Showing papers on "Toxicity published in 2005"
TL;DR: The microscopic studies demonstrated that nanoparticle-exposed cells at higher doses became abnormal in size, displaying cellular shrinkage, and an acquisition of an irregular shape, which suggested that cytotoxicity of Ag (15, 100 nm) in liver cells is likely to be mediated through oxidative stress.
1,949 citations
TL;DR: It is concluded that HP-beta-CD is well tolerated in the animal species tested (rats, mice and dogs), particularly when dosed orally, and shows only limited toxicity, and in short duration studies, there were slight biochemical changes whereas studies of a longer duration produced additional minor haematological changes but no histopathological changes.
633 citations
TL;DR: The role of phosphorylation of Ser129 in α-synuclein toxicity and inclusion formation is defined using a Drosophila model of Parkinson disease to show that increased number of inclusion bodies correlates with reduced toxicity, and inclusion bodies may protect neurons from α- synucleinoxicity.
Abstract: α-Synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies. These inclusion bodies are the characteristic pathologic lesions of Parkinson disease. Here we define the role of phosphorylation of Ser129 in α-synuclein toxicity and inclusion formation using a Drosophila model of Parkinson disease. Mutation of Ser129 to alanine to prevent phosphorylation completely suppresses dopaminergic neuronal loss produced by expression of human α-synuclein. In contrast, altering Ser129 to the negatively charged residue aspartate, to mimic phosphorylation, significantly enhances α-synuclein toxicity. The G protein–coupled receptor kinase 2 (Gprk2) phosphorylates Ser129 in vivo and enhances α-synuclein toxicity. Blocking phosphorylation at Ser129 substantially increases aggregate formation. Thus Ser129 phosphorylation status is crucial in mediating α-synuclein neurotoxicity and inclusion formation. Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from α-synuclein toxicity.
587 citations
TL;DR: Results show that aqueous C(60) suspensions prepared without using any polar organic solvent not only have no acute or subacute toxicity in rodents but they also protect their livers in a dose-dependent manner against free-radical damage.
Abstract: In the present work, we report the effects of C(60)-pretreatments on acute carbon tetrachloride intoxication in rats, a classical model for studying free-radical-mediated liver injury. Our results show that aqueous C(60) suspensions prepared without using any polar organic solvent not only have no acute or subacute toxicity in rodents but they also protect their livers in a dose-dependent manner against free-radical damage. To be sure, according to histopathological examinations and biological tests, pristine C(60) can be considered as a powerful liver-protective agent.
572 citations
TL;DR: To establish the role of CYP2E1-null mice in toxicity and carcinogenicity in vivo, gene knockout mice have been developed and activation of this pathway inhibits apoptotic cell death stimulated by reactive oxygen generating chemicals but accelerates necrotic cell death produced by polyunsaturated fatty acids.
Abstract: Cytochromes P450 are responsible for metabolism of most xenobiotics and are required for the efficient elimination of foreign chemicals from the body. Paradoxically, these enzymes also metabolically activate biologically inert compounds to electrophilic derivatives that can cause toxicity, cell death and sometimes cellular transformation resulting in cancer. To establish the role of these enzymes in toxicity and carcinogenicity in vivo, gene knockout mice have been developed. To illustrate the role of P450s in toxicity, CYP2E1-null mice were employed with the commonly used analgesic drug acetaminophen. CYP2E1 is the rate-limiting enzyme that initiates the cascade of events leading to acetaminophen hepatotoxicity; in the absence of this P450, toxicity will only be apparent at high concentrations. Other enzymes and nuclear receptors are also involved in activation or inactivating chemicals. CYP2E1 is induced by alcohol and the primary P450 that carries out ethanol oxidation that can lead to the production of activated oxygen species and oxidative stress that elevate ERK1/2 phosphorylation through EGRF/c-Raf signaling. Paradoxically, activation of this pathway inhibits apoptotic cell death stimulated by reactive oxygen generating chemicals but accelerates necrotic cell death produced by polyunsaturated fatty acids. CYP2E1 is thought to contribute to liver pathologies that result from alcoholic liver disease and non-alcoholic steatohepatitis.
