Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

Land, Belinda van‘t; Meijer, Helen P.; Frerichs, John B.; Koetsier, Marleen A.; Jager, De; Smeets, Roger; M’Rabet, Laura; Hoijer, Maarten

doi:10.1038/sj.bjc.6600342

Cited by 37 publications

(32 citation statements)

References 23 publications

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“…77 During tumor promotion and progression, 78 cancer cells lose sensitivity to transforming growth factor beta (TGFβ). TGFβ protects rodent small intestinal crypt stem cells and animal survival after irradiation during methotrexate treatment, 79,80 possibly by reducing stem-cell cycling. In vivo, 5 mg/kg UCN-01 induced inhibition in BrdU incorporation in intestinal epithelial cells and G 1 arrest bone marrow cells.…”

Section: Growth Arrest Protects From Cycle-dependent Chemotherapymentioning

confidence: 99%

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Blagosklonny¹,

Darżynkiewicz²

2002

Cell Cycle

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Avoidance of apoptosis and mitogen-independent growth are hallmarks of cancer. Mitogen-activated kinases (for example, ErbB1, Raf-1, MEK, PI-3-K, mTOR) can suppress chemotherapy-induced apoptosis in cancer cells. While kinase inhibitors restore susceptibility of cancer cells to apoptosis, they do not necessarily cause growth arrest in cancer cells harboring additional mutations in downstream signaling pathways such as inactivation of Rb and overexpression of c-myc. This article provides a conceptual basis for a novel use of inhibitors of mitogenic kinases. While arresting growth of normal cells, kinase inhibitors may not arrest cancer cells but instead can sensitize them to apoptosis. Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells.

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Section: Growth Arrest Protects From Cycle-dependent Chemotherapymentioning

confidence: 99%

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Blagosklonny¹,

Darżynkiewicz²

2002

Cell Cycle

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“…TGF-␤s have been reported to exert various functions in the gut in vivo, such as immunomodulation (30), regulation of intestinal cell proliferation and differentiation (9,40), and protection against intestinal injury in a NEC-like model (19). In intestinal epithelial cells (IECs), TGF-␤s mediate anti-inflammatory effects by inhibiting the secretion of the proinflammatory cytokines IL-6 and IL-8 (32,33), strengthen intestinal barrier functions by upregulating tight junction proteins (12), and stimulate epithelial restitution in wounded epithelial cell layers (25).…”

mentioning

confidence: 99%

Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine

Nguyen

Sangild

Østergaard

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…[8][9][10][11] Glucagon-like peptide 2 (GLP-2) has been demonstrated to have intestinotrophic effects. 12) GLP-2, a 33-amino acid peptide member of a family of proglucagon-derived peptides (PGDP) that also includes enteroglucagon, is secreted from L-type entero-endocrine cells of the distal small intestine and colon.…”

mentioning

confidence: 99%

Correlation between Plasma Glucagon-Like Peptide 2 Levels and Proliferative Makers in Small Intestinal Injury in Rats Induced by Methotrexate Administration

Hirotani

Yamamoto

Ikeda

et al. 2006

Biological & Pharmaceutical Bulletin

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Chemotherapy is an important primary and adjuvant therapy for cancer patients. The cytotoxicity of antineoplastic agents affects not only tumor cells but also rapidly proliferating normal cells, such as those of the gastrointestinal mucosa.1) Common complications of chemotherapy thus include stomatitis and enterocolitis.2) Methotrexate (MTX) is an antimetabolite drug that blocks the production of biologically active forms of folic acid. The major lesions resulting from its cytotoxic effects occur in bone marrow and the intestinal tract. High doses of MTX cause severe enterocolitis, weight loss, anorexia and intestinal atrophy. 3,4) The mucosa of the digestive tract, particularly that of the small intestine, is a critical site of action of anticancer agents including MTX, as the undifferentiated epithelial cells in the crypts, which ensure continuous and relatively fast regeneration of the epithelium, are particularly sensitive to these cytostatic drugs.5-7) Patients receiving these anticancer agents frequently experience gastrointestinal side effects, such as nausea, vomiting and diarrhea, reflecting gastrointestinal mucosal damage or enterocolitis.2) Chemotherapy-associated diarrhea may be problematic, and even life threatening, if complicated by mucosal ulceration and inflammatory changes. Moreover, patients with advanced malignancy often suffer from malnutrition, which increases toxicity and decreases tumor responses to treatment,2) and such conditions can be dose limiting in therapeutic regimens. A method for prediction of adverse reactions to chemotherapy is thus needed to avoid their occurrence.Gastrointestinal mucosal integrity is regulated by several growth factors and cytokines, such as transforming growth factors-beta and IL-11.8-11) Glucagon-like peptide 2 (GLP-2) has been demonstrated to have intestinotrophic effects. 12)GLP-2, a 33-amino acid peptide member of a family of proglucagon-derived peptides (PGDP) that also includes enteroglucagon, is secreted from L-type entero-endocrine cells of the distal small intestine and colon.12) GLP-2 increases crypt cell proliferation and decreases the rate of apoptosis in small intestinal epithelium.13) Acute or chronic administration of GLP-2 induces functional changes in the intestine, improving its capacity for nutrient absorption. [13][14][15] In addition, GLP-2 treatment has been shown to enhance intestinal adaptation following major small bowel resection, 16,17) to prevent 18) and to reduce the severity of dextran sulfate-induced colitis 19) and indomethacin-induced enteritis 20) in animal models. On the other hand, plasma GLP-2 levels appear to vary with intestinal mucosal condition and injury. However, although changes in various conditions of the intestinal mucosa are now being widely studied, [21][22][23] the relationship between plasma GLP-2 levels and intestinal mucosal injury induced by various drugs, including antineoplastic agents, has yet to be clearly determined. Moreover, no standard methods of diagnosis or therapeutic protocols exist for chemo...

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Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

Cited by 37 publications

References 23 publications

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine

Correlation between Plasma Glucagon-Like Peptide 2 Levels and Proliferative Makers in Small Intestinal Injury in Rats Induced by Methotrexate Administration

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