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Abstracts from the 8th Drug Hypersensitivity Meeting (DHM)

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Cardiotoxicity of Chemotherapy: A Multi-OMIC Perspective.

Chemotherapy-induced cardiotoxicity is a critical issue in cardio-oncology, as cancer treatments often lead to severe cardiovascular complications. Approximately 10% of cancer patients succumb to cardiovascular problems, with lung cancer patients frequently experiencing arrhythmias, cardiac failure, tamponade, and cardiac metastasis. The cardiotoxic effects of anti-cancer treatments manifest at both cellular and tissue levels, causing deformation of cardiomyocytes, leading to contractility issues and fibrosis. Repeated irradiation and chemotherapy increase the risk of valvular, pericardial, or

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… Antimetabolites, such as 5-fluorouracil (5-FU), a pyrimidine analog, inhibits thymidylate synthase and depletes thymidine, leading to DNA synthesis inhibition. It can cause cardiotoxicity through endothelial dysfunction, increased homocysteine levels, and pro-inflammatory pathways [ 16 ]. 1.2. …

LAMP5 modulates IRF4 stability and nuclear transport: a critical mechanism in myeloma progression and therapy.

Multiple myeloma is a malignant hematopoietic neoplasm characterized by unclear molecular mechanisms and lack of highly effective targeted therapies for clinical application. Interferon regulatory factor 4 (IRF4) is a well-known core transcription factor that regulates the progression of myeloma, but the molecular mechanisms underlying its protein homeostasis regulation are unknown. Our research shows that lysosomal-associated membrane protein 5 (LAMP5) interacts with IRF4 and prevents its degradation through the autophagy-lysosome pathway, thereby facilitating the progression of myeloma. Addi

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… Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma. Sci Transl Med. 2016;8:353ra113. 4. Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA et al. Diagnosis and management of multiple myeloma: a review. JAMA. 2022;327:464–77. 5. …

Tumour-Derived Extracellular Vesicles (EVs): A Dangerous "Message in A Bottle" for Bone.

Several studies have shown the importance of Extracellular Vesicles (EVs) in the intercellular communication between tumour and resident cells. Through EVs, tumour cells can trigger cell-signalling molecules and shuttle exogenous information to target cells, thus promoting spread of the disease. In fact, many processes are fuelled by EVs, such as tumour invasion and dormancy, drug-resistance, immune-surveillance escape, extravasation, extracellular matrix remodelling and metastasis. A key element is certainly the molecular profile of the shed cargo. Understanding the biochemical basis of EVs w

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… This suicide gene promotes the conversion of 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), which in turn is converted in 5-fluoro-deoxyuridine monophosphate (5-FdUMP), an irreversible inhibitor of thymidine synthetase that is more toxic for cancer cells than 5-FU. …

Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients.

IntroductionNail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy.ObjectivesWe aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management.MethodsRetrieved literature from PubMed regis

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… Fluorouracil: 5-Fluorouracil, Capecitabine and Tegafur 5-Fluorouracil (5-FU) is a pyrimidine analog that inhibits the enzyme thymidylate synthase, thereby interrupting thymidine synthesis required for DNA replication, and can cause myelosuppression, diarrhea, mucositis, and dermatitis [ 12 ]. …

Hematopoietic Tumors

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… to determine cytoreductive efficacy of various chemotherapeutic drugs and to document and predict early relapse in patients prior to more conventional methods. 215 , 216 , 217 , 218 , 219 Regarding biomarkers of MRD, preliminary investigations have suggested serum lactate dehydrogenase activity, 120 thymidine …

Targeted Drug Delivery in Periorbital Non-Melanocytic Skin Malignancies.

