Radioprotective Effect Of WR-2721 Research Articles

Acute toxicity and radioprotective effects of amifostine (WR-2721) or cystamine in single whole body fission neutrons irradiated rats

The radioprotective substances amifostine (WR-2721) and cystamine were tested in rats following their parenteral administration (i.p., i.m., and i.v.). Cystamine is more toxic than amifostine in mice as well as in rats. Amifostine was less toxic after intravenous injection. The radioprotective effects of WR-2721 (160 mg.kg-1) and cystamine (40 mg.kg-1) were not significant when they were administered parenterally 15 - 20 mins before lethal doses of whole body fission neutron irradiation in the thermal column of reactor VVR-S and 30-days lethality served as an integral criterion of postradiation injury to the rat body. The fission neutrons spectrum was characterized by mean energy 0.9-1.0 MeV with 30-40% fluency participation of moderate (E=0.1 MeV) neutrons. The contamination with gamma rays was 22-30 %; the dose rate of whole irradiation was within 0.3 to 0.8 Gy.min-1.

Radioprotective effects of WR-2721, Broncho-Vaxom and their combinations: survival, myelopoietic restoration and induction of colony-stimulating activity in mice.

The possibilities of combined radioprotection, using preirradiation WR-2721 administration and post- or preirradiation Broncho-Vaxom administration in lethally whole-body gamma-irradiated mice were investigated. LD50/30 dose reduction factors (DRFs) for mice treated with WR-2721 (200 mg/kg i.p. 30 min before irradiation), Broncho-Vaxom (25 mg/kg i.p. 24 h before irradiation), or both agents were 1.92, 1.17 and 2.07, respectively. These results demonstrated at least additive radioprotective effects of both agents, manifested in increased survival of irradiated mice. Radioprotection from 17 Gy was optimal when WR-2721 in combination with Broncho-Vaxom was given 30 min before irradiation and Broncho-Vaxom 24 h before or 4-8 h after irradiation. Combined modality treatments were also more effective than individual treatments alone in accelerating the bone marrow GM-CFC restoration. During the first days after irradiation enhanced colony-stimulating activity (CSA) of the lungs was observed in mice with postirradiation injection of Broncho-Vaxom alone or in mice injected with WR-2721 and Broncho-Vaxom (8 h after irradiation), as well as in mice only irradiated.

Comparison of behavioral and radioprotective effects of WR-2721 and WR-3689

The behavio ral effects of the radioprotectant agents ethiofo, S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) and S-2-(3-methylaminopropyl)aminoethylphosphorothioic acid (WR-3689) were evaluated in rats trained to respond under a multiple fixed-interval 120-s, fixed-ratio 50-response (mult FI FR) schedule of milk reinforcement. Each compound produced dose-dependent reductions in responding under both schedules over the same dose range (100–180 mg/kg, IP); ED 50 s indicated that WR-3689 was slightly more potent than WR-2721. On several performance measures, WR-3689 produced greater decrements during a second dose-effect determination, whereas WR-2721 had more pronounced effects during the initial one. In a second series of studies, low (56 mg/kg) and high (180 mg/kg) doses of both drugs were tested for radioprotective effects in rats responding under an FR-50 schedule of milk reinforcement and exposed to a nonlethal (5 gray, Gy) or lethal (10 Gy) dose of ionizing radiation ( 60Co gamma rays). Neither dose of radiation altered FR response rates on the day of exposure (day 1). Five Gy of gamma radiation produced a 25–40% reduction in response rates on days 2–5 (24–72 h) after exposure. Neither dose of WR-2721 or WR-3689 provided significant protection against these performance decrements. All groups exposed to 10 Gy experienced a progressive decline in FR responding on days 2–5 after exposure. Performance of groups that received pretreatment with the 180-mg/kg dose of either drug or the 56-mg/kg dose of WR-3689 was maintained at significantly higher levels than saline-treated controls on days 4–5 after exposure to 10 Gy; however, even at these higher levels of performance response rates remained below 50% of preirradiation control levels. Subsequently, 56 and 180 mg/kg WR-3689 and 180 mg/kg WR-2721 were found to provide protection against the lethal consequences of the 10-Gy exposure. Thus, neither WR-2721 nor WR-3689 afforded any significant short-term protection against radiation-induced performance decrements when these drugs were administered at either behaviorally ineffective or behaviorally disruptive doses. Rather, the beneficial effects of these drugs paralleled their ability to antagonize radiation-induced lethality.

Selenium pretreatment enhances the radioprotective effect and reduces the lethal toxicity of WR-2721.

