Anti-genotoxicity of trans-anethole and eugenol in mice.

The naturally occurring flavouring agents trans-anethole and eugenol were evaluated for antigenotoxic effects in mice. The test doses of trans-anethole (40-400 mg/kg body weight) and eugenol (50-500 mg/kg weight) were administered by gavage 2 and 20 h before the genotoxins were injected intraperitoneally. Anti-genotoxic effects were assessed in the mouse bone marrow micronucleus test. Pretreatment with trans-anethole and eugenol led to significant antigenotoxic effects against cyclophosphamide (CPH), procarbazine (PCB), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and urethane (URE). In addition, trans-anethole inhibited the genotoxicity of ethyl methane sulfonate (EMS). Both trans-anethole and eugenol exerted dose-related antigenotoxic effects against PCB and URE. There was no significant increase in genotoxicity when trans-anethole (40-400 mg/kg body weight) and eugenol (50-500 mg/kg body weight) were administered alone.

Protection of the germinal epithelium in the rat from the cytotoxic effects of chemotherapy by a luteinizing hormone-releasing hormone agonist and antiandrogen therapy.

OBJECTIVES: The protection of spermatogenesis during chemotherapy using an antiandrogen and a luteinizing hormone-releasing hormone (LHRH) agonist was examined in the rat. Previous studies using LHRH agonists alone have been inconclusive, as both protective and deleterious effects on the germinal epithelium have been reported. Flutamide has not previously been used in this manner but theoretically should protect the germinal epithelium, since flutamide rapidly blocks testosterone at the cellular level and also minimizes the testosterone "flare" when LHRH agonist therapy is initiated. METHODS: Mature Sprague-Dawley rats were pretreated with flutamide, sustained-release goserelin acetate (Zoladex), or a combination of flutamide and sustained-release goserelin acetate for 14 days before 4 weekly doses of procarbazine were initiated. The seminiferous tubules were evaluated histologically after a 90-day regeneration period using the stem cell assay test. RESULTS: After treatment with procarbazine alone, only 43% of the seminiferous tubules were active; however, 80% were active if protected with flutamide, 91% if protected with sustained-release goserelin acetate, and 95% if protected with both flutamide and goserelin acetate. CONCLUSION: Flutamide, sustained-release goserelin acetate, and a combination of these agents were effective in protecting the germinal epithelium of the rat during chemotherapy. A combination of flutamide and goserelin acetate provided the best protection. This study demonstrates for the first time the protective effect of flutamide and flutamide with goserelin acetate on the germinal epithelium during chemotherapy.

Protection against procarbazine-induced testicular damage by GnRH-agonist and antiandrogen treatment in the rat.

Suppression of spermatogenesis in LBNF1 rats by treatment with the GnRH agonist Zoladex combined with the antiandrogen flutamide was evaluated in order to rapidly achieve protection of spermatogenic stem cells against procarbazine with clinically used drugs. Zoladex-flutamide treatment required 3 weeks to suppress the completion of spermatogenesis; only a small degree of suppression was observed with Zoladex alone. The suppression of spermatogenesis was reversible. In rats pretreated for 3 weeks with Zoladex-flutamide, the recovery of spermatogenesis at 9 weeks after a single injection of procarbazine as measured by testis weight, testicular sperm head counts, or a histological end point was significantly better than without hormonal pretreatment. Thus Zoladex-flutamide treatment enhanced the recovery of spermatogenesis from stem spermatogonia after procarbazine treatment in the rat and might be applicable to protect spermatogenesis in patients undergoing chemotherapy for cancer.

Prolonged suppression of spermatogenesis by oestrogen does not preserve the seminiferous epithelium in procarbazine-treated rats.

We examined the hypothesis that induction of reversible testicular atrophy, subsequent to withdrawal of gonadotrophin support, would alleviate the testicular toxicity of the anti-cancer drug procarbazine. In rats, severe but reversible testicular atrophy and suppression of spermatogenesis were induced 56 days after the subcutaneous insertion of a silastic implant containing oestradiol-17 beta. The effect of this treatment upon the testicular toxicity of four weekly doses of procarbazine (200 mg kg-1) was examined 56 days after the termination of procarbazine/oestrogen treatment. At this time the testicular endocrine and spermatogenic functions were close to normal in rats which has received only oestradiol-17 beta. Procarbazine produced severe testicular atrophy which was associated with azoospermia and destruction of the germinal epithelium. Serum LH and FSH concentrations were raised and were associated with low serum concentrations of both testosterone and androgen-binding protein. The combination of procarbazine with the oestrogen treatment did not change any of the testicular toxicity and in some cases it appeared to be exacerbated. In contrast to these experiments other studies have indicated that the testis can be protected if spermatogenesis is reversibly suppressed by other agents which are also active via the pituitary endocrine system. The data would therefore suggest that protection is achieved either by some testicular change other than withdrawal of pituitary gonadotrophin support or that oestradiol-17 beta has additional activity which is permissive for the development of the testicular toxicity of procarbazine.

