Cytotoxic response of 5-fluorouracil-resistant cells to gene- and cell-directed enzyme/prodrug treatment

Durinikova, Erika; Plavá, Jana; Tyciakova, Silvia; Škvára, Pavel; Staňová, Andrea Vojs; Kozovská, Zuzana; Kučerová, Lucia; Matúšková, Miroslava

doi:10.1038/s41417-018-0030-5

Cited by 10 publications

(3 citation statements)

References 31 publications

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“…This strategy involves the introduction of a sequence of genetic material in tumor cells, triggering the necessary mechanisms to activate the apoptotic pathways themselves or facilitate the activation of certain compounds that can spread to neighboring malignant cells and mediate their destruction [ 4 ]. Suicidal genes promote a cytotoxic effect after their expression in the target cell, by encoding enzymes that convert non-toxic prodrugs into highly toxic metabolites [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Suicide gene therapy by canine mesenchymal stem cell transduced with thymidine kinase in a u-87 glioblastoma murine model: Secretory profile and antitumor activity

et al. 2022

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The role played by certain domestic species such as dogs as a translational model in comparative oncology shows great interest to develop new therapeutic strategies in brain tumors. Gliomas are a therapeutic challenge that represents the most common form of malignant primary brain tumors in humans and the second most common form in dogs. Gene-directed enzyme/prodrug therapy using adipose mesenchymal stem cells (Ad-MSCs) expressing the herpes simplex virus thymidine kinase (TK) has proven to be a promising alternative in glioblastoma therapy, through its capacity to migrate and home to the tumor and delivering local cytotoxicity avoiding other systemic administration. In this study, we demonstrate the possibility for canine Ad-MSCs (cAd-MSCs) to be genetically engineered efficiently with a lentiviral vector to express TK (TK-cAd-MSCs) and in combination with ganciclovir (GCV) prodrug demonstrated its potential antitumor efficacy in vitro and in vivo in a mice model with the human glioblastoma cell line U87. TK-cAd-MSCs maintained cell proliferation, karyotype stability, and MSCs phenotype. Genetic modification significantly affects its secretory profile, both the analyzed soluble factors and exosomes. TK-cAd-MSCs showed a high secretory profile of some active antitumor immune response cytokines and a threefold increase in the amount of secreted exosomes, with changes in their protein cargo. We also found that the prodrug protein is not released directly into the culture medium by TK-cAd-MSCs. We believe that our work provides new perspectives for glioblastoma gene therapy in dogs and a better understanding of this therapy in view of its possible implantation in humans.

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Section: Introductionmentioning

confidence: 99%

Suicide gene therapy by canine mesenchymal stem cell transduced with thymidine kinase in a u-87 glioblastoma murine model: Secretory profile and antitumor activity

et al. 2022

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“…In vivo , 5-FU is transformed into FU deoxynucleotide (F-duMP) via the OPRT-RR and TP-TK pathways, inhibiting thymidylate synthase (TS), preventing dUMP methylation to dTMP, inhibiting DNA synthesis, and arresting the cell cycle in the S phase ( 7 ). Several studies have reported that gene polymorphism and TS upregulation in CRC are closely related to 5-FU tolerance ( 7 , 99 , 100 ). Thymidine phosphorylase (TP) is upregulated in CRC, which has a poor prognosis.…”

Section: Tcm Reverses the Chemoresistance Of Crc And Inhibits Tumor G...mentioning

confidence: 99%

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

Lin

Yang

et al. 2023

Front. Oncol.

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In recent years, the incidences and mortalities from colorectal cancer (CRC) have been increasing; therefore, there is an urgent need to discover newer drugs that enhance drug sensitivity and reverse drug tolerance in CRC treatment. With this view, the current study focuses on understanding the mechanism of CRC chemoresistance to the drug as well as exploring the potential of different traditional Chinese medicine (TCM) in restoring the sensitivity of CRC to chemotherapeutic drugs. Moreover, the mechanism involved in restoring sensitivity, such as by acting on the target of traditional chemical drugs, assisting drug activation, increasing intracellular accumulation of anticancer drugs, improving tumor microenvironment, relieving immunosuppression, and erasing reversible modification like methylation, have been thoroughly discussed. Furthermore, the effect of TCM along with anticancer drugs in reducing toxicity, increasing efficiency, mediating new ways of cell death, and effectively blocking the drug resistance mechanism has been studied. We aimed to explore the potential of TCM as a sensitizer of anti-CRC drugs for the development of a new natural, less-toxic, and highly effective sensitizer to CRC chemoresistance.

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“…Polyethylenimine based polymers were used to transiently engineer MSC with HSV-TK, together with TRAIL: These modified cells were effective in vitro and in vivo against glioma through increased apoptosis and reduced angiogenesis[ 178 ]. MSC expressing CDy::UPRT by the same transfection method significantly inhibited in vivo temozolomide resistant glioma tumors[ 179 ] as well as 5-fluorouracil resistant colorectal adenocarcinoma cells[ 180 ].…”

Section: Arming Msc Toward Cancermentioning

confidence: 99%

Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications

Vicinanza¹,

Lombardi²,

Ros³

et al. 2022

WJSC

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Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.

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Cytotoxic response of 5-fluorouracil-resistant cells to gene- and cell-directed enzyme/prodrug treatment

Cited by 10 publications

References 31 publications

Suicide gene therapy by canine mesenchymal stem cell transduced with thymidine kinase in a u-87 glioblastoma murine model: Secretory profile and antitumor activity

Suicide gene therapy by canine mesenchymal stem cell transduced with thymidine kinase in a u-87 glioblastoma murine model: Secretory profile and antitumor activity

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications

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