5-Flourouracil-induced toxicity in both male and female reproductive systems: A narrative review.

The chemotherapeutic drug 5-flourouracil (5FU) is frequently used to treat a wide range of solid malignant tumors, such as colorectal, pancreatic, gastric, breast, and head and neck cancers. Its antitumoral effects are achieved by interfering with the synthesis of RNA and DNA and by inhibiting thymidylate synthase in both malignant and non-malignant cells. Therefore, it can be responsible for severe toxicities in crucial body organs, including heart, liver, kidney, and reproductive system. Given the fact that 5FU-induced reproductive toxicity may limit the clinical application of this drug, in this study, we aimed to discuss the main locations and mechanisms of the 5FU-induced reproductive toxicity. Initially, we discussed the impact of 5FU on the male reproductive system, which leads to damage of the seminiferous epithelial cells and the development of vacuoles in Sertoli cells. Although no noticeable changes occur at the histopathological level, there is a decrease in the weight of the prostate. Additionally, 5FU causes significant abnormalities in spermatogenesis, including germ cell shedding, spermatid halo formation, polynucleated giant cells, and decreased sperm count. Finally, in females, 5FU-induced reproductive toxicity is characterized by the presence of atretic secondary and antral follicles with reduced numbers of growing follicles, ovarian weight, and maturity impairment.

Effect of Ketorolac on Pharmacokinetics and Pharmacodynamics of 5-Fluorouracil: In Vivo and In Vitro Study.

Background: This study aimed to evaluate the impact of ketorolac on the pharmacokinetics of 5-FU and its effect on the efficacy of 5-fluorouracil (5-FU) on the HT-29 cell line. Methods: Cell culture: the HT-29 cell line was treated with different concentrations of 5-FU, ketorolac, and combination of 5-FU and ketorolac for 24 and 48 hours. The cell viability (%) was calculated by the MTT assay. Animal study: rats were randomly divided into control and pretreatment groups. The control group received physiological saline, whereas the pretreatment group received ketorolac by intraperitoneal (i.p.) injections on a daily basis for 14 days. On the 15th day, both groups received 5-FU (i.p.). Blood samples were collected at different times for HPLC analysis, and 5-FU pharmacokinetic parameters were calculated. Results: At cell culture study, in a certain concentration range, combination therapy showed synergistic effects (<0.05). However, at concentrations above this range, combination therapy showed antagonistic effects on 5-FU efficacy (<0.05). According to the pharmacokinetic analysis, pretreatment with ketorolac resulted in a significant increase in AUC, C max, and T max of 5-FU (<0.05) and a significant decrease in V/F and Cl/F of 5-FU (<0.05). Conclusions: Combination therapy with ketorolac and 5-FU, depending on time and concentration, has a synergistic effect on reducing the viability of cancer cells. Also, ketorolac is able to alter the pharmacokinetics of 5-FU. Since there is a close relationship between pharmacokinetic parameters of 5-FU and its effectiveness/toxicity, it seems that these changes are towards creating a synergistic effect on 5-FU cytotoxicity. These results suggest the need to optimize the dose of these drugs in order to increase clinical efficacy and reduce the toxicity associated with them.