Targeted drug delivery has emerged as a transformative approach in the treatment of periorbital skin malignancies, offering the potential for enhanced efficacy and reduced side effects compared to traditional therapies. This review provides a comprehensive overview of targeted therapies in the context of periorbital malignancies, including basal cell carcinoma, squamous cell carcinoma, sebaceous gland carcinoma, and Merkel cell carcinoma. It explores the mechanisms of action for various targeted therapies, such as monoclonal antibodies, small molecule inhibitors, and immunotherapies, and their

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… Currently, the possibility of using the combination of Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GC, cytosine deaminase/5-fluorocytosine, cytochrome P450/cyclophosphamide, and carboxypeptidase/4-[2-chloroethyl 2-mesyloxyetel-0-amino] benzoyl-l-glutamic acid) is being explored. 8.2. …

Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities.

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new tr

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… A recent study investigated the use of HSP90α (heat shock protein 90) combined with AFP and thymidine kinase 1 to diagnose HCC with more efficiency[ 26 ]. …

Herpes Zoster and Cardiovascular Disease: Exploring Associations and Preventive Measures through Vaccination.

Herpes zoster, induced by the reactivation of the varicella-zoster virus (VZV), is a unilaterally distributed vesicular rash that can cause multiple complications. VZV not only causes neurological problems, including postherpetic neuralgia and ocular zoster, but also causes inflammatory vasculopathy and increases the incidence of hemorrhagic or ischemic complications. Therefore, understanding the association between the development of herpes zoster and the subsequent occurrence of acute stroke or cardiovascular diseases, including myocardial infarction and heart failure, is of great interest.

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… Thymidine analog rivudine is an antiviral medication used to treat herpes zoster. Its molecular structure is similar to that of 5-fluorouracil (5-FU), which has been linked to coronary spasm in the past [ 69 ]. …

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Unders

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… Action | Compound | Mechanism of Action | Disease | FDA-Approval/Clinical Trial Amino Acid | L-Asparaginase | Asparagine and glutamine depletion | ALL | FDA-approved Nucleotide | 6-Mercaptopurine | Inhibits purine synthesis by inhibiting PPAT | ALL | FDA-approved Nucleotide | Methotrexate | Inhibits thymidine … synthesis by inhibiting folic acid metabolism (competitive inhibitor of DHFR) | ALL, AML | FDA-approved Nucleotide | 5-Fluorouracil | Blocks thymidine synthesis by inhibiting TS | ALL | FDA-approved Nucleotide | 6-Thioguanine | Guanine analogue, inhibits nucleotide biosynthesis | ALL, AML | FDA-approved …

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers.

Though early-stage colorectal cancer has a high 5 year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical

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… JX-594 is a vaccinia poxvirus with engineered loss of thymidine kinase, enabling its replication only in cells high levels of thymidine kinase [ 130 ]. …

Infectious Diseases

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Advances in the mechanism and therapies of achondroplasia.

Achondroplasia (ACH), is the prevailing type of genetic dwarfism in humans, caused by mutations in fibroblast growth factor receptor 3 (FGFR3) that are inherited in an autosomal dominant manner. FGFR3 is mainly expressed in condensed mesenchyme, chondrocytes, and mature osteoblasts and osteoclasts, in which it regulates the formation, development, growth, and remodeling of the skeletal system. Mutations in FGFR3 causing ACH result in enhanced FGFR3 signaling through combined mechanisms including enhancing FGF dimerization and tyrosine kinase activity and stabilizing FGF receptors. In ACH, supp

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… Through the utilization of cultured chondrocytes, metatarsal organs, and genetic mouse models, researchers have discovered that the proliferation of chondrocytes is inhibited by FGFR3 signaling. 41 , 42 , 43 , 44 The incorporation of [3H]thymidine labeling in the epiphyseal chondrocytes of cultured fetal …

Immunotherapy of Hematological Malignancies of Human B-Cell Origin with CD19 CAR T Lymphocytes.

Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Mara

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… One of the most commonly used models for GDEPT is the herpes simplex virus thymidine kinase/ganciclovir system (HSV-TK/GCV system), in which the HSV-TK gene in tumor cells, followed by a treatment with the prodrug GCV, causes tumor cell apoptosis [ 83 ]. …

Antidepressant Drug Sertraline against Human Cancer Cells.

