Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

Chan, Tze Sian; Hsu, Chung Chi; Pai, Vincent C.; Liao, Wen; Huang, Shu-Ching; Tan, Kok Tong; Yen, Chia Jui; Hsu, Shih-Hsin; Chen, Wei Yu; Shan, Yan Shen; Li, Chi–Rong; Lee, Michael T.; Jiang, Kuan; Chu, Jui Mei; Lien, Gi Shih; Weaver, Valerie M.; Tsai, Kelvin K.

doi:10.1084/jem.20151665

Cited by 141 publications

(163 citation statements)

References 68 publications

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“…The main efficacy of LDMC is induced by anti-angiogenesis and immune system modulation [25,26,27,28,29]. Furthermore, LDMC exerts inhibiting effects on the tumor and, in contrast to MTD regimens, also on tumor-initiating cells [30,31]. …”

Section: Discussionmentioning

confidence: 99%

Explorative Analysis of Low-Dose Metronomic Chemotherapy with Cyclophosphamide and Methotrexate in a Cohort of Metastatic Breast Cancer Patients

Krajnak¹,

Battista²,

Brenner³

et al. 2018

Breast Care

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Background: Low-dose metronomic chemotherapy (LDMC) is increasingly used in metastatic breast cancer (MBC). In this retrospective analysis, we examined the therapeutic effects and side effects of LDMC in a cohort of MBC patients. Methods: Patients with MBC were included when LDMC with oral cyclophosphamide (CTX) and methotrexate (MTX) was administered between 2009 and 2015. The primary endpoint was disease control rate (DCR) ≥ 24 weeks after the start of LDMC. Secondary endpoints were duration of progression-free survival (PFS), rates of discontinuation due to side effects, and DCR with regard to subgroups. Results: Retrospective data of 35 patients were available for this analysis. 31% patients achieved DCR. The median PFS was 12 weeks. 9% of patients discontinued LDMC due to adverse events. DCR was 37% in the first 2 lines and 25% in further lines of therapy. 22% of patients with multiple metastases and 35% with ≤2 different metastatic sites achieved DCR. DCR was achieved in 33% of hormone receptor(HR)-positive patients and 27% of HR-negative patients. Conclusion: The DCR of 31% is in line with the results of previous phase II studies. LDMC was well tolerated. Subgroup analysis was not able to identify a group in which LDMC was more efficient.

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Section: Discussionmentioning

confidence: 99%

Explorative Analysis of Low-Dose Metronomic Chemotherapy with Cyclophosphamide and Methotrexate in a Cohort of Metastatic Breast Cancer Patients

Krajnak¹,

Battista²,

Brenner³

et al. 2018

Breast Care

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“…The RNA samples were used for cDNA synthesis when the A260/280 ratio was assessed to be greater than 1.9. The Affymetrix cDNA microarray hybridization and analysis were performed by GeneChip Human Transcriptome Array 2.0 (NHRI Microarray Core, Zhunan, Taiwan) . All raw data can be accessed at the National Center for Biotechnology Information‐Gene Expression Omnibus (NCBI‐GEO): GSE101473.…”

Section: Methodsmentioning

confidence: 99%

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Wang

Jiang²,

Ting

et al. 2018

Stem Cells

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Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM-MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL-17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17-expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914.

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“…Another mechanism which explains benefits from this low dose frequently repeated dosing is averting secretion of certain proteins by stromal cells in tumors which occur after high-intensity chemotherapy. These proteins are believed to be responsible for recurrence of aggressive forms of tumors from residual cells [28]. Metronomic chemotherapy not only targets the microenvironment of tumor cells but has also been noted to causes direct cytotoxicity from prolonged exposure to low concentrations of chemotherapy [39].…”

Section: Discussionmentioning

confidence: 99%

“…Patients were followed with clinical response, and radiological studies were performed at frequent intervals to monitor tumor status. As we mentioned earlier, dosing schedule with metronomic chemotherapy has been varied and empiric and thus unclear pharmacokinetic profiles [28]. Similarly, we selected 50% dosing as a starting point, but we further titrated up or down based on the individual patient profile.…”

Section: Treatmentmentioning

confidence: 99%

An alternative approach with a low dose and prolonged chemotherapy for palliative treatment of locally advanced, metastatic or recurrent squamous cell head and neck cancer

et al. 2017

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Background: It is expected that about 65,000 new patients will be diagnosed with head and neck cancer in 2017 in the United States. Patients with recurrent or advanced or metastatic head and neck do not have good survival due to aggressive and recurrent nature of this cancer. Moreover, cumulative and residual toxicities from previous and ongoing treatments significantly impede quality of remaining part of their life. Currently available chemotherapeutic regimens for this group are derived from the treatments used for the potentially curable disease. These regimens and associated toxicity are obviously not the best matches for the treatment with palliative intent. We here present a retrospective study where we used dose-adjusted chemotherapy specifically for palliative treatment this sub-group of head and neck cancer patients.

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Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

Abstract: Chan et al. report that treatment of tumor-bearing mice with low-dose metronomic chemotherapy prevents stromal secretion of ELR+ chemokines and induction of tumor-initiating cells usually observed with administration of drugs at maximum tolerated dose.

Cited by 141 publications

References 68 publications

Explorative Analysis of Low-Dose Metronomic Chemotherapy with Cyclophosphamide and Methotrexate in a Cohort of Metastatic Breast Cancer Patients

Explorative Analysis of Low-Dose Metronomic Chemotherapy with Cyclophosphamide and Methotrexate in a Cohort of Metastatic Breast Cancer Patients

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

An alternative approach with a low dose and prolonged chemotherapy for palliative treatment of locally advanced, metastatic or recurrent squamous cell head and neck cancer

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