516 citations
470 citations
TL;DR: Results from tests with the crustacean Daphnia magna and fathead minnow showed limited toxicity with no‐observed‐effect concentrations at or near 10 mg/L, however, the selective toxicity of these compounds may have implications for aquatic community structure.
Abstract: Toxicity tests were performed with seven fluoroquinolone antibiotics, ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin, clinafloxacin, enrofloxacin, and flumequine, on five aquatic organisms. Overall toxicity values ranged from 7.9 to 23,000 μg/L. The cyanobacterium Microcystis aeruginosa was the most sensitive organism (5-d growth and reproduction, effective concentrations [EC50s] ranging from 7.9 to 1,960 μg/L and a median of 49 μg/L), followed by duckweed (Lemna minor, 7-d reproduction, EC50 values ranged from 53 to 2,470 μg/L with a median of 106 μg/L) and the green alga Pseudokirchneriella subcapitata (3-d growth and reproduction, EC50 values ranged from 1,100 to 22,700 μg/L with a median 7,400 μg/L). Results from tests with the crustacean Daphnia magna (48-h survival) and fathead minnow (Pimephales promelas, 7-d early life stage survival and growth) showed limited toxicity with no-observed-effect concentrations at or near 10 mg/L. Fish dry weights obtained in the ciprofloxacin, levofloxacin, and ofloxacin treatments (10 mg/L) were significantly higher than in control fish. The hazard of adverse effects occurring to the tested organisms in the environment was quantified by using hazard quotients. An estimated environmental concentration of 1 μg/L was chosen based on measured environmental concentrations previously reported in surface water; at this level, only M. aeruginosa may be at risk in surface water. However, the selective toxicity of these compounds may have implications for aquatic community structure.
432 citations
University of California, San Francisco1, Harvard University2, University of California, Los Angeles3, University of Michigan4, University of Virginia5, University of Texas MD Anderson Cancer Center6, University of Texas at Austin7, Memorial Sloan Kettering Cancer Center8, University of Texas at San Antonio9, National Institutes of Health10
TL;DR: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM, and the low toxicity profile may merit exploration in combination with other modalities.
Abstract: Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug. Experimental Design: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival. Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks. Conclusions: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.
386 citations
TL;DR: Zinc administration to chlorpyrifos-treated animals resulted in overall improvement in the hepatic histoarchitecture, emphasizing the protective potential of zinc.
369 citations
319 citations
TL;DR: Data from mouse hepatocytes used to determine the role of mitochondrial permeability transition (MPT) in acetaminophen (APAP) toxicity are consistent with a hypothesis where APAP-induced cell death occurs by two phases, a metabolic phase and an oxidative phase.
Abstract: Freshly isolated mouse hepatocytes were used to determine the role of mitochondrial permeability transition (MPT) in acetaminophen (APAP) toxicity. Incubation of APAP (1 mM) with hepatocytes resulted in cell death as indicated by increased alanine aminotransferase in the media and propidium iodide fluorescence. To separate metabolic events from later events in toxicity, hepatocytes were preincubated with APAP for 2 h followed by centrifugation of the cells and resuspension of the pellet to remove the drug and reincubating the cells in media alone. At 2 h, toxicity was not significantly different between control and APAP-incubated cells; however, preincubation with APAP followed by reincubation with media alone resulted in a marked increase in toxicity at 3 to 5 h that was not different from incubation with APAP for the entire time. Inclusion of cyclosporine A, trifluoperazine, dithiothreitol (DTT), or N-acetylcysteine (NAC) in the reincubation phase prevented hepatocyte toxicity. Dichlorofluorescein fluorescence increased during the reincubation phase, indicating increased oxidative stress. Tetramethylrhodamine methyl ester perchlorate fluorescence decreased during the reincubation phase indicating a loss of mitochondrial membrane potential. Inclusion of cyclosporine A, DTT, or NAC decreased oxidative stress and loss of mitochondrial membrane potential. Confocal microscopy studies with the dye calcein acetoxymethyl ester indicated that MPT had also occurred. These data are consistent with a hypothesis where APAP-induced cell death occurs by two phases, a metabolic phase and an oxidative phase. The metabolic phase occurs with GSH depletion and APAP-protein binding. The oxidative phase occurs with increased oxidative stress, loss of mitochondrial membrane potential, MPT, and toxicity.
