Implications of reiterative DNA—Metal ion complexes in the induction and development of neoplastic cells

Abstract

Experimental data on the content in metal ions of DNA preparations from various neoplastic and healthy tissues are summarized: metal ions are preferentially bound to reiterative DNA sequences, where they may induce conformational variations and thus modify the binding of effector molecules such as repressors and polymerases.A model is described where essential and toxic metals are successively loaded on ligand acceptor groups of increasing affinity and thus may reach the final active sites: enzymes and reiterative DNA sequences (equated at least partially to regulative DNA sequences). The effects of some molecules, including peptides, antibiotics, growth factors, hormones, and antineoplastic substances, on DNA conformation could be explained in part by their chelating ability.The neoplastic state may be induced by a modification of metal ion transfer chains: quantitatively by a continuous derepression of genes coding for metal ligands, genes that are only temporarily derepressed during development in normal cells, and qualitatively by modifications of the nucleotidic sequence of structural genes leading to an increase of the chelating ability of the coded metal ligand.

A comparison of genome modifications leading to genetic and epigenetic tumorous transformation in Nicotiana spp. tissue cultures

“…This hypothesis is supported by the increase in the highly repetitive fraction found in the transformed strain and by the fact that one of the two additional peaks shown after Ag+-Cs2S04 ultracentrifugation has also been found in the early stages of N. glauca pith tissue proliferation. In our case as in others (GuillC et al, 1979(GuillC et al, , 1981 both tumorous transformations (genetic and epigenetic) were correlated with higher DNA-bound ion content.…”

Toxicity and mutual interactions of cadmium and zinc ions in normal and carcinogen-transformed mouse cells

“…The indicated concentrations correspond to the molarity of Zn concentration in one of the two lots the pure metalionin complete medium. The ÷+ ' " of serum used was measured by anodic stripping voltametry (Guille et al, 1979) and found to be 9.1 /.tM. Both sera gave rise to comparable results in the cytotoxicity experiments.…”

“…The experiments were carried out with normal mouse fibroblast cells as well as their carcinogen-transformed counterparts. It has been shown that malignant cells bind metal ions to their DNA more efficiently than do normal cells, and that this phenomenon may vary in different species (Andronikashvili et al, 1974;Guille et al, 1979). The toxicity and the mutual interactions of zinc and cadmium are reported here.…”

“…Metals such as zinc or manganese appear to play a key role in the function of metalloenzymes including RNA and DNA polymerases and superoxide dismutases (Vallee and Falchuk, 1981). The presence of certain metals in particular sequences of nuclear DNA suggests that they may play a role in DNA function (Guille et al, 1979). On the other hand, the metabolism of these metal ions, their sites of regulation, and their overall regulatory functions are as yet poorly understood.…”

Iron metabolism during infection and neoplasia

“…High concentrations of iron have been shown to inhibit the phagocytic activity of monocytes [106] and the tumorcidal action of macrophages [107]. Furthermore, excess iron has been shown to enhance the chromosome damage induced by ascorbate in cultured Chinese hamster ovary cells [109]. It has been theorized that high intracellular iron concentrations could lead to neoplasia by causing conformational variation in reiterative DNA sequences, thus modifying binding of repressors and polymerases, or by leading to a continuous derepression of genes coding for metal ligands [109].…”