sensitivity and 90% specificity at a concentration of 30× the maximal efficacious concentration or 100 μM when efficaciousness was not considered. We conclude that human hepatotoxicity is highly concordant with in vitro cytotoxicity in this novel model and as detected by HCS.
579 citations
TL;DR: What fraction of drug toxicity actually involves metabolism, and how species and human interindividual variations affect pharmacokinetics and toxicity are considered are considered.
Abstract: The cytochrome P450 (P450) enzymes are the major catalysts involved in the metabolism of drugs. bioavailability and toxicity are 2 of the most common barriers in drug development today, and P450 and the conjugation enzymes can influence these effects. The toxicity of drugs can be considered in 5 contexts: on-target toxicity, hypersensitivity and immunological reactions, off-target pharmacology, bioactivation to reactive intermediates, and idiosyncratic drug reactions. the chemistry of bioactivation is reasonably well understood, but the mechanisms underlying biological responses are not. In the article we consider what fraction of drug toxicity actually involves metabolism, and we examine how species and human interindividual variations affect pharmacokinetics and toxicity.
546 citations
TL;DR: In this article, quantitative structure-property relationship models are developed to assess the factors that govern the toxicity of a range of different ionic liquids to two aquatic organisms (Vibrio fischeri and Daphnia magna).
525 citations
TL;DR: Further research is needed to ascertain the areas of the world in which subclinical toxicity exists and to evaluate its effects on overall health and well-being, because emerging evidence suggests that subtoxicity without clinical signs of toxicity may be a growing concern.
450 citations
TL;DR: In this article, the effects of 13 drugs merged to mimic both the association and low concentration (ng/L) profiles detected in the environment were investigated, with the highest effect observed as a 30% decrease in cell proliferation compared to controls.
Abstract: The potential risk associated with the presence of low levels of pharmaceuticals in aquatic environments is currently under debate. In this study we investigated the effects of 13 drugs merged to mimic both the association and low concentration (ng/L) profiles detected in the environment. The mixture comprised atenolol, bezafibrate, carbamazepine, cyclophosphamide, ciprofloxacin, furosemide, hydrochlorothiazide, ibuprofen, lincomycin, ofloxacin, ranitidine, salbutamol, and sulfamethoxazole. At environmental exposure levels, the drug mix inhibited the growth of human embryonic cells HEK293, with the highest effect observed as a 30% decrease in cell proliferation compared to controls. Pharmaceuticals activated stress-response signaling protein kinases (ERK1/2), and induced overexpression of glutathione-S-transferase P1 gene. No evidence was found for apoptosis or necrosis in HEK293 cells, although morphological changes were observed. The drug mixture effectively stimulated the expression of cell-cycle progression-mediating genes p16 and p21, with a slight accumulation of cells in the G2/M phase of the cell-cycle. Our results suggest that a mixture of drugs at ng/L levels can inhibit cells proliferation by affecting their physiology and morphology. This also suggests that water-borne pharmaceuticals can be potential effectors on aquatic life.
438 citations
TL;DR: It is found that surface area is the variable that best predicts the potential toxicity of these refined carbon nanomaterials, in which SWCNTs induced the strongest cellular apoptosis/necrosis.
391 citations
TL;DR: The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials.
Abstract: Purpose UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent. Patients and Methods In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy. Results UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (O...
326 citations
TL;DR: Histologic and ERG results in all groups showed no retinal toxicity of varying doses of bevacizumab when injected intravitreally in rabbits, however, some inflammatory cells were found in the vitreous at the 5–mg dose.
Abstract: Purpose:To evaluate the retinal toxicity of varying doses of bevacizumab when injected intravitreally in rabbits. Bevacizumab has been approved by the US Food and Drug Administration for the treatment of metastatic colorectal cancer.Materials and Methods:Twelve New Zealand albino rabbits were used f
316 citations
TL;DR: With long-term follow-up for toxicity, it is demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC.