TL;DR: Results indicate that over a short-term, a high-dose of selenite caused more pronounced oxidative stress, greater liver injury, and prominent retardation of growth as compared to Nano-Se.
Journal Article•
TL;DR: Patients with genotypes conferring low UGT1A7 activity and/or the UGT 1A9 (dT)(9/9) genotype may be particularly likely to exhibit greater antitumor response with little toxicity in CRC patients treated with capecitabine plus irinotecan.
Abstract: Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m 2 ) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m 2 , twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response ( p = 0.013) and lack of severe gastrointestinal toxicity ( p = 0.003). In addition, the UGT1A9 −118 (dT) 9/9 genotype was significantly associated with reduced toxicity ( p = 0.002) and increased response ( p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT) 9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.
TL;DR: Acute exposure to MCLR results in a decrease in the antioxidant enzymes and an increase in lipid peroxidation in liver and kidney rats, suggesting the oxidative stress as an important role in the pathogenesis of M CLR-induced toxicity.
TL;DR: It is concluded that Nrf2 may underlie a feedback system limiting oxidative load during chronic metabolic stress using antioxidant response element-dependent gene expression providing a potential mechanism for the increased sensitivity of NRF2–/– animals to 3-NP toxicity in vivo.
TL;DR: Combined treatment of lead-exposed animals with Vitamin C and silymarin showed marked improvement of the biochemical, molecular and histopathological findings, which strongly indicate the protective effect of VitaminC and sallymarin against toxic effects of lead on liver tissue.
TL;DR: Results of several studies indicate that the different xenobiotic-metabolising CYPs, present in the human lung and lung-derived cell lines, likely contribute to in situ activation of pulmonary toxins, among them, pro-carcinogens.
TL;DR: In the authors' ART dose escalation study, rectal wall or rectum relative > or =V50 are closely predictive for chronic rectal toxicity.
Abstract: Purpose We analyzed our experience treating localized prostate cancer with image-guided off-line correction with adaptive high-dose radiotherapy (ART) in our Phase II dose escalation study to identify factors predictive of chronic rectal toxicity. Materials and Methods From 1999–2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated in our Phase II 3D conformal dose escalation ART study to a median dose of 75.6 Gy (range, 63.0–79.2 Gy), minimum dose to confidence limited-planning target volume (cl-PTV) in 1.8 Gy fractions (median isocenter dose=79.7 Gy). Seventy-four patients (22%) also received neoadjuvant/adjuvant androgen deprivation therapy. A patient-specific cl-PTV was constructed using 5 computed tomography scans and 4 sets of electronic portal images by applying an adaptive process to assure target accuracy and minimize PTV margin. For each case, the rectum (rectal solid) was contoured from the sacroiliac joints or rectosigmoid junction (whichever was higher) to the anal verge or ischial tuberosities (whichever was lower), with a median volume of 81.2 cc. The rectal wall was defined using the rectal solid with an individualized 3-mm wall thickness (median volume=29.8 cc). Rectal wall dose-volume histogram was used to determine the prescribed dose. Toxicity was quantified using the National Cancer Institute Common Toxicity Criteria 2.0. Multiple dose-volume endpoints were evaluated for their association with chronic rectal toxicity. Results Median follow-up was 1.6 years. Thirty-four patients (crude rate=10.3%) experienced Grade 2 chronic rectal toxicity at a median interval of 1.1 years. Nine patients (crude rate=2.7%) experienced Grade ≥3 chronic rectal toxicity (1 was Grade 4) at a median interval of 1.2 years. The 3-year rates of Grade ≥2 and Grade ≥3 chronic rectal toxicity were 20% and 4%, respectively. Acute toxicity predicted for chronic: Acute Grade 2–3 rectal toxicity ( p p = 0.02) and pain ( p = 0.008) were significant predictors of chronic Grade ≥2 rectal toxicity. Any acute rectal toxicity ( p = 0.001), any acute tenesmus ( p = 0.03), and any acute diarrhea ( p t test, linear regression) and when divided into subgroups (chi-square table). The chronic rectal toxicity Grade ≥2 risk was 9%, 18%, and 25% for the rectal wall relative V70 40% respectively. The volume of rectum or rectal wall radiated to ≥50 Gy was a strong predictor for chronic rectal toxicity. Nonpredictive factors: Rectal solid/wall absolute or relative volumes irradiated to ≤40 Gy, dose level, and use of androgen deprivation were not found predictive. Conclusions In our ART dose escalation study, rectal wall or rectum relative ≥V50 are closely predictive for chronic rectal toxicity. If rectal dose-volume histogram constraints are used to select the dose level, the risk of chronic rectal toxicity will reflect the risk of toxicity of the selected constraint rather than the dose selected as found in our study using an adaptive process. To select the prescribed dose, different dose-volume histogram constraints may be used including the rectal wall V70. Patients experiencing acute rectal toxicity are more likely to experience chronic toxicity.
