Mutagenic effects of some anticancer antibiotics.

Considering the strong correlation observed between carcinogenic and mutagenic properties of chemicals, a study of the genetic effects of antineoplastic agents is warranted in as much as these agents may ‘cure’ certain types of cancers but may initiate some other types; in addition, an understanding of the effects of these antibiotics on possible transmissible alterations in the genetic material would be beneficial. The genetic effects of some antibiotic anticancer agents, viz., daunomycin (daunorubicin), adriamycin, bleomycin, actinomycin D, and mitomycin C are reviewed. Even though these are structurally unrelated (except for adriamycin and daunomycin), all these chemicals interfere with DNA synthesis through intercalation (daynomycin, adriamycin, and actinomycin), removal of basis from DNA (bleomycin), or co-valent bonding with DNA (mitomycin C) and strand breakage. In some case a parallelism is found between these chemicals and radiation (e.g., mitomycin C vs UV and bleomycin vs X-rays). All these chemicals have a reversible effect on the cell cycle only when applied at low concentrations. The G 0 stage is the most resistant and the S phase, the most sensitive to these chemicals, bleomycin having a general non-phase-specific effect. Actinomycin binds to chromatin differentially along the length of chromosome, and about 90% of this binding is with the DNA. Andriamycin, daunomycin and bleomycin also bind to chromatin, but not enough is known about differential binding. Phenomena such as enzymatic reduction, e.g., in the case of anthracyclines, seem to confer tissue specificity. The ability of actinomycin D to induce point mutations has been challeged, and most mutation-like effects appear to be epigenetic. The anthracyclines do not appear to be mutagenic either. Mitomycin C is mutagenic, however, perhaps because of its alkylating properties, as shown by studies with several species of micro-organisms, Drosophila, Habrobracon, mice, and human HLA system. Bleomycin has recently been shown to be a locus-specific mutagen in yeast. The study of chromosomes from lymphocytes and bone marrow of individuals receiving chemotherapy, and also in vitro studies, have revealed aberrations, an effect common to all other chemicals. However, the major effect is found when the treatment affects the S phase, except with bleomycin, which also happens to be the only chemical with an effect on prophase chromosomes. Mitomycin and bleomycin alos appear to effect the G 0 chromatin in mammals. The major effect of mitomycin C is the production of quadriradials by way of involving homologous chromosomes at corresponding, and preferentially heterochromatic, areas. No other chemical with such great specificity, has been found. Aberrations produced by mitomycin and actinomycin are exclusively of chromatid type, whereas others produce both chromatidand chromosome-type aberrations — both fragments and exchanges. The aberrations are localized in a nonrandom fashion along the length of the genome except with bleomycin, which does not show ‘hot sports’ as convincingly as other chemicals do. Mitomycin C, daunomycin, and adriamycin are very potent inducers of sister chromatid exchanges (SCEs), whereas bleomycin is a poor inducer of this phenomenon. There appears to be a cell-type specificity for induction of both chromosome aberrations and sister chromatid exchanges, though it is not the same at the two end points. The study of somatic crossing-over and meiotic effects has been confined primarily to plants, except for the study of meiotic phenomena in mice and Hebrobracon and Drosophila. Again mitomycin C turns out to be the most effective chemical in these regards. From these and other data on synergistic effects observed in a variety of organisms, there is an urgent need to draw conclusions on the effects of these chemicals on human genetic material in relation to transmissible changes, origin of neoplasia, and the control of cell growth as affected by genetic alterations brought about by these chemicals.