Document Detail

Random population-wide genetic damage induced in replicating cells treated with methotrexate.
MedLine Citation:
PMID:  9651539     Owner:  NLM     Status:  MEDLINE    
Low lethality treatment of the NIH 3T3 mouse cell line with methotrexate (MTX) during exponential multiplication results in heterogeneous, heritable reduction in growth rate of most if not all the replicatively surviving cells. The effective concentrations of MTX are 10 to 100 times higher in molecular, cellular and developmental biology medium 402 (MCDB 402) than in Dulbecco's modification of Eagle's medium (DMEM) medium because of the folate-sparing presence of adenine, thymidine and, particularly, of folinic acid in MCDB 402 medium. The reduced growth rates are detectable during early passages of surviving populations before the faster growing cells dominate them. The heritable effect is most clearly demonstrated by sequestered cloning of many individual cells immediately after drug treatment, and repeatedly measuring the growth rates of the clones in serial passages. After 7-10 passages of the clones, there is an increase in growth rate of some of the slow growing clones presumably due to the generation and selection of faster growing cells. Evidence from mutagenic studies at a single genetic locus in other cell lines suggests that heritable reductions in growth rate arise from chromosome aberrations although point mutations may also contribute to the effect. Clastogenic changes can be induced by a wide variety of mutagens and carcinogens, many of which are used in chemotherapy of cancer and other chronic diseases. The population-wide, heritable damage to cells may be the source of, or may contribute to, late-occurring side effects of treatment in cancer and other chronic diseases.
M Chow; J Koo; P Ng; H Rubin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Mutation research     Volume:  413     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  1998 Mar 
Date Detail:
Created Date:  1998-07-28     Completed Date:  1998-07-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  251-64     Citation Subset:  IM    
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3206, USA.
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MeSH Terms
3T3 Cells
Adenine / pharmacology
Antimetabolites, Antineoplastic / toxicity*
Cell Cycle / drug effects
Culture Media
DNA Damage
Folic Acid Antagonists / toxicity*
Hypoxanthine / pharmacology
Methotrexate / toxicity*
Mutagenicity Tests*
Thymidine / pharmacology
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Culture Media; 0/Folic Acid Antagonists; 50-89-5/Thymidine; 59-05-2/Methotrexate; 68-94-0/Hypoxanthine; 73-24-5/Adenine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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