The objective of this study is to obtain the data on experimental animals as well as on patients treated with Adriamycin (ADR) that will allow prediction of the magnitude of the genetic risk to the offspring of these patients resulting from ADR treatment. ADR was selected for study because it is the only chemotherapeutic drug that appears to produce chromosomal mutations in stem spermatogonia, allows relatively large numbers of patients to recover fertility after treatment with it, and currently used methods for interspecies extrapolation of the testicular doses and biological effects based on administered doses appear to be inadequate. We will measure genetic damage induced by ADR in the stem spermatogonia of mouse testes. Chromosomal aberrations in dividing germ cells, abnormal DNA content in spermatids and sperm detected by flow cytometry, and sperm head malformations will be measured in the treated mice. In their progeny, dominant lethal mutations, sperm abnormalities and heritable translocations will be scored. The appropriate method for interspecies extrapolation of the effective dose of ADR to the spermatogonial cells will be determined. The pharmacokinetics of ADR in the testes of mice, rats, rabbits, dogs, and rhesus monkeys will be measured to determine the testicular dose from ADR, which will be compared with survival of spermatogonia. We shall use these data to determine whether the testicular toxicity of ADR in different species can be explained using pharmacokinetics and if so to determine a relationship between animal size and the fraction of the administered dose reaching the testis. We will use this relationship to extropolate the testicular dose, and hence the predicted mutagenic effects, from small test animals to man. The adverse action on sperm production of selected chemotherapy combinations that contain ADR will concurrently be studied in patients treated for lymphomas and sarcomas. The time course of alterations in sperm count and quality, and the probability of recovery of sperm production will be determined for each regimen. The effects of therapy on the variability in DNA content of spermatozoa will be measured by flow cytometry. In addition, reproductive histories of these patients, including untoward pregnancy outcomes and possible genetic abnormalities in their offspring, will be determined to directly estimate the genetic risk.
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