Inhibition of in vivo genotoxicity by coffee.

The possible role of coffee in modulating the in vivo genotoxicity of the well established genotoxic chemicals, mitomycin C, cyclophosphamide, procarbazine and adriamycin, was evaluated. Coffee was administered orally to mice that received the genotoxic chemicals ip. Genotoxicity was assessed in the bone-marrow micronucleus test. Doses of coffee in the range 225 to 1125 mg (dry weight)/kg body weight caused significant reductions in the in vivo genotoxicity of mitomycin C, cyclophosphamide and procarbazine but not adriamycin. The inhibitory effect was significant when the coffee was given about 2 hr before the genotoxin; there was a lesser effect when coffee was given together with the genotoxin but there was no inhibition when coffee was given 2-4 hr after the genotoxin. An experiment with mitomycin C demonstrated that the reduction in genotoxicity was dependent on the coffee dose. The inhibition of genotoxicity by coffee was observed in bone-marrow cells sampled 24, 48 or 68 hr after injecting cyclophosphamide. Freshly brewed coffee extract, standard instant coffee, decaffeinated instant coffee and freeze-dried home-brew coffee all exerted inhibitory effects.

Protective effects of analogs of luteinizing hormone-releasing hormone against chemotherapy-induced testicular damage in rats.

Possible protective effects of analogs of luteinizing hormone-releasing hormone (LH-RH) against testicular damage caused by various cytotoxic agents were investigated in rats. The agonist [D-Trp6]LH-RH (in which Gly-6 is replaced by D-tryptophan) and the antagonist N-Ac-[D-Phe(pCl)1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH were administered for 12 weeks: [D-Trp6]LH-RH was given once a month in the form of long-acting microcapsules liberating 25 micrograms of agonist per day, and the antagonist was injected s.c. at a dose of 1000 micrograms per kg of body weight per day for the first 3 weeks and, thereafter, at a dose of 500 micrograms per kg of body weight per day. After a recovery period of 3 months, most seminiferous tubules in the antagonist-treated group showed a normal morphology, while patches of tubules in the agonist-treated group continued to show some suppression of spermatogenesis. Administration of busulfan, cisplatin, or cyclophosphamide produced only a reversible testicular injury, and pretreatment with LH-RH analogs seemed to temporarily enhance the tubular damage. Administration of procarbazine (200 mg per kg of body weight per week for 6 weeks) resulted in decreased testicular weights and increased serum LH levels 1 and 3 months after the discontinuation of treatment. The histology showed severe diffuse damage to seminiferous tubules. The germinal cells completely disappeared and the Sertoli cells were markedly degenerated. This damage was not restored even after a recovery period of 5 months. Some animals were pretreated for 6 weeks with the agonist or antagonist and then received procarbazine for 6 weeks while administration of analogs was continued. In these animals, the decrease in testicular weights and increase in serum LH levels after procarbazine were less marked than in the group not pretreated with the analogs. Three and 5 months after cessation of treatment, a large number of tubules showed a complete restoration of structural morphology in 30-45% of the animals that received procarbazine and the LH-RH agonist or antagonist. These results indicate that pretreatment with LH-RH analogs may protect testes against damage caused by some cytotoxic agents.

[Clinico-biochemical aspects of the polychemotherapy of disseminated lymphogranulomatosis resistant to the COPP protocol]. / Kliniko-biokhimicheskie aspekty polikhimioterapii rasprostranennogo limfogranulematoza, rezistentnogo k programme TsOPP.

With a purpose of providing efficient treatment of extended lymphogranulomatosis resistant to the routine COPP program, new programs of polychemotherapy including the use of an antibiotic, plant alkaloid, alkylating agent and glucocorticoid were developed and studied. The optimal rhythm and regimen of the drug administration were developed. The study was based on the treatment of 65 patients. The clinical trials showed that the ALVP program including the use of adriablastin, lofenal, vinblastin and prednisolone was the most efficient. Its use provided a significant therapeutic effect in 77 per cent of the patients. The BrLVP program including the use of bruneomycin, lofenal, vinblastin and prednisolone, the RLVP program including the use of rubomycin, lofenal, vinblastin and prednisolone, the DLVP program including the use of dactinomycin, lofenal, vinblastin and prednisolone and the BlLVP program including the use of bleomycin, lofenal, vinblastin and prednisolone were less efficient and provided the therapeutic effect in 66, 63, 60 and 60 per cent of the patients respectively. The direction of shifts in the spectrum of the blood serum enzymes mainly corresponded to the results of clinical trials. This first of all referred to the ALVP and BrLVP programs. The use of these programs provided normalization of the hexokinase and lactate dehydrogenase activity of the serum and positive shifts in the isoenzyme spectrum.