Mutagenicity of anticancer drugs in mammalian germ cells

The evidence for mammalian germ cell mutagenicity induced by anticancer drugs is summarized. Primary attention is paid to the three major mouse germ cell mutagenicity tests- the dominant lethal, heritable translocation, and morphological specific locus tests- from which most germ cell mutagenicity data historically have been obtained. Of the 21 anticancer drugs reviewed, 16 have been tested in one or more of these three tests; with all 16 tested in the most common germ cell test, the male dominant lethal test, and 9 of the 16 also tested in the female dominant lethal test. The patterns of germ cell stage specificity for most of the anticancer drugs are similar, and generally resemble the patterns seen with other types of chemicals; however, some of the patterns are unique. For example, 2 of the 8 chemicals shown to induce dominant lethal mutations in female oocytes, do not induce dominant lethal mutations in male germ cells (adriamycin and platinol). Ten of the 16 chemicals tested in the dominant lethal test were positive in post-meiotic stages (spermatids through mature sperm), and seven also induced reciprocal translocations and/or specific locus mutations in post-meiotic stages. This propensity to induce mutations in post-meiotic stages has been observed with most mutagens. However, 5 of the anticancer drugs also induced dominant lethal mutations in spermatocytes (meiotic prophase cells) and one of them, 6-mercaptopurine, uniquely induced dominant lethal mutations exclusively in preleptotene spermatocytes. Finally, three of the anticancer drugs (melphalan, mitomycin C, procarbazine) are members of a very select group of chemicals shown to induce specific locus mutations in spermatogonial stem cells of mice. The implications for human risk are discussed.