Search results for "toxicity."

Regulation of CD1d expression by murine tumor cells: escape from immunosurveillance or alternate target molecules?

2002

alpha beta+ TCR T cells recognize peptide fragments displayed by MHC-class I or -class II molecules. Recently, additional mechanisms of antigen recognition by T cells have been identified, including CD1-mediated presentation of nonpeptide antigens. Only a limited number of CD1 antigens is retained in the mouse, i.e., the group II CD1 antigens, which are split into CD1D1 and CD1d2. Several T cell subsets have been shown to interact with murine CD1 antigens, including NK cells or "natural T cells" with the invariant V alpha 14 J alpha 281 TCR chain. Even if TAP defects may prevent classical endogenous antigen presentation in tumor cell lines, antigen presentation via CD1 is still functional. …

Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of

2021

Simple Summary Genetic variability in transforming growth factor beta pathway (TGFB) has been reported to affect adverse events in radiotherapy. We investigated 40 germline polymorphisms in peripheral blood cells, covering the entire common genetic variability in the TGFβ1 ligand (gene TGFB1) and the TGFβ receptor-1 (TGFBR1) in 240 patients treated with primary radiotherapy for prostate cancer. Human lymphoblastoid cell lines (LCLs) were used to assess whether TGFB1 and TGFBR1 polymorphisms impact DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, for one polymorphism (rs10512263 in TGFBR1, C-variant allele, n = 35), a statistically signifi…

Bovine seminal ribonuclease is cytotoxic for both malignant and normal telomerase-positive cells

2005

Bovine seminal-ribonuclease (BS-RNase) is a member of the 'ribonucleases with special biological actions' family since it possesses specific anti-tumour, anti-spermatogenic and embryotoxic activities and exerts an immunosuppressive effect on T lymphocytes. In previous studies it was demonstrated that BS-RNase induced apoptosis in proliferating, malignant and normal cells and that telomerase activity loss also caused apoptotic death in neoplastic cells. Since an obvious relationship between cell proliferation and telomerase activity exists, the aim of this work was to study if the pro-apoptotic cytotoxic action exerted by BS-RNase on proliferating malignant cells (HT29) and proliferating nor…

2021

Late-stage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via posttranslational modifications (PTMs). While the relevance of p53 C-terminal acetylation for transcriptional regulation is well-defined, it is unknown whether this PTM controls mitochondrially mediated apoptosis directly. We used wild-type p53 or p53-negative human CRC cells, cells with acetylation-defective p53, transformation assays, CRC organoids, and xenograft mouse models to assess how p53 acetylation determines cellular stress responses. The topoisomerase-1 inhibitor irinotecan induces acetylation of several lysine residues within p53. Inhibition of …

Mechanisms of skin toxicity of paclitaxel: An in vitro preclinical assessment.

2020

e15511 Background: Paclitaxel skin toxicity is a frequent side effect extensively evaluated in the clinical setting. However little is known about the preclinical mechanisms that lead to this toxicity. The endpoint of this study was to analyse the cutaneous mechanisms that drive paclitaxel toxicity in a preclinical model. Methods: Primary human keratinocytes were co-cultured with human dermal fibroblast in collagen gel under air-liquid interface conditions to generate a multilayered 3D epidermis. Paclitaxel was added to 3D epidermis at 0.3 µM, 3 µM and 30 µM and total RNA and protein was extracted after 24h of incubation. Markers of cell senescence (p21 and p53), anti-apoptotic mediators (…

The synergistic apoptotic effects of thiophenfurin, an inosine monophosphate dehydrogenase inhibitor, in combination with retinoids in HL60 cells

2006

New effective cytotoxic agents and combinations are urgently needed in cancer treatment. The enzyme inosine monophosphate dehydrogenase is a potentially useful target for drug development, since its activity has been shown to be amplified in malignant cells. Thiophenfurin, an inhibitor of the enzyme synthesized by us, is endowed with a significant apoptotic activity in promyelocytic leukaemia HL60 cells. Since retinoids were successfully employed in the treatment of patients with leukaemia, demonstrating significant differentiation-inducing and apoptotic effects, we carried out this study to evaluate the effects of the combination of thiophenfurin and several retinoid molecules, acting in d…

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with e…

2015

Overexpression and mutation of the epidermal growth factor receptor (EGFR) gene play a causal role in tumorigenesis and resistance to treatment of glioblastoma (GBM). EGFR inhibitors such as erlotinib are currently used for the treatment of GBM; however, their efficacy has been limited due to drug resistance. New treatment strategies are therefore urgently needed. Shikonin, a natural naphthoquinone, induces both apoptosis and necroptosis in human glioma cells, but the effectiveness of erlotinib-shikonin combination treatment as well as the underlying molecular mechanisms is unknown yet. In this study, we investigated erlotinib in combination with shikonin and 14 shikonin derivatives in pare…

Lysosomal alterations in heart and liver of mice treated with doxorubicin.

1985

This study was carried out to evaluate the influence of long-term treatment with doxorubicin (DXR) (4mg/kg IV for 5 weeks) on heart and liver lysosomes of mice. We evaluated the variations in both total and "sedimentable" enzyme activity of cathepsin D, which is the major endopeptidase of myocites and probably involved in physiologic and pathologic degradation of actomyosin and mitochondria, and that of acid phosphatase, which is more prominent in interstitial cells. Our results show that marked changes occur in both total and sedimentable enzyme activity of cathepsin D in the heart of treated animals and to a lesser extent in the liver. In contrast, no modification of either total or sedim…

Trabectedin-Related Liver Toxicity in Soft Tissue Sarcoma Patients: Always a Good Reason to Discontinue the Treatment?

2014

ABSTRACT Aim: A transient increase in liver enzymes is a well described side effect developed by almost 40% of soft tissue sarcoma (STS) patients treated with trabectedin, often leading to treatment delays or discontinuation. We retrospectively analysed the correlation between trabectedin-related liver toxicity and treatment outcome. Methods: Data from a total of 113 patients receiving trabectedin administered at the dose of 1.5 mg/m2 iv 24 hours in 3 reference centers were evaluated. This exploratory analysis was performed to assess the impact of liver toxicity (grade 3-4 AST and ALT increases) on the trabectedin efficacy and outcome in STS patients. All the patients included had metastati…

Blood flow and metabolic microenvironment of brain tumors

1994

Summarizing thesein vivo data in the context of brain tumor therapy, the following aspects are of particular importance: Low and heterogeneous tumor blood flow may — in addition to the limiting effects of the blood-brain barrier — result in compromised delivery of drugs from blood to the tissue. Low tumor pO2 reduces sensitivity to standard radiation and ‘O2-dependent’ anticancer drugs. Treatment efficacy may be further altered by changes of tumor pH. Particularly acidosis can decrease radiation sensitivity and modulate the cytotoxicity of anticancer drugs. In the following presentations, these aspects will be discussed regardingin vivo data obtained with positron emission tomography.