Document Detail

Prevention of bone growth defects, increased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate.
MedLine Citation:
PMID:  23071661     Owner:  NLM     Status:  MEDLINE    
The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.
Chia-Ming Fan; Bruce K Foster; Susanta K Hui; Cory J Xian
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-05
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-04-11     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e46915     Citation Subset:  IM    
Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
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MeSH Terms
Adiposity / drug effects*
Antimetabolites, Antineoplastic / adverse effects
Apoptosis / drug effects
Bone Marrow / drug effects,  metabolism
Bone Resorption / chemically induced,  prevention & control*
Chondrocytes / cytology,  drug effects,  metabolism
Cytokines / blood,  genetics
Femur / drug effects,  growth & development,  metabolism
Gene Expression / drug effects
Leucovorin / administration & dosage,  therapeutic use*
Methotrexate / adverse effects*
Osteoblasts / cytology,  drug effects,  metabolism
Osteoclasts / cytology,  drug effects,  metabolism
Osteogenesis / drug effects*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
RANK Ligand / blood,  genetics
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Vitamin B Complex / administration & dosage,  therapeutic use
X-Ray Microtomography
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Cytokines; 0/RANK Ligand; 12001-76-2/Vitamin B Complex; 58-05-9/Leucovorin; 59-05-2/Methotrexate

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