Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia

Abstract

This study investigated whether chemotherapy using fludarabine (FLU) caused testicular damage and if cytotoxicity could be detected as sperm DNA damage in the single cell Comet assay. A patient with chronic lymphocytic leukaemia requesting preservation of fertility was treated with seven monthly cycles of fludarabine (45.8 mg total dose per cycle). Testicular assessments, serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone measurements, semen analysis and sperm Comet assays were carried out at presentation (pre-FLU therapy), after 1 and 7 months of FLU treatment, and finally at 11 months after completion of chemotherapy. We found that testicular damage occurred within a month, as indicated by reduced testicular volume, oligozoospermia, elevated FSH and LH, and lower testosterone concentrations. Spermatozoa with a large range of DNA damage were detected in the samples from both the control and treated men. DNA damage in the spermatozoa was marked by 7 months of FLU treatment. The high levels of sperm DNA damage seen during and possibly persisting after treatment suggests that caution should be exercised if the ejaculates from these men are used for in-vitro fertility treatment. Further experiments are needed to assess the biological significance of these DNA changes; it may, however, be prudent at present to be cautious when counselling these patients.

Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies

“…3 Although it may be expected that multiagent chemotherapy such as BEAM will induce more gonadal injury than melphalan and fludarabine alone, we have shown evidence of testicular injury even with fludarabine used as monotherapy in a patient with CLL. 9 Although there are no human data on reproductive or gonadotoxic potential in our nonmyeloablative protocol, melphalan protocols are less gonadotoxic than others using busulphan/cyclophosphamide or cyclophosphamide alone 11 based on an increased number of pregnancies. 12 However, these studies did not look into sperm parameters or gametogenic/steroidogenic endocrine function.…”

“…We have recently reported that it can induce sperm-DNA damage in humans, which may persist for several months after the return of spermatogenesis. 9 The primary end point of this study was to investigate whether the combined regimen of fludarabine, melphalan and CAMPATH-1H can induce damage to GC and LC compartments. A second end point was to compare this protocol with regimens used in myeloablative transplants.…”

Sperm DNA damage in male infertility: etiologies, assays, and outcomes

“…These causes are many and range from environmental conditions such as cigarette smoking [99], irradiation [8], and chemotherapy [20,88] to pathophysiologic conditions such as leukocytospermia [5,35], varicoceles [105,107], and cancer [70]. Even iatrogenic causes such as sperm cryopreservation [32,73] have been associated with sperm DNA damage.…”

Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications

“…Thus, the heteroplasmic mutation seen in the patient under chemotherapy was most likely induced by the therapeutic agents (fludarabine/ cyclophosphamide), which are known to have DNA-damaging properties and cause mutations. [16][17][18][19][20][21] Importantly, substitution of the G nucleotide at position 7762 by a C nucleotide resulted in an amino-acid change (Gln-His) at codon #59 of the COII enzyme, a key component of mitochondrial electron transport complex IV. Interestingly, comparison of the cellular levels of the superoxide radical (O 2 À , a product of mitochondrial (Figure 2b).…”