MUTAGENICITY OF ANTICANCER DRUGS IN MAMMALIAN GERM-CELLS

The evidence for mammalian germ cell mutagenicity induced by anticance r drugs is summarized. Primary attention is paid to the three major mo use germ cell mutagenicity tests - the dominant lethal, heritable tran slocation, and morphological specific locus tests - from which most ge rm cell mutagenicity data historically have been obtained. Of the 21 a nticancer 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 p atterns seen with other types of chemicals; however, some of the patte rns are unique. For example, 2 of the 8 chemicals shown to induce domi nant 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-me iotic stages (spermatids through mature sperm), and seven also induced reciprocal translocations and/or specific locus mutations in post-mei otic stages. This propensity to induce mutations in post-meiotc stages has been observed with most mutagens. However, 5 of the anticancer dr ugs also induced dominant lethal mutations in spermatocytes (meiotic p rophase cells) and one of them, 6-mercaptopurine, uniquely induced dom inant lethal mutations exclusively in preleptotene spermatocytes. Fina lly, three of the anticancer drugs (melphalan, mitomycin C, procarbazi ne) are members of a very select group of chemicals shown to induce sp ecific locus mutations in spermatogonial stem cells of mice, The impli cations for human risk are discussed.