Low dosages: new chemotherapeutic weapons on the battlefield of immune-related disease

Liu, Jing; Zhao, Jie; Hu, Liang; Cao, Yu; Huang, Bo

doi:10.1038/cmi.2011.6

Cited by 9 publications

(6 citation statements)

References 81 publications

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“…Typically, the drug doses needed to suppress tumor growth in cancer therapy are significantly higher than needed for therapeutic efficacy in other indications, such as in autoimmune diseases (Liu et al 2011). Accordingly, we hypothesize that a lower dose of CB-5083 could be effective in VCP disease than that used in the previous Phase 1 cancer trial, resulting in milder side effects on visual function.…”

Section: Discussionmentioning

confidence: 96%

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6

Leinonen

Cheng

Pitkänen

et al. 2021

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 96%

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6

Leinonen

Cheng

Pitkänen

et al. 2021

J Pharmacol Exp Ther

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“…Apparently, the therapeutic effect versus the toxicity of MTX are dose dependent. In addition to its use in cancer, MTX is also widely used for treatment of inflammatory diseases, such as rheumatoid arthritis, SLE, psoriasis and Crohn’s disease for decades, due to its beneficial immunosuppressive and anti-inflammatory effects when administered in low dosage [ 20 ]. Although not yet fully understood, it is believed MTX’s low dosage immunosuppressive effect is not through DHFR.…”

Section: Discussionmentioning

confidence: 99%

Folic acid derived-P5779 mimetics regulate DAMP-mediated inflammation through disruption of HMGB1:TLR4:MD-2 axes

Sun

Wang

et al. 2018

PLoS ONE

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High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that mediates inflammatory responses after infection or injury. Previously, we reported a peptide inhibitor of HMGB1 (P5779) that acts by directly interrupting HMGB1/MD-2 binding. Here, fingerprint similarity search and docking studies suggest folic acid derived-drugs function as P5779 mimetopes. Molecular dynamic (MD) simulation studies demonstrate that folic acid mimics the binding of P5779 at the TLR4 and MD-2 intersection. In surface plasmon resonance (SPR) studies, these drugs showed direct binding to TLR4/MD-2 but not HMGB1. Furthermore, these P5779 mimetopes inhibit HMGB1 and MD-2 binding and suppress HMGB1-induced TNF release in human macrophages in the nanomolar range. We assert from our findings that their demonstrated anti-inflammatory effects may be working through TLR4-dependent signaling.

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“…Data from both preclinical studies and clinical trails highlight that some chemotherapeutic drugs reduce regulatory T-cell (Treg) numbers, although the detailed mechanism of this action remains unknown. These drugs include cyclophosphamide (Cy), [38][39][40] fludarabine 41,42 and gemcitabine, 43 among which, Cy is the best described. In mouse models, it was reported that Cy depletes CD4 1 CD25 1 Tregs, 38 and in vitro studies revealed that Cy reduces the suppressive function of Tregs by decreasing the expression of the transcription factors GITR and FoxP3.…”

Section: Chemotherapymentioning

confidence: 99%

“…In addition, different doses of chemotherapeutic drugs have distinct effects in tumor and autoimmune disease models. 40 Therefore, future studies examining how different cytotoxic drugs affect the immune system are necessary. Understanding the proper timing and dosing of chemotherapy for a combination with immunotherapy will be necessary to optimize synergy between these therapies resulting in better antitumor activity.…”

Section: Chemotherapymentioning

confidence: 99%

Targeting and utilizing primary tumors as live vaccines: changing strategies

Yang

Mortenson

2011

Cell Mol Immunol

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Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system. Thus, when established, this response should be able to control metastatic growth and tumor relapse. This review summarizes the mechanisms by which antitumor immune responses are generated, and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse. Keywords: chemotherapy; immunotherapy; metastasis; radiotherapy; tumor vaccine INTRODUCTION Conventional treatments such as surgery and chemotherapy are effective means of eliminating or reducing primary tumor growth, but have not proved effective in eradicating metastases. Because metastatic disease may not respond similarly to chemotherapies used in treating the primary tumor, 1 recent research has focused on the importance of generating an antitumor immune response to control metastatic disease. Presumably, both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system; yet, there has been no clear strategy formulated in which a patient's own tumor tissues is used to generate an antitumor adaptive immune response for the eradication of metastases and prevention of relapse. Once tumors metastasize, curing the disease is difficult and rare. This review summarizes recent findings supporting the hypothesis that targeting primary tumors with both conventional and new therapies can potentially generate antitumor adaptive immune responses that prevent metastases and relapse.Due to the vast number of genetic changes associated with carcinogenesis, tumors express many neo-antigens and mutated antigens. Indeed, much evidence exists to indicate that many cancers are antigenic and thus recognizable by the adaptive immune system. 2 Mere recognition by adaptive immunity, however, is insufficient, given that these antigenic cancers rarely regress spontaneously. Effective antitumor immunity depends on both the presence of tumor-reactive lymphocyte precursors and means by which these precursor lymphocytes can be activated. Most T cells with high affinity to tissue-specific antigens are deleted in the thymus or later tolerized in the peripheral

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Low dosages: new chemotherapeutic weapons on the battlefield of immune-related disease

Cited by 9 publications

References 81 publications

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6

Folic acid derived-P5779 mimetics regulate DAMP-mediated inflammation through disruption of HMGB1:TLR4:MD-2 axes

Targeting and utilizing primary tumors as live vaccines: changing strategies

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