Utility of the murine erythroleukemic cell (MELC) in assessing mechanisms of action of DNA-active developmental toxicants: Application to 5-fluorouracil
| Autor: | Robert M. Zucker, Christopher Lau, John M. Rogers, Kenneth H. Elstein, Neil Chernoff, Dana L. Shuey |
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| Rok vydání: | 1993 |
| Předmět: |
Embryology
Cell Survival Health Toxicology and Mutagenesis Cell Biology Decitabine Toxicology Mice Limb bud Fetus In vivo Culture Techniques Tumor Cells Cultured medicine Animals Cyclophosphamide Cell Cycle DNA Thymidylate Synthase Cell cycle Embryonic stem cell In vitro Cell biology Teratogens medicine.anatomical_structure Mechanism of action Toxicity Azacitidine Fluorouracil Leukemia Erythroblastic Acute medicine.symptom Developmental Biology |
| Zdroj: | Teratology. 48:75-87 |
| ISSN: | 1096-9926 0040-3709 |
| Popis: | 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 tissuespecific 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. © 1993 Wiley-Liss, Inc.1 |
| Databáze: | OpenAIRE |
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