TL;DR: This work discusses the polymorphisms of paraoxonase (PON1), a liver and serum enzyme that hydrolyzes a number of OP compounds, and its role in modulating the toxicity of OPs, and stresses the importance of determining PON1 status.
TL;DR: Radiation-induced T-lymphocyte apoptosis could be used as a rapid screen for hypersensitive patients to radiotherapy and in future dose escalation studies, patients could be selected using the apoptosis assay.
Abstract: Purpose: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. Experimental Design: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. Results: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Gray9s test, P 24, respectively. Conclusions: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.
TL;DR: With a median follow-up of 66 months, the long-term results after high-dose hypofractionation are excellent, and high- doses of hypofractated intensity-modulated radiotherapy is an alternative dose escalation method in the treatment of localized prostate cancer.
Abstract: Purpose: To analyze the long-term relapse-free survival and toxicity rates in patients treated with hypofractionated intensity-modulated radiotherapy. Methods and Materials: The study sample includes the first 100 consecutive localized prostate cancer patients treated to 70.0 Gy at 2.5 Gy per fraction. The median follow-up was 66 months (range, 3 to 75 months). Biochemical failure was the study endpoint, using both the ASTRO definition (A-bRFS) and the alternate “nadir + 2 ng/mL” definition (N-bRFS). RTOG scores were used to assess toxicity. Results: The 5-year A-bRFS and N-bRFS rates were 85% (95%CI, 78–93%) and 88% (95%CI, 82–95%) for all cases, respectively. For low, intermediate and high-risk disease, the 5-year A-bRFS rates were 97%, 88%, and 70%. The corresponding 5-year N-bRFS rates were 97%, 93%, and 75%, respectively. The acute rectal toxicity scores were 0 in 20, 1 in 61, and 2 in 19 patients. The acute urinary toxicity scores were 0 in 9, 1 in 76, and 2 in 15 patients. The late rectal toxicity scores were 0 in 71, 1 in 19, 2 in 7, and 3 in 3 patients. The actuarial late Grade 3 rectal toxicity rate at 5 years was 3%. A number of the toxicities observed either resolved spontaneously or were corrected. At last follow-up, the rate of combined Grades 2 and 3 late rectal toxicity at 5 years was only 5%. The late urinary toxicity scores were 0 in 75, 1 in 13, 2 in 11, and 3 in 1 patients. The actuarial late Grade 3 urinary toxicity rate at 5 years was 1%. Conclusion: With a median follow-up of 66 months, the long-term results after high-dose hypofractionation are excellent. Late toxicity, urinary and rectal, has been limited. High-dose hypofractionation is an alternative dose escalation method in the treatment of localized prostate cancer.
TL;DR: Opsonization effect in the stimulation of Kupffer cell uptake is proposed as an explanation for the differences in the pharmacokinetic properties of plasmid DNA after lipoplex injection and sequential injection.
TL;DR: This report is the first that shows hepatoprotective effects of Hibiscus, Rosmarinus and Salvia species against Azathioprine-induced acute liver damage and it is shown that animals pretreated with water extracts from any of the three herbs under investigation not only failed to show necrosis of the liver after azathiopine administration, but also retained livers that, for the most part, were histologically normal.
TL;DR: Dose-limiting toxicity and maximum tolerated dose are established, and 17AAG doses between 10 and 295 mg/m2 are well tolerated, and peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers.
