ASSESSMENT OF GENETIC DAMAGE INDUCED BY CHEMOTHERAPY

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The increasingly complex and effective modalities of chemotherapy has resulted in a rapidly increasing number of patients that are being cured of cancer. One of the major side effects of chemotherapy has been the impairment of gonadal functions. In the present study, several different approaches will be used to investigate gonadal toxicity induced by MOPP and ABVD therapies. These are the two most effective and commonly used drugs treatments for Hodgkin's lymphoma. These drugs include nitrogen, mustard, vincristine, procarbazine and prednisone (MOPP) and adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). Both of these combination drug treatments are effective in producing complete remission in approximately 80% of the treated patients. However, ABVD appears to cause considerable less germ-cell toxicity than MOPP. The studies are divided into two major parts: human studies and studies with experimental animals. Human studies will involve determinations of sperm count, sperm motility, sperm morphology and chromosomal constitutions in semen samples of patients that have been treated with MOPP and ABVD. The former two endpoints will give indications of fertility whereas the latter two will yield information about the induced genetic damage. In addition, reproductive histories of patients, during and after the therapies, will be recorded so that the incidence of birth defects in the offspring of the two treatment groups can be compared. Studies on experimental animals will include treatments with each agent in single and multiple injections, as well as treatments with clinically equivalent schedules so that synergistic or antagonistic effects of drugs used in combination can be determined. Comparisons between the extent of germinal damage in human and mice will be made and an extrapolation factor will be determined. Studies with experimental animals will also allow determination of the effects of individual drugs on producing stem cell killing, genetic damage; and stage-specific toxicity. Therefore, the above studies represent a comprehensive assessment of the effects of a selected number of chemotherapeutic drugs on spermatogenesis. Results from the present study are expected to provide valuable information with regard to the antifertilizing and genetic risks from exposure to these therapies.