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Chemotherapy-induced acute kidney injury: epidemiology, pathophysiology, and therapeutic approaches.

Despite significant advancements in oncology, conventional chemotherapy remains the primary treatment for diverse malignancies. Acute kidney injury (AKI) stands out as one of the most prevalent and severe adverse effects associated with these cytotoxic agents. While platinum compounds are well-known for their nephrotoxic potential, other drugs including antimetabolites, alkylating agents, and antitumor antibiotics are also associated. The onset of AKI poses substantial risks, including heightened morbidity and mortality rates, prolonged hospital stays, treatment interruptions, and the need for

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… Its pharmacological efficacy lies in inhibiting key enzymes within the folate metabolic pathway and impeding the synthesis of purine and thymidine nucleotides ( 174 ). … Thymidine may be considered an antidote for pemetrexed-related toxicity if administered within 36 hours of the drug infusion, however, the interpretation of this positive outcome is complicated by the simultaneous use of hemodialysis in the reported case ( 186 ). …

Mesenchymal-Stem-Cell-Based Therapy against Gliomas.

Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they c

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… Another example in oncotherapy is the thymidine kinase gene of the herpes simplex virus (HSV-tk). Thymidine kinase is an anticancer, prodrug-converting enzyme. It converts ganciclovir into its toxic form, which inhibits DNA synthesis, and, consequently, cell death occurs. … Improving the Safety of Mesenchymal Stem Cell-Based Ex Vivo Therapy Using Herpes Simplex Virus Thymidine Kinase Mol. Cells 2022 45 479 494 10.14348/molcells.2022.5015 35356894 PMC9260133 57. Dührsen L. Hartfuß S. Hirsch D. Geiger S. Maire C.L. Sedlacik J. Guenther C. Westphal M. Lamszus K. …

Safety Strategies of Genetically Engineered T Cells in Cancer Immunotherapy.

T-cell therapy using genetically engineered T cells modified with either T cell receptor or chimeric antigen receptor holds great promise for cancer immunotherapy. The concerns about its toxicities still remain despite recent successes in clinical trials. Temporal and spatial control of the engineered therapeutic T cells may improve the safety profile of these treatment regimens. To achieve these goals, numerous approaches have been tested and utilized including the incorporation of a suicide gene, the switch-mediated activation, the combinatorial antigen recognition, etc. This review will sum

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… The first suicide gene to be clinically tested is herpes simplex virus thymidine kinase (HSV-tk) which can convert ganciclovir into ganciclovir triphosphate, a toxic substance for dividing cells [ 41 ]. … Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood. 2001;97(1):63–72. doi: 10.1182/blood.v97.1.63. 43. Straathof K.C., Pulè M.A., Yotnda P., et al. An inducible caspase 9 safety switch for T-cell therapy. …

Immunomodulatory effects of the Agaricus blazei Murrill-based mushroom extract AndoSan in patients with multiple myeloma undergoing high dose chemotherapy and autologous stem cell transplantation: a randomized, double blinded clinical study.

Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable fo

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… Proliferation Assay A 3 H-thymidine incorporation assay was performed on MOPC315.BM cells, that is, mouse myeloma cells [ 24 ]. … For the last 16 hours of culture, 0.17 μ Ci of [Methyl- 3 H] thymidine (Perkin Elmer, Zaventem, Belgium) was added to each well. DNA was harvested on Multiscreen Harvest Plates (Millipore, Carrightwohill, Cork, Ireland) using Filter Mate Harvester (Perkin Elmer). …

Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol.

BackgroundDespite effective treatments, metastatic colorectal cancer (mCRC) prognosis is still poor, mostly in RAS-mutated tumors, thus suggesting the need for novel combinatorial therapies. Epigenetic alterations play an important role in initiation and progression of cancers, including CRC. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with chemotherapy in the treatment of solid tumors. Owing to its HDACi activity and its safe use for epileptic disorders, valproic acid (VPA) is a good candidate for anticancer therapy that we have largely explored preclinically tra

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… Mol Cancer Ther 2009 ; 8 : 3075 – 3087 . 19887547 10.1158/1535-7163.MCT-09-0254 24 Di Gennaro E Piro G Chianese MI , et al Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase . … J Cell Physiol 2011 ; 226 : 2378 – 2390 . 21660961 10.1002/jcp.22574 26 Terranova-Barberio M Roca MS Zotti AI , et al Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression . …

Anti-cancer mechanisms of action of therapeutic alternating electric fields (tumor treating fields [TTFields]).

