PMID- 7688913
OWN - NLM
STAT- MEDLINE
DCOM- 19930916
LR  - 20181130
IS  - 0040-3709 (Print)
IS  - 0040-3709 (Linking)
VI  - 48
IP  - 1
DP  - 1993 Jul
TI  - Utility of the murine erythroleukemic cell (MELC) in assessing mechanisms of 
      action of DNA-active developmental toxicants: application to 5-fluorouracil.
PG  - 75-87
AB  - Murine erythroleukemic cells (MELC) exposed to 2'-deoxy-5-azacytidine (D-AZA) or 
      to the active cyclophosphamide (CP) metabolites phosphoramide mustard (PAM) and 
      4-hydroxycyclophosphamide (OHCP) exhibit cell-cycle perturbations similar to 
      those seen in limb bud nuclei of gestational day (GD) 10 CD-1 mouse embryos 
      exposed in utero to D-AZA or CP, respectively. The similarities in response 
      suggest MELC may be a useful model for determining mechanisms of action of 
      DNA-active developmental toxicants. As such, we used the MELC model to 
      investigate the mechanism of action of 5-fluorouracil (5-FU), an antimetabolite 
      that induced in GD 14 rat fetuses an apparent S-phase accumulation in limb cells 
      8 hr after in utero exposure, but S-phase depletion in liver cells 24 hr 
      postexposure. MELC timed-recovery and synchronization studies suggest that in 
      proliferative tissues, 5-FU induces an early S-phase accumulation, followed by a 
      synchronous, concentration-dependent delay in progression through the cell cycle. 
      Consequently, it is the tissue-specific rate of delay, rather than different 
      mechanisms of action, that results in apparent tissue-specific perturbations. 
      Moreover, growth and cell-cycle data suggest that cells entering S phase (when TS 
      activity is greatest) are the most sensitive to 5-FU toxicity. Assays of the TS 
      activity of recovering MELC reveal that although the initial extent of TS 
      inhibition does not appear to be concentration-dependent, the time to recovery 
      is, suggesting that the rate of S-phase progression is closely associated with TS 
      activity. Together, the induction of similar cell-cycle perturbations in 
      embryonic/fetal tissues and MELC following exposure to CP (or CP metabolites), 
      D-AZA, or 5-FU, as well as the adaptability of MELC to a variety of kinetic 
      assays suggests that, for those developmental toxicants suspected of inducing 
      cell-cycle perturbations in embryonic/fetal tissues, MELC may prove useful for 
      elucidating mechanisms of action.
FAU - Elstein, K H
AU  - Elstein KH
AD  - ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 
      27709.
FAU - Zucker, R M
AU  - Zucker RM
FAU - Shuey, D L
AU  - Shuey DL
FAU - Lau, C
AU  - Lau C
FAU - Chernoff, N
AU  - Chernoff N
FAU - Rogers, J M
AU  - Rogers JM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Teratology
JT  - Teratology
JID - 0153257
RN  - 0 (Teratogens)
RN  - 776B62CQ27 (Decitabine)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - 9007-49-2 (DNA)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - M801H13NRU (Azacitidine)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Animals
MH  - Azacitidine/analogs & derivatives/toxicity
MH  - Cell Cycle/drug effects
MH  - Cell Survival/drug effects
MH  - Culture Techniques
MH  - Cyclophosphamide/toxicity
MH  - DNA/*drug effects
MH  - Decitabine
MH  - Fetus/drug effects
MH  - Fluorouracil/toxicity
MH  - Leukemia, Erythroblastic, Acute
MH  - Mice
MH  - Teratogens/*toxicity
MH  - Thymidylate Synthase/metabolism
MH  - Toxicology/*methods
MH  - Tumor Cells, Cultured/*drug effects
EDAT- 1993/07/01 00:00
MHDA- 1993/07/01 00:01
CRDT- 1993/07/01 00:00
PHST- 1993/07/01 00:00 [pubmed]
PHST- 1993/07/01 00:01 [medline]
PHST- 1993/07/01 00:00 [entrez]
AID - 10.1002/tera.1420480112 [doi]
PST - ppublish
SO  - Teratology. 1993 Jul;48(1):75-87. doi: 10.1002/tera.1420480112.