The role of caspases in methotrexate-induced gastrointestinal toxicity

Papaconstantinou, Harry T.; Xie, Chuncheng; Zhang, Weiping; Ansari, Naseem H.; Hellmich, Mark R.; Townsend, Courtney M.; Ko, Tien C.

doi:10.1067/msy.2001.117376

Cited by 43 publications

(25 citation statements)

References 18 publications

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“…Gastrointestinal side effects often occur in rheumatic patients during oral application of MTX as nausea, abdominal pain, stomatitis and diarrhea (Hoekstra et al 2003). Enterocolitis is the major toxicity of methotrexate-based cancer chemotherapy, which limits its clinical applications (Papaconstantinou et al 2001). Mao et al (1996) showed that administration of lactobacilli, especially L. plantarum, is helpful in reducing the severity of the methotrexate-induced enterocolitis in rats.…”

Section: Discussionmentioning

confidence: 99%

Treatment of adjuvant-induced arthritis with the combination of methotrexate and probiotic bacteria Escherichia coli O83 (Colinfant®)

et al. 2009

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A certain relationship was observed between the gastrointestinal system, arthritis and immune system. Patients with rheumatoid arthritis have an altered microflora composition and disturbed intestinal defensive barrier. Effect of probiotic bacteria (Colinfant; COL) with known favorable effect on intestinal microflora was determined on the methotrexate (MTX) treatment of adjuvant arthritis. Rats with adjuvant arthritis were administered methotrexate 0.5 mg/kg body mass 2-times weekly per os, COL 1 mL/kg body mass every second day per os, and a combination of MTX+COL for a period of 28 d from the immunization. Levels of serum albumin, body mass, changes in hind paw swelling, and arthrogram score were estimated in rats as variables of inflammation and destructive arthritis-associated changes. Treatment with MTX, as well as with the combination treatment with MTX+COL significantly inhibited both inflammation and destructive arthritis-associated changes. The combination treatment inhibited both the hind paw swelling and arthrogram score more remarkably than MTX alone; on the other hand, the difference between combination treatment and MTX alone was not significant. Treatment with COL alone had no effect on adjuvant arthritis in rats. Colinfant can increase the preventive effect of MTX treatment in rat adjuvant arthritis by improving its antiarthritic effects.

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Section: Discussionmentioning

confidence: 99%

Treatment of adjuvant-induced arthritis with the combination of methotrexate and probiotic bacteria Escherichia coli O83 (Colinfant®)

et al. 2009

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“…It also inhibits epithelial proliferation and enterocyte function and increases the risk of gutassociated sepsis due to disruption of the mucosal barrier. Gastrointestinal toxicity is now the major dose-limiting factor for methotrexate administration [141,198]. The toxicity of MTX to the gastrointestinal epithelium is dependent on the duration of cytotoxic exposure rather than the peak levels achieved by the drug.…”

Section: Methotrexate and The Gastrointestinal Tractmentioning

confidence: 99%

Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage

Bowen

Gibson

Cummins

et al. 2006

Support Care Cancer

113

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Intestinal mucositis occurs as a consequence of cytotoxic treatment through multiple mechanisms including induction of crypt cell death (apoptosis) and cytostasis. The molecular control of these actions throughout the gastrointestinal tract has yet to be fully elucidated; however, they are known to involve p53, the Bcl-2 family and caspases. This review will provide an overview of current research as well as identify areas where gaps in knowledge exist.

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“…Methotrexate (MTX), an anti-metabolite inhibiting purine synthesis enzyme dihydrofolate reductase (Papaconstantinou et al, 2001), is commonly used to treat many pediatric cancers including leukemia and solid tumors. The current study characterized cellular and structural damage caused by short-term MTX treatment in the proximal tibial growth plate cartilage, metaphyseal bone and bone marrow, and examined potential effects of supplementary treatment with one clinically used agent (folinic acid (FA)) in protecting the bone growth mechanisms during MTX chemotherapy.…”

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confidence: 99%

Folinic acid attenuates methotrexate chemotherapy‐induced damages on bone growth mechanisms and pools of bone marrow stromal cells

Chen

Cool

Scherer

et al. 2007

Journal Cellular Physiology

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Chemotherapy often induces bone growth defects in pediatric cancer patients; yet the underlying cellular mechanisms remain unclear and currently no preventative treatments are available. Using an acute chemotherapy model in young rats with the commonly used antimetabolite methotrexate (MTX), this study investigated damaging effects of five once-daily MTX injections and potential protective effects of supplementary treatment with antidote folinic acid (FA) on cellular activities in the tibial growth plate, metaphysis, and bone marrow. MTX suppressed proliferation and induced apoptosis of chondrocytes, and reduced collagen-II expression and growth plate thickness. It reduced production of primary spongiosa bone, volume of secondary spongiosa bone, and proliferation of metaphyseal osteoblasts, preosteoblasts and bone marrow stromal cells, with the cellular activities being most severely damaged on day 9 and returning to or towards near normal levels by day 14. On the other hand, proliferation of marrow pericytes was increased early after MTX treatment and during repair. FA supplementation significantly suppressed chondrocyte apoptosis, preserved chondrocyte proliferation and expression of collagen-II, and attenuated damaging effects on production of calcified cartilage and primary bone. The supplementation also significantly reduced MTX effects on proliferation of metaphyseal osteoblastic cells and of bone marrow stromal cells, and enhanced pericyte proliferation. These observations suggest that FA supplementation effectively attenuates MTX damage on cellular activities in producing calcified cartilage and primary trabecular bone and on pools of osteoblastic cells and marrow stromal cells, and that it enhances proliferation of mesenchymal progenitor cells during bone/bone marrow recovery.

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The role of caspases in methotrexate-induced gastrointestinal toxicity

Cited by 43 publications

References 18 publications

Treatment of adjuvant-induced arthritis with the combination of methotrexate and probiotic bacteria Escherichia coli O83 (Colinfant®)

Treatment of adjuvant-induced arthritis with the combination of methotrexate and probiotic bacteria Escherichia coli O83 (Colinfant®)

Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage

Folinic acid attenuates methotrexate chemotherapy‐induced damages on bone growth mechanisms and pools of bone marrow stromal cells

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