Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer

doi:10.1054/bjoc.2000.1669

Cited by 24 publications

(4 citation statements)

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“…IFNα could potentiate 5-FU activity for CRC treatment by enhancing activities of effector cell or modulating display of HLA class I antigens [ 118 ]. Meta-analysis of data from multiple trials concluded however that IFNα did not increase the efficacy of 5-FU or 5-FU+LV and that 5-FU+IFNα was significantly inferior to 5-FU+LV [ 9 ]. The type II IFN IFNγ was also evaluated for enhancing 5-FU’s anti-tumor activity.…”

Section: Modulation Of 5-fu-induced Anti-tumor Immunitymentioning

confidence: 99%

“…Both type I and II interferons also were evaluated in combination with 5-FU and strong efficacy was found in some clinical studies consistent with their immunomodulatory properties [ 8 ]. Ultimately, immunomodulatory approaches to enhancing 5-FU efficacy were shown to be inferior to biochemical modulation with leucovorin (LV) [ 9 ], a reduced folate [ 10 ] that promotes thymidylate synthase (TS) inhibition by 5-FU [ 11 ]. TS is essential for de novo pyrimidine biosynthesis and its inhibition causes malignant cells to undergo “thymineless death” [ 12 ], a well-validated strategy for cancer treatment [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Fluoropyrimidine Modulation of the Anti-Tumor Immune Response―Prospects for Improved Colorectal Cancer Treatment

Gmeiner

2020

Cancers

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Chemotherapy modulates the anti-tumor immune response and outcomes depend on the balance of favorable and unfavorable effects of drugs on anti-tumor immunity. 5-Florouracil (5-FU) is widely used in adjuvant chemotherapy regimens to treat colorectal cancer (CRC) and provides a survival benefit. However, survival remains poor for CRC patients with advanced and metastatic disease and immune checkpoint blockade therapy benefits only a sub-set of CRC patients. Here we discuss the effects of 5-FU-based chemotherapy regimens to the anti-tumor immune response. We consider how different aspects of 5-FU’s multi-factorial mechanism differentially affect malignant and immune cell populations. We summarize recent studies with polymeric fluoropyrimidines (e.g., F10, CF10) that enhance DNA-directed effects and discuss how such approaches may be used to enhance the anti-tumor immune response and improve outcomes.

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Section: Modulation Of 5-fu-induced Anti-tumor Immunitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluoropyrimidine Modulation of the Anti-Tumor Immune Response―Prospects for Improved Colorectal Cancer Treatment

Gmeiner

2020

Cancers

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“…Interferon-α does not enhance activity of 5-fluorouracil (5-FU) in colon cancer (Hill et al, 1995 ; Thirion et al, 2001 ). Interferon-α plus retinoid adds no benefit to pulsed cisplatin in cervical cancer (Basu et al, 2016 ).…”

Section: Master Modulators the Backbone Of Anakoinosis Inducing Thermentioning

confidence: 99%

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

et al. 2018

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Classic tumor therapy, consisting of cytotoxic agents and/or targeted therapy, has not overcome therapeutic limitations like poor risk genetic parameters, genetic heterogeneity at different metastatic sites or the problem of undruggable targets. Here we summarize data and trials principally following a completely different treatment concept tackling systems biologic processes: the principle of communicative reprogramming of tumor tissues, i.e., anakoinosis (ancient greek for communication), aims at establishing novel communicative behavior of tumor tissue, the hosting organ and organism via re-modeling gene expression, thus recovering differentiation, and apoptosis competence leading to cancer control – in contrast to an immediate, “poisoning” with maximal tolerable doses of targeted or cytotoxic therapies. Therefore, we introduce the term “Master modulators” for drugs or drug combinations promoting evolutionary processes or regulating homeostatic pathways. These “master modulators” comprise a broad diversity of drugs, characterized by the capacity for reprogramming tumor tissues, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs etc., or for example differentiation inducing therapies. Data on 97 anakoinosis inducing schedules indicate a favorable toxicity profile: The combined administration of master modulators, frequently (with poor or no monoactivity) may even induce continuous complete remission in refractory metastatic neoplasia, irrespectively of the tumor type. That means recessive components of the tumor, successively developing during tumor ontogenesis, are accessible by regulatory active drug combinations in a therapeutically meaningful way. Drug selection is now dependent on situative systems characteristics, to less extent histology dependent. To sum up, anakoinosis represents a new substantive therapy principle besides novel targeted therapies.