Abstract: Purpose: We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non–small-cell lung cancer (NSCLC) by quantifying the dose–volume toxicity relationship of the lung. Methods and Materials: A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months. Results: There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly ( p Conclusions: With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose–volume toxicity–based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients.
306 citations
DSM1
TL;DR: From these studies a no-observed adverse effect level of 500 mg EGCG preparation/kg/day was established, and this dose caused morbidity when administered to fasted dogs as a single bolus dose, although this model was considered an unrealistic comparison to the human condition.
TL;DR: It is concluded that severe renal damage could occur in the N-Zn treated mice, though no significant change of blood biochemical levels occurred, which indicated that N- Zn powder could cause severe anemia.
01 Jan 2006
TL;DR: Mechanisms by which heme can exert biological damage, together with a wide spectrum of adaptations developed by blood-feeding insects and ticks to counteract its deleterious effects are reviewed.
Abstract: A blood-sucking habit appeared independently several times in the course of arthropod evolution. However, from more than a million species of insects and arachnids presently living on earth, only about 14,000 species developed the capacity to feed on vertebrate blood. This figure suggests the existence of severe physiological constraints for the evolution of hematophagy, implying the selective advantage of special adaptations related to the use of blood as a food source. Digestion of vertebrate hemoglobin in the midgut of blood-feeding arthropods results in the production of large amounts of heme, a potentially cytotoxic molecule. Here we will review mechanisms by which heme can exert biological damage, together with a wide spectrum of adaptations developed by blood-feeding insects and ticks to counteract its deleterious effects. In spite of the existence of a great molecular diversity of protective mechanisms, different hematophagous organisms developed convergent solutions that may be physiologically equivalent. r 2006 Elsevier Ltd. All rights reserved.
TL;DR: It is concluded that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose.
Abstract: Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer Silybin-phytosome is a commercially available formulation containing silibinin This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose Silybin-phytosome was administered orally to prostate cancer patients, giving 25-20 g daily, in three divided doses Each course was 4 weeks in duration Thirteen patients received a total of 91 courses of silybin-phytosome Baseline patient characteristics included: median age of 70 years, median baseline prostate specific antigen (PSA) of 43 ng/ml, and a median ECOG performance status of 0 The most prominent adverse event was hyperbilirubinemia, with grade 1-2 bilirubin elevations in 9 of the 13 patients The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was noted No objective PSA responses were observed We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose Asymptomatic liver toxicity is the most commonly seen adverse event
TL;DR: It is demonstrated here that coexposure of zebrafish embryos to the PAH-type AHR agonist beta-naphthoflavone (BNF) and the CYP1A inhibitor alpha- naphth oflav one (ANF) significantly enhanced toxicity above that observed for single-compound exposures, and suggested that mechanisms underlying developmental toxicity of PAH -type A HR agonists are different from those of pHAHs.
TL;DR: Higher serum levels and prolonged administration of anti-CTLA-4 antibody resulted in a trend toward a greater incidence of grade III/IV autoimmune toxicity than previously reported, but did not seem to increase objective response rates.
Abstract: We previously reported our experience in treating 56 patients with metastatic melanoma using a human anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody. Durable tumor regressions were seen that correlated with the induction of autoimmune toxicities. In this study, we treated 46 additional patients using an intrapatient dose escalation schema to test whether higher doses of anti-CTLA-4 antibody would induce increased autoimmunity and concomitant tumor regression. Twenty-three patients started anti-CTLA-4 antibody administration at 3 mg/kg and 23 patients started treatment at 5 mg/kg, receiving doses every 3 weeks. Patients were dose-escalated every other dose to a maximum of 9 mg/kg or until objective clinical responses or grade III/IV autoimmune toxicity were seen. Escalating doses of antibody resulted in proportionally higher plasma concentrations. Sixteen patients (35%) experienced a grade III/IV autoimmune toxicity. Five patients (11%) achieved an objective clinical response. Two of the responses are ongoing at 13 and 16 months, respectively. Flow cytometric analysis of peripheral blood revealed significant increases in both T-cell surface markers of activation and memory phenotype. Thus, higher serum levels and prolonged administration of anti-CTLA-4 antibody resulted in a trend toward a greater incidence of grade III/IV autoimmune toxicity than previously reported, but did not seem to increase objective response rates.
