Abstract 2768: Treosulfan induces differential gonadal toxicity profile compared with Busulfan

Abstract

Abstract Background: Treosulfan (L-treitol-1,4-bis-methanesulfonate), an alkylating agent with myeloablative and immunosuppressive traits, has been increasingly incorporated as a main conditioning protocol for hematopoietic stem cell transplantation (HSCT) in pediatric malignant and non-malignant diseases. Treosulfan has been shown to present lower toxicity profile compared with conventional myeloablative regimens such as busulfan. Yet, while busulfan is considered highly gonadotoxic, the gonadal toxicity profile of treosulfan remains to be elucidated. Our aim was to study the short and long term gonadal effect of treosulfan in comparison to busulfan. Methods: Mature 2 months old male and 3 months old female mice (“pubertal cohort”) were injected with treosulfan 2000 mg/kg or busulfan 40 mg/kg and were sacrificed one week, one month or six months post drug administration. Immature male and female mice (“prepubertal cohort”) were injected with treosulfan 750 mg/kg or busulfan 15 mg/kg and were sacrificed one week or three months post drug administration. Testicular function was assessed by measurements of sperm count and motility, testes and epididymides weight, serum anti-Mullerian Hormone (AMH) and testicular ID4 or GFRA1 mRNA (markers for stem spermatogonia). Immunohistochemistry was performed to evaluate testicular proliferation (Ki-67), apoptosis (TUNEL) and meiotic-active spermatocytes (DAZL-PCNA). Ovarian function was assessed by measurements of ovary weight, serum AMH, follicles count and ovarian SOHLH2, NOBOX of FIGLA mRNA (markers for primordial follicles). Immunohistochemistry was performed to evaluate ovarian proliferation (Ki-67), apoptosis (TUNEL) and growing follicles (AMH-PCNA). Results: Treosulfan testicular toxicity was milder compared to busulfan toxicity, in both mature and immature male mice, while stem spermatogonia were spared. However, ovarian toxicity of both treosulfan and busulfan was severe and permanent in both mature and immature female mice; possibly by a short term irreversible reduction of reserve primordial follicles in the ovaries. Conclusion: Our results indicate that treosulfan exerts a differential gonadal toxicity profile compared with busulfan, manifested by mild testicular toxicity and severe ovarian toxicity. Citation Format: Mattan Levi, Salomon Stemmer, Jerry Stein, Ruth Shalgi, Irit Ben-Aharon. Treosulfan induces differential gonadal toxicity profile compared with Busulfan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2768. doi:10.1158/1538-7445.AM2017-2768