Despite improved survival outcomes across many cancer types, the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer. Invariably in these cancers, the control achieved by time-limited interventions such as traditional surgical resection, radiation therapy, and chemotherapy is short-lived. A new form of anti-cancer therapy called therapeutic alternating electric fields (AEFs) or tumor treating fields (TTFields) has been shown, either by itself or in combination with chemotherapy, to have anti-cancer effects that translate to improved survival outc

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… Similar to previous studies, they found that TTFields had minimal effects on non-cancer cells but they also found that TTFields did not affect thymidine-treated cancer cells ( Jeong et al., 2021 ). … Thymidine decreases the DNA damage and apoptosis caused by tumor-treating fields in cancer cell lines. Genes Genomics 43, 995–1001. Jo Y., Han Y.I., Lee E.et al. (2022). …

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. TNBC diagnoses account for approximately one-fifth of all breast cancer cases globally. The lack of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER-2, CD340) results in a lack of available molecular-based therapeutics. This increases the difficulty of treatment and leaves more traditional as well as toxic therapies as the only available standards of care in many cases. Recurrence is an additional serious problem, contributing substantially to its higher mortality rate as compared to

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… It took until 1991 for genetic engineering to be used for OVs, with the deletion of viral thymidine kinase (TK) in herpes simplex virus-1 (HSV) for the treatment of glioma [ 113 ]. … Both viruses carry deletions of viral thymidine kinase (TK, ORF 66R), as is the case in many other poxviruses, to provide preferential replication in tumor cells. …

Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity.

A prodrug is a molecule that lacks pharmacological activity, but upon enzymatic bioactivation, it can generate a therapeutically active molecule. The primary reason behind the design of a prodrug is to help circumvent challenges associated with the physicochemical properties of a drug molecule, such as solubility, absorption, distribution, and instability. Chemotherapy has been at the forefront of cancer treatment for over 70 years due to its ability to target rapidly proliferating tumor cells. However, a major concern with conventional chemotherapy is the lack of selectivity and its associate

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… Non-Alkylating Prodrug | Target Cancer | Bioactivation Mechanism | Off Target Toxicity 5-Fluorouracil | Adenocarcinomas and head and neck cancer [ 124 , 125 , 126 ] | Orotate phosphoribosyltransferase, uridine kinase, uridine phosphorylase, thymidine phosphorylase, and thymidine kinase | Angina, myocardial … Alternatively, 5-Fluorouracil can be converted to FdUMP via thymidine phosphorylase (TP) and thymidine kinase (TK). The resulting FdUMP can subsequently inhibit TS [ 122 ]. Dihydropyrimidine dehydrogenase (DPD) catalyzes the degradation of 5-Fluorouracil to dihydrofluorouracil. …

An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer.

Chemotherapy resistance and peculiar tumor microenvironment, which diminish or mitigate the effects of therapies, make pancreatic cancer one of the deadliest malignancies to manage and treat. Advanced immunotherapies are under consideration intending to ameliorate the overall patient survival rate in pancreatic cancer. Oncolytic viruses therapy is a new type of immunotherapy in which a virus after infecting and lysis the cancer cell induces/activates patients' immune response by releasing tumor antigen in the blood. The current review covers the pathways and molecular ablation that take place

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… AdV-tk is a recombinant adenovirus encoding herpes simplex virus thymidine kinase ( 157 ). The intratumoral injection of AdV-tk is given to 27 patients divided into two groups including resectable tumor and unresectable LAPC. … SJ-815 is a recombinant oncolytic vaccinia virus, specifically designed to express IFN β 1 and CES2 transgenes with deleted thymidine kinase-encoding (TK) gene. …

DNA Damaging Drugs

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Targeted therapy in the treatment of malignant gliomas.