TL;DR: Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described, and only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity.
Abstract: Purpose: The α/β ratio for prostate cancer is postulated to be between 1 and 3, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. The dosimetry and acute toxicity are described in the first 100 men enrolled in a randomized trial. Patients and Methods: The trial compares 76 Gy in 38 fractions (Arm I) to 70.2 Gy in 26 fractions (Arm II) using intensity modulated radiotherapy. The planning target volume (PTV) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions. The PTV D95% was at least the prescription dose. Results: The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy. There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity acutely. However, there was a slight but significant increase in Arm II GI toxicity during Weeks 2, 3, and 4. In multivariate analyses, only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity. Conclusion: Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described.
TL;DR: The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug-induced diarrhea, with implications for optimizing treatment with such agents.
Abstract: Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non-small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related adverse events that potentially limit its use. Gefitinib is a substrate for ABCG2 (ABCP, BCRP, MXR), a polymorphic efflux transporter protein that is highly expressed in the intestines and liver. Here we investigated associations between allelic variants of EGFR, ABCG2, and the transporter protein ABCB1 with diarrhea and skin toxicity in gefitinib-treated patients. One variant, a common functional single-nucleotide polymorphism (SNP) in the ABCG2 gene, was associated with diarrhea in 124 patients treated with oral gefitinib 250 mg once daily; seven (44%) of 16 patients heterozygous for ABCG2 421C>A (Q141K) developed diarrhea, versus only 13 (12%) of 108 patients homozygous for the wild-type sequence (P = .0046). However, this SNP was not associated with skin toxicity (P = .99). The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug-induced diarrhea, with implications for optimizing treatment with such agents.
TL;DR: A complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity is indicated, for parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon.
Abstract: A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity ...
TL;DR: Significant pharmacokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be necessary.
TL;DR: Results show that MCs exposure induces adaptive responses such as increase in the antioxidant enzymatic activities, mainly those of SOD and CAT, as well as in LPO values.
TL;DR: The use of linezolid with medications that increase concentrations of serotonin in the central nervous system may result in serotonin toxicity, and doctors and patients should be cognizant of signs and symptoms of serotonin toxicity and should initiate appropriate measures if such symptoms develop.
Abstract: Background: Linezolid is the first oxazolidinone antimicrobial marketed in the United States. It exhibits monoamine oxidase (MAO) type A and MAO type B inhibitory effects. The concomitant administration of nonselective MAO inhibitors or MAO‐A inhibitors with drugs that increase serotonin concentrations is associated with serotonin toxicity.
Methods: We requested from the US Food and Drug Administration all postmarketing adverse event reports regarding linezolid that included serotonin toxicity or any report describing cognitive or behavioral symptoms and autonomic and neuromuscular excitability. We assessed the case summaries obtained from the Adverse Event Reporting System database for serotonin toxicity. A case of serotonin toxicity was defined as having the following: (1) linezolid as the primary suspect drug; (2) concurrent administration of 1 secondary suspect drug known to increase serotonin concentrations in the central nervous system; and (3) serotonin toxicity, as defined by the modified Hunter Serotonin Toxicity Criteria or by the reporter.
Results: Twenty‐nine cases were classified as serotonin toxicity. Patients' ages ranged from 17–83 years, and the ratio of females to males was 1:1. The most common class of drugs received concurrently with linezolid was selective serotonin reuptake inhibitors (26 of 43 patients). Thirteen patients required an intervention to prevent permanent impairment or required hospitalization for the adverse event.
