BIOLOGICAL MARKERS IN CIS DDP TREATED TESTICULAR CANCER

Cisplatinum (cis-DDP) is a widely-used chemotherapy agent which is also mutagenic and carcinogenic in experimental systems. Thus it is a model compound for purposes of validating methods to biomonitor humans with exposure to mutagens/carcinogens. We are proposing to study several complementary markers of the biologically effective dose of cis-DDP-based chemotherapy in testicular cancer patients. These markers include chemical specific DNA intrastrand adducts formed by cis-DDP, as well as somatic cell mutation (glycophorin A locus) and several generic cytogenetic markers (sister chromatid exchange, micronuclei in lymphocytes, and chromosomal aberrations) attributable to cis- DDP combination therapy. These will be evaluated in peripheral blood cells (PBLs) and sperm cells in order to permit direct comparison of genetic damage in somatic cells and germ cells in the same individuals. Markers will be evaluated in serial samples of peripheral blood and semen obtained from a total of 30 previously untreated testicular cancer patients prior to and following chemotherapy. Adducts and chromosomal aberrations will also be assessed in blood and semen samples from 12-15 testicular cancer patients who were treated with cis-DDP and combination drugs several years previously. The purpose of the study is three-fold: (1) to relate genetic damage in somatic cells to that occurring in germ cells; (2) to validate the selected markers as dosimeters by evaluating the relationship between administered and cumulative dose of cis- DDP/combination drugs and changes in levels of markers; and (3) to assess the relationship between chemotherapy treatment and potential risk of second malignancy or germ cell malignancy (reproductive risk). This research should contribute to our understanding of the biological activity of cis-DDP and combination drugs, the variability in human response, and the potential cancer and reproductive risk associated with treatment. Very importantly, if validated as dosimeters in this model population, the markers could be applicable to populations exposed to other environmental mutagens/carcinogens and reproductive toxicants, and thus could become useful in disease prevention.