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Clinical and experimental evidence of inhibition of testosterone production by suramin
R Danesi1, R V La Rocca, M R Cooper
1Scuola Superiore di Studi Universitari e di Perfezionamento S. Anna, Pisa, Italy. mbxdanesi@mail.cnuce.cnr.it.
Abstract:
The effect of suramin on testosterone production was evaluated in cancer patients, adult male rats, rat Leydig cells, and NCI-H295 human adrenal cancer cells. Testosterone plasma levels markedly decreased in 14 patients receiving suramin as a therapy for refractory cancer, and in 8 of them, the plasma LH and/or FSH levels increased beyond the normal range. The hCG stimulation test (5000 IU, im) was performed in 8 patients and induced an average 2.1-fold increase in testosterone levels over baseline values. Testicular histology after suramin treatment was available in 1 patient who died of progressive disease; this revealed atrophy of seminiferous tubules and reduced Leydig cells in the interstitium. A significant reduction in plasma testosterone was also observed in rats given 18 mg/kg suramin, ip, twice weekly for 8 weeks, whereas plasma LH and FSH levels did not change significantly. Cytohistochemistry of testes from suramin-treated rats showed a reduced number of 3 beta-hydroxysteroid dehydrogenase-positive cells within the interstitium compared to controls, and light microscopy revealed severe impairment of spermatogenesis. Suramin inhibited the production of testosterone by isolated rat Leydig cells as well as the conversion of pregnenolone to progesterone by the 3 beta-hydroxysteroid dehydrogenase enzyme extracted from rat testes, with 50% inhibitory concentrations (IC50 values) of 108.2 and 87.5 micrograms/mL, respectively. Furthermore, suramin reduced the release of testosterone into the culture medium of NCI-H295 adrenal cancer cells with IC50 values of 91.2 and 83.9 micrograms/mL after 6 and 12 days, respectively. These data provide the first evidence in patients that suramin treatment produces a marked reduction in the circulating levels of testosterone, a result that was also obtained in experimental models.
Insights
Suramin significantly reduces testosterone levels in cancer patients and experimental models. This drug impacts Leydig cells and spermatogenesis, indicating potential endocrine disruption.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Suramin is an antiparasitic drug with potential anticancer applications.
- The endocrine effects of suramin, particularly on testosterone production, are not well-established.
Purpose of the Study:
- To investigate the impact of suramin on testosterone production in various models, including cancer patients, rats, and cell lines.
- To elucidate the mechanisms by which suramin may affect the male reproductive system.
Main Methods:
- Clinical observation of testosterone and gonadotropin levels in cancer patients treated with suramin.
- Animal studies involving suramin administration to rats, followed by hormonal assays and testicular histology.
- In vitro experiments using isolated rat Leydig cells and NCI-H295 human adrenal cancer cells to assess suramin's direct effects on testosterone synthesis and enzyme activity.
Main Results:
- Marked decrease in plasma testosterone levels observed in cancer patients receiving suramin.
- In rats, suramin treatment led to reduced plasma testosterone, testicular atrophy, and impaired spermatogenesis.
- Suramin inhibited testosterone production in isolated Leydig cells and NCI-H295 cells, with significant IC50 values.
Conclusions:
- Suramin treatment causes a significant reduction in circulating testosterone levels in humans and experimental models.
- The drug appears to disrupt testosterone synthesis and affect testicular function, highlighting potential endocrine side effects.