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Stage-Specific Inhibition of Deoxyribonucleic Acid Synthesis and Induction of Apoptosis by Antracyclines in Cultured Rat Spermatogenic Cells¹

^a Pediatric Endocrinology Unit, ^b Karolinska Institute; Karolinska Pharmacy, Karolinska Hospital, SE-171 76 Stockholm, Sweden ^c Departments of Pediatrics and Anatomy, University of Turku, FIN-20520 Turku, Finland

ABSTRACT

A rapid in vitro method has been developed to detect early effects of cytostatic drugs on rat spermatogenesis. The induction of programmed cell death (apoptosis) and changes in DNA synthesis induced by doxorubicin and idarubicin were measured in specific stages of the cycle of seminiferous epithelium including mitotic (stage V) and meiotic (stage VIII-IX) S-phase cells. The model was used to investigate the protective effect of an organic thiophosphate, amifostine, against the toxicity of antracyclines. Premitotic DNA synthesis was found to be more sensitive than premeiotic DNA synthesis to antracyclines. Idarubicin was more toxic than doxorubicin to germ cells in inducing apoptosis and suppressing DNA synthesis. Amifostine had no protective effect against doxorubicin- or idarubicin-induced inhibition of DNA synthesis. In contrast, a significant stimulation of DNA synthesis in premitotic cells by amifostine was found, suggesting that this compound may have a stimulative effect on spermatogenic stem cells. These data show that stage-specific dissection of the seminiferous tubules and their in vitro exposure to predetermined doses of drugs may give us a unique possibility to detect drug action and protection against the cytotoxicity of antineoplastic agents at the cellular level of the spermatogenic cycle.

FOOTNOTES

First decision: 15 December 1999.

¹ This research was supported by the Swedish Child Cancer Fund, the Swedish Medical Research Council (PN 8282 and 11412), the Magnus Bergvall Foundation, Frimurare Barnhuset in Stockholm, the H.R.H. Crown Princess Lovisa Society of Pediatric Health Care, the Society for Child Care, the Swedish Medical Association, the Finnish Cancer Society, the Finnish Cultural Foundation, the Finnish Pediatric Research Foundation, and Sigrid Juselius Foundation.

² Correspondence: Kirsi Jahnukainen, Pediatric Endocrinology Unit, Astrid Lindgren Children's Hospital, Karolinska Institute, SE-171 76 Stockholm, Sweden. FAX: 46 8 51 77 51 28; kirsi.jahnukainen{at}tyks.fi

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