Abstract: Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics. Experimental Design: Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly × 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot. Results: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m 2 . The maximum tolerated dose was 295 mg/m 2 . Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m 2 . Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content. Conclusions: 17AAG doses between 10 and 295 mg/m 2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m 2 weekly × 3, repeated every 4 weeks.
TL;DR: Investigation of the expression of various inflammation-associated markers known to be overexpressed in patients with glaucoma after contact with the three major commercially available eye drops containing prostaglandin analogues showed that none of them appeared to induce direct stimulation of the inflammatory pathways involving adhesion molecules or class II antigens, although these markers have been found ex vivo in conjunctival specimens from patients treated with prostag landins.
Abstract: Purpose Conjunctiva-derived epithelial cells were used to investigate, in vitro, the expression of various inflammation-associated markers known to be overexpressed in patients with glaucoma after contact with the three major commercially available eye drops containing prostaglandin analogues. The impact on cellular viability and apoptosis in the same cell line was evaluated, to address the possible proinflammatory and/or toxic origin of the most frequent clinical impairments induced by prostanoids (i.e., conjunctival hyperemia). Methods Conjunctiva-derived cells were treated in vitro with the commercial solutions of latanoprost, travoprost, bimatoprost, prostaglandin (PG)F2alpha, tumor necrosis factor (TNF)-alpha, and different concentrations of benzalkonium chloride (BAC). Expressions of three inflammation- and immune-related markers, intercellular adhesion molecule (ICAM)-1, platelet-endothelial cell adhesion molecule (PECAM)-1 and HLA DR, were evaluated with flow cytometry after 24 to 72 hours of contact at low, subtoxic concentrations. Toxicological tests were also performed with cold-light cytofluorometry, in which cellular viability and apoptosis were evaluated with the neutral red and Hoechst/propidium iodide tests, respectively. Results TNFalpha induced or stimulated expression of the three inflammatory markers, whereas the PGF2alpha, latanoprost, travoprost, and bimatoprost solutions did not induce an increase in these markers and even produced a marked reduction of ICAM-1 and PECAM-1 expression in those solutions most concentrated in BAC, thus suggesting a toxic phenomenon in cellular membranes induced by the preservative rather than the medication itself. Cytotoxic assays confirmed this hypothesis and showed significant toxicity with prostaglandin analogues after prolonged contact, proportional to the concentration of BAC in the solution and similar to that of the corresponding concentration of BAC alone, bimatoprost having both the least concentration of BAC and the least cytotoxic in these experimental conditions. Conclusions The comparison of latanoprost, travoprost, and bimatoprost, in their commercial formulations, showed that none of them appeared to induce direct stimulation of the inflammatory pathways involving adhesion molecules or class II antigens, although these markers have been found ex vivo in conjunctival specimens from patients treated with prostaglandins. In fact, their toxicity was mild and seemed to be primarily related to the concentration of BAC, their common preservative, which may be the major factor responsible for long-term ocular surface reactions in patients receiving topical prostaglandins, but most likely is not a factor in early and transient conjunctival hyperemia.
TL;DR: The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.
Abstract: Purpose: IMMU-110 is a drug immunoconjugate composed of doxorubicin conjugated to the humanized anti-CD74 monoclonal antibody, hLL1, at a doxorubicin/monoclonal antibody ratio of ∼8:1 (mol/mol). CD74 is a rapidly internalizing molecule associated with HLA-DR, which has high expression by several tumor types. Here, we describe safety evaluations of IMMU-110 in mice and monkeys as well as efficacy studies in a xenograft model of the human multiple myeloma cell line, MC/CAR.
Experimental Design: In vitro binding of IMMU-110 was determined by a cell-based ELISA and cytotoxicity of IMMU-110 assayed with a tetrazolium assay. Pharmacokinetics and biodistribution of radiolabeled IMMU-110 were examined in tumor-free BALB/c mice, and the therapeutic effectiveness was evaluated in severe combined immunodeficient mice bearing MC/CAR cells. Acute toxicity of IMMU-110 was studied in CD74-positive cynomolgus monkeys ( Macaca fascicularis ).