The use of FDA-approved drugs for new indications represents a faster and more economical way to find novel therapeutic agents for cancer therapy, compared to the development of new drugs. Repurposing drugs is advantageous in a pharmacological context since these drugs already have extensive data related to their pharmacokinetics, facilitating their approval process for different diseases. Several studies have reported the promising anticancer effects of sertraline, both alone and combined, in different types of cancer cell lines. Here, we performed a literature review on the anticancer potent

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… Using the [ 3 H] thymidine incorporation assay, they also evaluated the effect of sertraline in cell proliferation and found that this drug is able to decrease the number of proliferative cells [ 61 ]. …

Biotechnological Innovations from Ocean: Transpiring Role of Marine Drugs in Management of Chronic Disorders.

Marine drugs are abundant in number, comprise of a diverse range of structures with corresponding mechanisms of action, and hold promise for the discovery of new and better treatment approaches for the management of several chronic diseases. There are huge reserves of natural marine biological compounds, as 70 percent of the Earth is covered with oceans, indicating a diversity of chemical entities on the planet. The marine ecosystems are a rich source of bioactive products and have been explored for lead drug molecules that have proven to be novel therapeutic targets. Over the last 70 years, m

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… The chemical structure of this anticancer compound has been found to be related to Spong uridine and Spong thymidine, which are natural products isolated from the marine sponge Tectitethya cripta . …

Current landscape of clinical development and approval of advanced therapies.

Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product's benefit-risk balance at the time of approval, the limitations of nonclinical development, and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval, and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges, and some of the efforts several stakeholde

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… other immunostimulants/L03AX17 | prostatic neoplasms/standard approval—withdrawn Zalmoxis (orphan medicine) | allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low-affinity nerve growth factor receptor (ΔLNGFR) and the herpes simplex I virus thymidine …

Recent Advances of Acute Kidney Injury in Hematopoietic Cell Transplantation.

Acute kidney injury (AKI) is a common complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is associated with non-relapse mortality (NRM) and quality of life (QOL). Multiple factors may contribute to AKI during allo-HCT and are often present at the same time making it difficult to determine the cause of AKI in each patient. Nephrotoxic drugs, infections, thrombotic microangiopathy (TMA), and sinusoidal obstruction syndrome (SOS) are well described causes of AKI during allo-HCT. Acute graft-versus-host disease (aGVHD) is a major complication of allo-HCT that mainly targe

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… Methotrexate-Induced Renal Impairment: Clinical Studies and Rescue From Systemic Toxicity With High-Dose Leucovorin and Thymidine . J Clin Oncol ( 1983 ) 1 ( 3 ): 208–16 . doi: 10.1200/JCO.1983.1.3.208 6607976 64 Perazella MA . Pharmacology Behind Common Drug Nephrotoxicities . …

Preventive strategies for acute kidney injury in cancer patients.

Acute kidney injury (AKI) is a common complication of cancer that occurs in up to 50% of neoplastic patients during the natural history of their disease; furthermore, it has a huge impact on key outcomes such as overall prognosis, length of hospitalization and costs. AKI in cancer patients has different causes, either patient-, tumour- or treatment-related. Patient-related risk factors for AKI are the same as in the general population, whereas tumour-related risk factors are represented by compression, obstruction, direct kidney infiltration from the tumour as well by precipitation, aggregatio

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… Oncologist 2006 ; 11 : 694 – 703 16794248 10.1634/theoncologist.11-6-694 46 Wideman BC , Balis FM , Kim A et al Glucarpidase, leucovorin and thymidine for high-dose-methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome . …

Gambogic Acid as a Candidate for Cancer Therapy: A Review.

Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form mice

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… gastrointestinal cancer cells, possibly related to the suppression of mRNA expression, including β-tubulin III, tau and surviving. 132 Wang et al made similar findings of the synergistic effect of 5-fluorouracil and GA on BGC-823 human gastric carcinoma, with the underlying mechanism of the gene expressions of thymidine …