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“…Apart from the critical role in modulating immune responses [ 38 ], Type I IFN is also known to have a direct effect on cancer cells [ 39 ] and can potentiate 5FU cytotoxicity by inducing S-phase accumulation and apoptosis [ 40 – 43 ]. In clinical studies, recombinant IFNs in combination with 5FU have been shown to be effective in some [ 44 – 47 ], but not in others [ 48 , 49 ]. Significant challenges limiting the clinical benefits include the issues of systemic toxicities and short half-life of recombinant IFNb [ 41 , 50 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced anti-tumor efficacy with multi-transgene armed mesenchymal stem cells for treating peritoneal carcinomatosis

Ho,

Woo,

Loke

et al. 2024

J Transl Med

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Background Mesenchymal stem cells (MSCs) have garnered significant interest for their tumor-tropic property, making them potential therapeutic delivery vehicles for cancer treatment. We have previously shown the significant anti-tumour activity in mice preclinical models and companion animals with naturally occurring cancers using non-virally engineered MSCs with a therapeutic transgene encoding cytosine deaminase and uracil phosphoribosyl transferase (CDUPRT) and green fluorescent protein (GFP). Clinical studies have shown improved response rate with combinatorial treatment of 5-fluorouracil and Interferon-beta (IFNb) in peritoneal carcinomatosis (PC). However, high systemic toxicities have limited the clinical use of such a regime. Methods In this study, we evaluated the feasibility of intraperitoneal administration of non-virally engineered MSCs to co-deliver CDUPRT/5-Flucytosine prodrug system and IFNb to potentially enhance the cGAS-STING signalling axis. Here, MSCs were engineered to express CDUPRT or CDUPRT-IFNb. Expression of CDUPRT and IFNb was confirmed by flow cytometry and ELISA, respectively. The anti-cancer efficacy of the engineered MSCs was evaluated in both in vitro and in vivo model. ES2, HT-29 and Colo-205 were cocultured with engineered MSCs at various ratio. The cell viability with or without 5-flucytosine was measured with MTS assay. To further compare the anti-cancer efficacy of the engineered MSCs, peritoneal carcinomatosis mouse model was established by intraperitoneal injection of luciferase expressing ES2 stable cells. The tumour burden was measured through bioluminescence tracking. Results Firstly, there was no changes in phenotypes of MSCs despite high expression of the transgene encoding CDUPRT and IFNb (CDUPRT-IFNb). Transwell migration assays and in-vivo tracking suggested the co-expression of multiple transgenes did not impact migratory capability of the MSCs. The superiority of CDUPRT-IFNb over CDUPRT expressing MSCs was demonstrated in ES2, HT-29 and Colo-205 in-vitro. Similar observations were observed in an intraperitoneal ES2 ovarian cancer xenograft model. The growth of tumor mass was inhibited by ~ 90% and 46% in the mice treated with MSCs expressing CDUPRT-IFNb or CDUPRT, respectively. Conclusions Taken together, these results established the effectiveness of MSCs co-expressing CDUPRT and IFNb in controlling and targeting PC growth. This study lay the foundation for the development of clinical trial using multigene-armed MSCs for PC.

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Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer

Cited by 24 publications

References 24 publications

Fluoropyrimidine Modulation of the Anti-Tumor Immune Response―Prospects for Improved Colorectal Cancer Treatment

Fluoropyrimidine Modulation of the Anti-Tumor Immune Response―Prospects for Improved Colorectal Cancer Treatment

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

Enhanced anti-tumor efficacy with multi-transgene armed mesenchymal stem cells for treating peritoneal carcinomatosis

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