Results: In vitro , IMMU-110 specifically binds to CD74 and is cytotoxic against MC/CAR cells. In vivo , IMMU-110 displayed a pharmacokinetic and biodistribution profile identical to that of unconjugated hLL1 monoclonal antibody, except for higher kidney uptake. Treatment with a single dose of IMMU-110 as low as 50 μg antibody/mouse (or 1.4 μg doxorubicin/mouse), 5 days postinjection of the multiple myeloma cells, resulted in cure of most mice. In mice, no host toxicity of IMMU-110 was observed at the highest protein dose tested (125 mg/kg). In cynomolgus monkeys, bone marrow toxicity was observed at 30 and 90 mg/kg doses.
Conclusions: The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.
TL;DR: The present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity.
TL;DR: Results show that AOB can be generally regarded as safe for use as a food additive, and suggested a no-observed-adverse-effect level (NOAEL) of 4.30 g/kg per day.
TL;DR: A variety of dosimetric parameters are predictive of acute and late esophageal injury after radiotherapy for non-small-cell lung cancer, and the presence of acute injury was the most predictive factor for the development of late injury.
Abstract: Purpose To evaluate the clinical and three-dimensional dosimetric parameters associated with esophageal injury after radiotherapy (RT) for non–small-cell lung cancer. Methods and materials The records of 254 patients treated for non–small-cell lung cancer between 1992 and 2001 were reviewed. A variety of metrics describing the esophageal dose were extracted. The Radiation Therapy Oncology Group toxicity criteria for grading of esophageal injury were used. The median follow-up time for all patients was 43 months (range, 0.5–120 months). Logistic regression analysis, contingency table analyses, and Fisher's exact tests were used for statistical analysis. Results Acute toxicity occurred in 199 (78%) of 254 patients. For acute toxicity of Grade 2 or worse, twice-daily RT, age, nodal stage of N2 or worse, and most dosimetric parameters were predictive. Late toxicity occurred in 17 (7%) of 238 patients. The median and maximal time to the onset of late toxicity was 5 and 40 months after RT, respectively. Late toxicity occurred in 2%, 3%, 17%, 26%, and 100% of patients with acute Grade 0, 1, 2, 3, and 4 toxicity, respectively. For late toxicity, the severity of acute toxicity was most predictive. Conclusion A variety of dosimetric parameters are predictive of acute and late esophageal injury. A strong correlation between the dosimetric parameters prevented a comparison between the predictive abilities of these metrics. The presence of acute injury was the most predictive factor for the development of late injury. Additional studies to define better the predictors of RT-induced esophageal injury are needed.
TL;DR: The toxicities of liposomal doxorubicin formulations could be reduced and even overcome by targeting with anti-CD19 antibodies, and therapeutic effects were intermediate between those found for liposomes with the fastest and slowest drug release rates.
Abstract: Some formulations of liposomal doxorubicin with intermediate rates of drug release have shown increased levels of toxicity in mice. Because antibody-mediated targeting of liposomal drugs influences the pharmacokinetics, mechanism of uptake, and selectivity of the associated drugs, we hypothesized that anti-CD19-mediated targeting of liposomal doxorubicin might moderate the toxicity of the problem formulations. Phosphatidylcholine/cholesterol liposomal formulations of doxorubicin having faster, intermediate, and slower drug release rates were prepared by altering the fatty acyl chain length or degree of saturation of the phosphatidylcholine component. Pharmacokinetic and biodistribution studies and in vivo drug release rates were determined in mice using liposomes dual labeled with [3H]cholesteryl hexadecylether and [14C]doxorubicin. Therapeutic studies were done in xenograft models of human B lymphoma (Namalwa cells). The rate of clearance of the liposomal lipid was similar for all formulations (average t1/2, 18 hours), but the rate of clearance of doxorubicin was dependent on the release rate of the formulation (t1/2, 2-315 hours). Liposomes with the slowest drug release rates showed no toxicity and exhibited therapeutic activity that was superior to the other formulations when targeted with anti-CD19; liposomes with the most rapid drug release rates also showed no toxicity but showed little therapeutic effect even when targeted. Liposomes with intermediate drug release rates exhibited varying degrees of toxicity. The toxicities could be reduced and even overcome by targeting with anti-CD19 antibodies. For these formulations, therapeutic effects were intermediate between those found for liposomes with the fastest and slowest drug release rates.