Conclusion: The use of linezolid with medications that increase concentrations of serotonin in the central nervous system may result in serotonin toxicity. Prescribers must weigh risks and benefits of this combination. Patients and prescribers should be cognizant of signs and symptoms of serotonin toxicity and should initiate appropriate measures if such symptoms develop.
TL;DR: These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity, and the growing use of molecular and genomic tools for research on zebrafish have led to advances in understanding of the mechanism of TCDd developmental toxicity at the molecular level.
Abstract: Zebrafish (Danio rerio) have advantages over mammals as an animal model for investigating developmental toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a persistent global contaminant, is the most comprehensively studied developmental toxicant in zebrafish. The hallmark responses of TCDD developmental toxicity manifested in zebrafish larvae include edema, anemia, hemorrhage, and ischemia associated with arrested growth and development. Heart and vasculature development and function are severely impaired, and jaw malformations occur secondary to inhibited chondrogenesis. The swim bladder fails to inflate, and the switch from embryonic to adult erythropoiesis is blocked. This profile of developmental toxicity responses, commonly referred to as "blue sac syndrome" because the edematous yolk sac appears blue, is observed in the larval form of all freshwater fish species exposed to TCDD at the embryonic stage of development. Components of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AHR/ARNT) signaling pathway in zebrafish have been identified and functionally characterized. Their role in mediating TCDD toxicity has been determined using morpholinos to specifically knockdown the translation of zfAHR1, zfAHR2, zfARNT1, and zfARNT2 mRNAs, respectively, and a line of zfARNT2 null mutant zebrafish has provided further insight. These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity. In addition, the growing use of molecular and genomic tools for research on zebrafish have led to advances in our understanding of the mechanism of TCDD developmental toxicity at the molecular level, including the recent finding that toxicity is not mediated by increased cytochrome P4501A (zfCYP1A) expression.
TL;DR: Fullerenes did not cause genetic damage in Salmonella typhimurium TA100, TA1535, TA98 and TA1537 and Escherichia coli WP2uvrA/pKM101 and were not of high toxicological significance.
TL;DR: The results indicate that the anti-cancer effect of endo-polysaccharide is not directly tumorcidal but rather is immuno-stimulating.
TL;DR: The induction in hepatic glutathione- S -transferase (GST) levels indicates the protection against the toxicity of xenobiotic-induced lipid peroxidation and the increase of biomarker enzymes in plasma might be due to the necrosis of liver.
TL;DR: The findings of the present study suggest that beta-glucan, through its antioxidant and immunoregulatory effects, may be of therapeutic value in alleviating the leukocyte apoptosis, oxidative tissue injury and thereby the intestinal and hepatorenal side effects of methotrexate treatment.
TL;DR: Exposure to an environmental sample over 7 days confirmed the mussel sensitivity to water contaminants, detected both by the comet assay and the micronucleus test and allowed the golden mussel to be suggested as a potential biomonitor organism.
Abstract: The development of methodologies for biomonitoring freshwater ecosystems is of particular relevance in view of the serious problem of aquatic environmental pollution. The mussel species Limnoperna fortunei (golden mussel) was chosen to be tested as a biomonitor organism based on its population data and distribution. L. fortunei individuals were exposed to UV radiation in vitro, and in vivo to pentachlorophenol (PCP) and copper sulphate (CuSO(4)), with the aim of standardizing comet assay and micronucleus test methodologies and evaluating the potential of this organism as a biomonitor. Haemolymph cells immobilized in agarose on slides exposed to UV radiation showed a dose-response relationship with maximum damage at 4.2 J/m(2). For the chemical tests, individuals were exposed for 2h for the comet assay and 24 and 48 h for the micronucleus test. A dose-response relationship was observed for both chemicals. 3x10(-5) M CuSO(4) induced high genotoxicity, also producing some toxicity after 48 h of exposure. PCP induced maximum damage in both assays at 150 μg/L. Individuals exposed to PCP showed 100% repair 2 h after the exposure period, as assessed by the comet assay. Exposure to an environmental sample over 7 days confirmed the mussel sensitivity to water contaminants, detected both by the comet assay and the micronucleus test. The results allow us to suggest the golden mussel as a potential biomonitor organism.
