Selective gene mutation in MEL cells

Effect of bacitracin on erythroid differentiation of MEL cells

“…The effects of bacitracin on erythroid differentiation are similar to those induced in MEL cells by mutagens such as mitomicin C, 1-nitropyrene, 9-aminoacridine, cyclophosphamide and many others (Foresti et al, 1986(Foresti et al, , 1990a in a similar range of concentrations or by UV irradiation (Foresti et al, 1992). Furthermore, Gutteridge (1989, 1991) reported that bacitracin causes DNA-base damage by chemical reactions leading to the formation of reactive oxygen species.…”

“…It has been previously reported that the ability of MEL cells to undergo erythroid differentiation can be permanently blocked by exposing the cells for a few hours at a sublethal dose of any of the several chemical mutagens (Foresti et al, 1990a,b), or UV irradiation (Foresti et al, 1992). However, it was shown that the period of sensitivity to mutagens corresponds to the start of the S phase in MEL cell cultures parasynchronized in G1/S by induction with DMSO (Foresti et al, 1986) or synchronized in G1/S by thymidine and hydroxyurea blocks (Foresti et al, 1990a;Foresti et al, 1992). A strict correlation has been observed between the ability of a tested compound to damage the DNA and the inhibition of erythroid differentiation in MEL cells, as many chemicals that do not interact with DNA are without effect (Foresti et al, 1990a,b).…”

“…The inhibition of differentiation, or of any other cellular function tested, such as G6PD or 6PGD or HPRT, caused by mutagenic agents is the result of a genetic damage, as a very high frequency (30-50%) of cellular mutant clones can easily be isolated from the treated cultures (Foresti et al, 1990a(Foresti et al, ,b, 1992. Studies on DNA repair activity during the cell cycle of MEL cells indicate that the DNA repair in the early S phase is less efficient than in the remaining periods of the cell cycle (Foresti et al, 1990a;Foresti et al, 1992). The fixation of a mutation into the cellular genome is the result of several causes, all acting at the same time: (1) ability of the tested compound to damage DNA; (2) efficiency of DNA repair; (3) the period of the cell cycle when the cells are treated.…”

Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

“…Excluding tumours due to the effect of external factors such as viruses [5], stem cells appear to be good candidates for tumour origination because they are able to duplicate and have not reached a final and stable genetic stage and because their genomes must undergo reprogramming to express the proper differentiated phenotype. In line with this hypothesis is the finding that cultured tumour mouse erythroleukemia cells are particularly sensitive to mutations in specific periods during erythroid differentiation [6], [7], [8]. Random mutations are expected to occur more frequently in nucleotide positions that are not relevant for molecular functions and in genes not necessary to express a differentiated phenotype.…”