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In additi

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… Viral thymidine kinase enzyme, which is targeted by the antivirals acyclovir (Zovirax ® ; GlaxoSmithKline, Philadelphia, PA), has been incorporated into the tumor cells DNA. … Klatzmann D Valery CA Bensimon G A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma: Study Group on Gene Therapy for Glioblastoma Hum Gene Ther 1998 9 17 2595 2604 9853526 10.1089/hum.1998.9.17-2595 112. …

Воздействие остаточных клональных плазменных клеток в фазе S во время аутологической трансплантации стволовых клеток на клинические результаты.

Автологическая трансплантация стволовых клеток (ASCT) является ключевой терапевтической стратегией для многих пациентов, у которых диагностируется миелома (ММ), однако ранние рецидивы после трансплантации остаются серьезной клинической проблемой. Испытание на распространение плазменных клеток (ПХПРО), в ходе которого определяется доля клональных плазменных клеток в костном мозге в фазе S-фазе (S-фаза %), представляет собой масштабируемую альтернативу измерению их скорости распространения по сравнению со старым индексом плазменных клеток (PCLI). Воздействие S-фазы в остаточных клональных плазме

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… Greipp PR Lust JA O’Fallon WM Katzmann JA Witzig TE Kyle RA Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma Blood 1993 81 3382 7 10.1182/blood.V81.12.3382.3382 8507875 Greipp PR, Lust JA, O’Fallon WM, Katzmann … Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood. 1993;81:3382–7. 8507875 17. …

Advances in CAR-T-cell therapy in T-cell malignancies.

Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classificati

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… The herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV) system acts as a powerful suicide switch, converting GCV into its active form, which integrates into DNA and causes strand termination and cell death [ 101 ]. … Abbreviations: allo-HSCT: allogeneic hematopoietic stem cell transplantation; CAR-NK cells: chimeric antigen receptor natural killer cells; CAR-T cells: chimeric antigen receptor T cells; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; DNTs: double-negative T cells; HSV-TK: herpes simplex virus thymidine …

Protective Role of Eosinophils and TNFa after Ozone Inhalation.

INTRODUCTION: Exposure to ozone induces deleterious responses in the airways that include shortness of breath, inflammation, and bronchocons … sure from those that already existed, by injecting animals with bromodeoxyuridine (BrdU). BrdU is a thymidine analogue that is incorporated into the DNA of dividing cells, serving as a marker of newly produced cells. Therefore, a snapshot can be obtained of the proportion of newly synthesized (BrdU-positive) versus pre-existing (BrdU-negative) cell types. …

Unlocking the potential: advancements and applications of gene therapy in severe disorders.

INTRODUCTION: Several severe disorders, such as inherited diseases (e.g. cystic fibrosis and beta thalassemia), genetic diseases (e.g. malignant tumors and diabetes), and infectious diseases (e.g. HIV) are pose significant challenges to human health. BACKGROUND: Over the past few decades, researchers have been working on gene therapies, and currently, terrible dreams have come true. To date, the Food and Drug Administration (FDA) has approved multiple gene therapies such as Kynamro for familial hypercholesterolaemia, Exondys51 for duchenne muscular dystrophy, Spinraza for spinal muscular atro

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… The most dominant suicide gene therapy is the herpes simplex virus (HSV thymidine kinase/ganciclovir) system. Recent studies have revealed that HSV thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy and radiofrequency hyperthermia combination is a promising technique. … Osteosarcoma and chondrosarcoma as targets for virus vectors and herpes simplex virus thymidine kinase/ganciclovir gene therapy. Int J Mol Med. 2004;13(5):705–710. doi: 10.3892/ijmm.13.5.705. 59. Cemazar M, Ambrozic Avgustin J, Pavlin D, et al. …

Herpes Simplex Virus and Varicella Zoster Virus Infections in Cancer Patients.

