PMID- 17324445
OWN - NLM
STAT- MEDLINE
DCOM- 20070515
LR  - 20151124
IS  - 0027-5107 (Print)
IS  - 0027-5107 (Linking)
VI  - 617
IP  - 1-2
DP  - 2007 Apr 1
TI  - Aneugenic potential of the nitrogen mustard analogues melphalan, chlorambucil and 
      p-N,N-bis(2-chloroethyl)aminophenylacetic acid in cell cultures in vitro.
PG  - 125-37
AB  - Melphalan (MEL), chlorambucil (CAB) and p-N,N-bis(2-chloroethyl)aminophenylacetic 
      acid (PHE) are nitrogen mustard analogues, which are clinically used as 
      chemotherapeutic agents. They also exert carcinogenic activity. The aim of this 
      study was to investigate the aneugenic potential of the above drugs and the 
      possible mechanism responsible for this activity. The Cytokinesis Block 
      Micronucleus (CBMN) assay in combination with fluorescence in situ hybridization 
      (FISH) was used in human lymphocyte cultures to evaluate micronucleus (MN) 
      frequency. Pancentromeric probe (alpha-satellite) was applied to identify 
      chromosomes in micronuclei and an X-chromosome specific centromeric probe was 
      used to asses micronucleation and non-disjunction of this chromosome in 
      binucleated cells. The effect of the above compounds on the organization of 
      mitotic apparatus, as a possible target of chemicals with aneugenic potential, 
      was investigated in C(2)C(12) mouse cell line by double immunofluorescence of 
      alpha- and gamma-tubulin. We found that the studied drugs increased MN frequency 
      in a linear dose-dependent manner primarily by chromosome breakage and in a 
      lesser extent by an aneugenic mechanism. Non-disjunction and micronucleation of 
      X-chromosome were also induced. Abnormal metaphase cells were linearly increased 
      with concentration and characterized by abnormal centrosome number. Interphase 
      cells with micronuclei and abnormal centrosome number were also observed. Since 
      nitrogen mustards are highly reactive agents, with low selectivity and form 
      covalent bonds with different nucleophilic sites in proteins and nucleic acids, 
      it is reasonable to consider that one possible pathway for nitrogen mustard 
      analogues to exert their aneugenic activity is through reaction with nucleophilic 
      moieties of proteins or genes that are involved in the duplication and/or 
      separation of centrosomes, resulting in abnormal centrosome number. Based on our 
      results the carcinogenicity of nitrogen mustard analogues studied may be 
      attributed not only to their activity to trigger gene mutation and chromosome 
      breakage, but also to their aneugenic potential. Further studies are warranted to 
      clarify the above two hypotheses.
FAU - Efthimiou, M
AU  - Efthimiou M
AD  - Division of Genetics, Cell and Developmental Biology, Department of Biology, 
      University of Patras, Patras 265 00, Greece.
FAU - Andrianopoulos, C
AU  - Andrianopoulos C
FAU - Stephanou, G
AU  - Stephanou G
FAU - Demopoulos, N A
AU  - Demopoulos NA
FAU - Nikolaropoulos, S S
AU  - Nikolaropoulos SS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070130
PL  - Netherlands
TA  - Mutat Res
JT  - Mutation research
JID - 0400763
RN  - 0 (Aneugens)
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Azasteroids)
RN  - 0 (Phenylacetates)
RN  - 18D0SL7309 (Chlorambucil)
RN  - ER5I1W795A (phenylacetic acid)
RN  - Q41OR9510P (Melphalan)
SB  - IM
MH  - Adult
MH  - Aneugens/*pharmacology
MH  - *Aneuploidy
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/pharmacology
MH  - Azasteroids/pharmacology
MH  - Cells, Cultured/drug effects
MH  - Centromere
MH  - Chlorambucil/*pharmacology
MH  - *Chromosome Aberrations
MH  - Female
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - In Vitro Techniques
MH  - Lymphocytes/*drug effects
MH  - Male
MH  - Melphalan/*pharmacology
MH  - Mice
MH  - Micronuclei, Chromosome-Defective
MH  - Micronucleus Tests
MH  - Nondisjunction, Genetic
MH  - Phenylacetates/chemistry/*pharmacology
EDAT- 2007/02/28 09:00
MHDA- 2007/05/16 09:00
CRDT- 2007/02/28 09:00
PHST- 2006/07/24 00:00 [received]
PHST- 2007/01/15 00:00 [revised]
PHST- 2007/01/17 00:00 [accepted]
PHST- 2007/02/28 09:00 [pubmed]
PHST- 2007/05/16 09:00 [medline]
PHST- 2007/02/28 09:00 [entrez]
AID - S0027-5107(07)00038-3 [pii]
AID - 10.1016/j.mrfmmm.2007.01.009 [doi]
PST - ppublish
SO  - Mutat Res. 2007 Apr 1;617(1-2):125-37. doi: 10.1016/j.mrfmmm.2007.01.009. Epub 
      2007 Jan 30.