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Effects of GSH and WR-2721 on induction of micronuclei by cyclophosphamide
1Department of Animal Physiology, Institute of Zoology, Jagiellonian University, Cracow, Poland. maz@zuk.iz.uj.edu.pl
Abstract:
The frequency of micronucleated polychromatic erythrocytes (MNPCEs) was assessed in the bone marrow and peripheral blood of adult male Swiss mice treated with reduced glutathione (GSH) and/or S-2-/3-aminopropylamino/ethyl phosphorothioic acid (WR-2721), at a dose of 400 mg/kg body weight, and/or with cyclophosphamide (CP), at a dose of 200 mg/kg body weight. GSH was given 60 or 15 min and/or WR-2721 was applied 30 min before CP administration. The number of MNPCEs was determined at 24 h after the drug application. After treatment of mice with CP, the frequency of MNPCEs was distinctly increased. The stronger chemoprotective effect against CP-induced cytotoxicity was obtained following GSH administration than after WR-2721 injection. WR-2721 characterized greater cytotoxicity than GSH. The combination of GSH and WR-2721 given alone, or before CP administration resulted in the most cytotoxic and chemoprotective effects, compared with the respective single-thiol treatment of mice. The most effective protection against CP-induced genotoxicity was observed in the case of treatment of mice with WR-2721and GSH, respectively, 30 and 15 min before CP administration. The most cytotoxic effect of the thiols was found when GSH given 30 min prior to WR-2721 application. The chemoprotection and cytotoxicity caused in the mouse erythroblasts by GSH and WR-2721, as indicated by the number of MNPCEs were dependent on the thiol(s) given, and the time intervals between the drug administration. The modulatory effect of the thiols GSH and WR-2721 on 'delayed apoptosis' induced in the erythropoietic system by cyclophosphamide was shown.
Insights
Reduced glutathione (GSH) and WR-2721 protect against cyclophosphamide (CP)-induced genotoxicity in mice. Combining GSH and WR-2721 provided superior chemoprotection and cytotoxicity, with optimal timing enhancing these effects.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Cyclophosphamide (CP) is a widely used chemotherapeutic agent with known genotoxic and cytotoxic side effects.
- Glutathione (GSH) and S-2-/3-aminopropylamino/ethyl phosphorothioic acid (WR-2721) are radioprotective thiols with potential chemoprotective properties.
- Assessing the protective effects of these thiols against CP-induced damage is crucial for improving cancer treatment strategies.
Purpose of the Study:
- To evaluate the chemoprotective and cytotoxic effects of reduced glutathione (GSH) and WR-2721 against cyclophosphamide (CP)-induced genotoxicity in mice.
- To determine the optimal administration timing and combination of GSH and WR-2721 for maximum chemoprotection.
- To investigate the modulatory effects of these thiols on CP-induced delayed apoptosis in the erythropoietic system.
Main Methods:
- Adult male Swiss mice were treated with GSH (400 mg/kg) and/or WR-2721 (400 mg/kg) before cyclophosphamide (CP) administration (200 mg/kg).
- The frequency of micronucleated polychromatic erythrocytes (MNPCEs) in bone marrow and peripheral blood was assessed 24 hours post-treatment.
- Different time intervals between thiol and CP administration were tested to identify optimal protective and cytotoxic effects.
Main Results:
- CP treatment significantly increased MNPCEs, indicating genotoxicity.
- GSH demonstrated stronger chemoprotection against CP-induced cytotoxicity than WR-2721.
- The combination of GSH and WR-2721 exhibited the most significant chemoprotective and cytotoxic effects, with specific timing (WR-2721 30 min before CP, GSH 15 min before CP) yielding the best protection against genotoxicity.
Conclusions:
- GSH and WR-2721 effectively protect against cyclophosphamide-induced genotoxicity and cytotoxicity in mice.
- The combination of GSH and WR-2721, administered at specific intervals, offers superior chemoprotection compared to single-agent treatment.
- These thiols modulate CP-induced delayed apoptosis in the erythropoietic system, highlighting their potential therapeutic application in mitigating chemotherapy side effects.