Herpes simplex virus (HSV) and varicella zoster virus (VZV) are alpha herpesviruses that establish life-long latent infection in neuronal ganglia after primary infection. Periodic reactivation of these viruses results in recurrent infections that can have significant impact on patients' quality of life. HSV commonly causes oral and genital mucocutaneous infections whereas VZV is responsible for varicella/chickenpox and herpes zoster/shingles, but cancer patients are at particularly higher risk of complications including disseminated and visceral infections due to impaired cell-mediated immunit

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… The most common mechanism of acyclovir resistance in HSV arises from the mutation of viral thymidine kinase, while the mutation of viral DNA polymerase is much less frequent [ 53 ]. … Other Nucleoside or Nucleotide Analogues Brivudin Brivudin is a thymidine analogue with potent antiviral activities against HSV and VZV. …

Modern radiopharmaceuticals for lung cancer imaging with positron emission tomography/computed tomography scan: A systematic review.

IntroductionIn this study, we evaluated the use and the contribution of radiopharmaceuticals to the field of lung neoplasms imaging using positron emission tomography/computed tomography.MethodsWe conducted review of the current literature at PubMed/MEDLINE until February 2020. The search language was English.ResultsThe most widely used radiopharmaceuticals are the following:Experimental/pre-clinical approaches: (18)F-Misonidazole (18F-MISO) under clinical development, D(18)F-Fluoro-Methyl-Tyrosine (18F-FMT), 18F-FAMT (L-[3-18F] (18)F-Fluorothymidine (18F-FLT)), (18)F-Fluoro-Azomycin-Arabinosi…

The Emerging Role of Oncolytic Virotherapy in Glioblastoma Management.

Glioblastoma (GBM) is an aggressive and common form of central nervous system primary malignant tumor in adults. GBM accounts for about half of all gliomas. Despite maximal resection, radiotherapy, and temozolomide, median survival is still 12-15 months because of tumor heterogeneity, diffuse infiltration, and therapeutic resistance. Recurrence is nearly universal, underscoring the need for novel therapies. Oncolytic virotherapy demonstrates a promising strategy that combines direct tumor cell lysis with immune activation. Tumor-selective viruses replicate within malignant cells, induce cell d

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… . | Solid tumors, multiple myeloma | Reolysin (Pelareorep) [ 62 , 63 ], Dearing Type 3 Reovirus [ 61 ] Reovirus T3D [ 61 ] Vaccinia Virus | dsDNA | Modified by deletion of thymidine kinase (TK) and vaccinia growth factor (VGF) genes; relies on high TK expression and EGF signaling found in cancer cells … For DNA viruses such as HSV, deleting ICP34.5 and UL39 genes mitigates neurovirulence while preserving a pharmacologic “off switch” via retained thymidine kinase [ 98 , 99 , 137 ], for RNA viruses like VSV and poliovirus, attenuation (e.g., VSV-IFNβ, pseudotyping) limits systemic toxicity [ 100 , 131 …

Twenty-fifth annual general meeting of the British Association for Cancer Research. Abstracts of invited and profferred papers.

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… Assessment of in vitro drug sensitivity of human tumor cells using [3H]thymidine incorporation in a modified human tumor stem cell assay. 42 11 11 1982 4683 4689 Cancer Res 7127304 Funa K. Alm G. V. Rönnblom L. Oberg K. …

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021.

Solid cancers are the most common types of cancers diagnosed globally and comprise a large number of deaths each year. The main challenge currently in drug development for tumors raised from solid organs is to find more selective compounds, which exploit specific molecular targets. In this work, the small molecule drugs registered by the Food and Drug Administration (FDA) for solid cancers treatment between 2011 and 2022 were identified and analyzed by investigating a type of therapy they are used for, as well as their structures and mechanisms of action. On average, 4 new small molecule agent

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… Trifluridine is an inhibitor of thymidylate synthase (TS), while tripacil is an inhibitor of thymidine phosphorylase (TP). Trifluridine is a thymidine-based nucleoside analog that was originally approved by the FDA on April 10 1980 as an antiviral drug with the brand name VIROPTIC [ 264 ]. … A generic name of a drug is an international nonproprietary name (INN). 1 TS : thymidylate synthase. 2 TP : thymidine phosphorylase. …