TL;DR: Acute GI toxicity is an independent significant predictor of lateGI toxicity, and suggests a significant consequential component in the development of late GI toxicity.
Abstract: Purpose: Late gastrointestinal (GI) toxicity after radiotherapy can be partly explained by late effects of acute toxicity (consequential late damage) We studied whether there is a direct relationship between acute and late GI toxicity Patients and Methods: A total of 553 evaluable patients from the Dutch dose escalation trial (68 Gy vs 78 Gy) were included We defined three outcomes for acute reactions: 1) maximum Radiation Therapy Oncology Group acute toxicity, 2) maximum acute mucous discharge (AMD), and 3) maximum acute proctitis Within a multivariable model, late endpoints (overall toxicity and five toxicity indicators) were studied as a function of acute toxicity, pretreatment symptoms, and relevant dose parameters Results: At multivariable analysis, AMD and acute proctitis were strong predictors for overall toxicity, “intermittent bleeding,” and “incontinence pads” (p ≤ 001) For “stools ≥6/day” all three were strong predictors No significant associations were found for “severe bleeding” and “use of steroids” The predictive power of the dose parameters remained at the same level or became weaker for most late endpoints Conclusions: Acute GI toxicity is an independent significant predictor of late GI toxicity This suggests a significant consequential component in the development of late GI toxicity
TL;DR: It is concluded that resveratrol in the diet can reduce susceptibility to mammary cancer, while EGCG in the drinking water at the dose used was not effective.
Abstract: Despite the advent of new and aggressive therapeutics, breast cancer remains a leading killer among women; hence there is a need for the prevention of this disease. Several naturally occurring polyphenols have received much attention for their health benefits, including anti-carcinogenic properties. Two of these are resveratrol, a component of red grapes, and epigallocatechin-3-gallate (EGCG), the major catechin found in green tea. In this study, we tested the hypothesis that these two polyphenols protect against chemically-induced mammary cancer by modulating mammary gland architecture, cell proliferation, and apoptosis. Female Sprague-Dawley CD rats were exposed to either resveratrol (1 g/kg AIN-76A diet), EGCG (0.065% in the drinking water), or control diet (AIN-76A) for the entirety of their life starting at birth. At 50 days postpartum, rats were treated with 60 mg dimethylbenz[a]anthracene (DMBA)/kg body weight to induce mammary cancer. Resveratrol, but not EGCG, suppressed mammary carcinogenesis (fewer tumors per rat and longer tumor latency). Analysis of mammary whole mounts from 50-day-old rats revealed that resveratrol, but not EGCG, treatment resulted in more differentiated lobular structures. Bromodeoxyuridine (BrdU) incorporation studies showed that resveratrol treatment caused a significant reduction in proliferative cells in mammary terminal ductal structures at 50 days postpartum, making them less susceptible to carcinogen insult. The epithelial cells of terminal end buds in the mammary glands of resveratrol-treated rats also showed an increase in apoptotic cells compared to the control or EGCG-treated rats as measured by a DNA fragmentation assay. At the given doses, resveratrol treatment resulted in a serum resveratrol concentration of 2.00 μM, while treatment with EGCG resulted in a serum EGCG concentration of 31.06 nM. 17β-Estradiol, progesterone, and prolactin concentrations in the serum were not significantly affected by resveratrol or EGCG. Neither polyphenol treatment resulted in toxicity as tested by alterations in body weights, diet and drink consumptions, and day to vaginal opening. We conclude that resveratrol in the diet can reduce susceptibility to mammary cancer, while EGCG in the drinking water at the dose used was not effective.