Although WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, is an effective radioprotector, its use is limited by its toxicity. Combining WR-2721 with other agents might decrease its toxicity and/or increase its effectiveness. The effect of selenium (Se) pretreatment on the acute toxicity and radioprotective effect of WR-2721 was studied in male CD2F1 mice. Injection of 1.6 mg/kg Se 24 hr before WR-2721 (800-1200 mg/kg, IP) decreased the lethality of WR-2721 significantly. Lower doses of Se were also effective, but simultaneous administration was not effective. Se injection alone (1.6 mg/kg) 24 hr before cobalt-60 irradiation increased the survival (dose reduction factor, DRF = 1.1) significantly. A synergistic effect on post-irradiation survival was observed when Se was injected 24 hr before WR-2721 (200-600 mg/kg IP 1/2 before irradiation). For example, after exposure to 22 Gy (1 Gy/min), 30-day survival was 100% when mice were treated with both Se and 600 mg/kg WR-2721, and was 13% with WR-2721 alone. The DRF after 400 mg/kg WR-2721 was 2.6 with Se compared to 2.2 without Se pretreatment. Alkaline phosphatase activity in bone marrow cells and serum was significantly depressed after treatment with 1.6 mg/kg Se, suggesting that a retardation of conversion of WR-2721 to its active free sulfhydryl form through the action of alkaline phosphatase might be partly responsible for the effects of Se. Other possible mechanisms related to the antioxidant properties of Se are under investigation.

Late Functional and Biochemical Changes in Mouse Lung after Irradiation: Differential Effects of WR-2721

The radioprotective effect of WR-2721 on late damage after whole thorax irradiation has been studied after split doses of radiation using the standard death and breathing rate assays at monthly intervals between 3 and 15 months after irradiation, as well as two biochemical measurements of injury at 15 months, hydroxyproline (HP), an indicator of tissue fibrosis, and DNA content, an indicator of tissue cellularity. A comparison of HP/lung and breaths per minute (BPM) in each dose group in the WR-2721 and non-WR-2721-treated mice 15 months after irradiation showed that the relationship between these two assays of late lung injury was not the same. There were large dose-related increases in breathing rate corresponding to relatively small changes in HP in the lungs of mice given radiation alone. In contrast, the mice given WR-2721 before irradiation showed large dose-related increases in HP/lung, but BPM remained relatively constant independent of dose. These data suggest then that changes in breathing rate and deaths later than 9 months after whole lung irradiation may not be due to collagen accumulation in the lung. WR-2721 did protect better against late lung functional changes (protection factors (PF) = 1.6) and late deaths (PF = 1.51) than against earlier changes in these same assays (PF = 1.4 and 1.28, respectively). Although the earlier-appearing injury after whole thoracic irradiation is most likely related to lung damage with deaths and increases in breathing rate resulting from pneumonitis, the cause of the late-appearing functional injury in the lung after radiation is not clear. Thus protection of late lung damage measured from either lethality or breathing rate is not related to the prevention of lung fibrosis.

Protection of mouse lung by WR-2721 after fractionated doses of irradiation

The radioprotective effect of WR-2721 on mouse lung has been studied after single doses, 4 or 7 equal fractions of X rays. Using breathing rate and lethality to measure lung injury up to 1 year after radiation, significant protection against both pneumonitis at 7 months and fibrosis at 12 months was observed using 300 mg/kg of WR-2721. The degree of radioprotection was similar for pneumonitis and fibrosis and was not less after doses per fraction of 4.0 Gy. These data indicate that protection of mouse lung by WR-2721 will not be less in a multifractionated schedule of radiation, at least for doses per fraction greater than 4.0 Gy.

WR-2721 protection of pneumonitis and fibrosis in mouse lung after single doses of x rays.

The radioprotective effect of WR-2721 has been studied in mouse lung after single doses of radiation. Using the breathing rate assay and lethality, radioprotection was assessed at monthly intervals between 3 and 18 months after irradiation during both pneumonitis and chronic fibrosis. The degree of radioprotection was greater for fibrosis than for pneumonitis using both assays. In replicate experiments, dose modifying factors (DMF's) ranging from 1.2 to 1.4 were obtained for pneumonitis and 1.5 and 1.6 for fibrosis. The differences in DMF's for the two phases of lung damage were significant. A difference in the time course of expression of damage was seen in both the breathing rate and lethality assays between mice irradiated with and without WR-2721: the damage ended sooner in the drug-treated mice. This difference is best explained by protection of all damage after 5 months by WR-2721. No evidence of drug toxicity was found. We conclude that WR-2721 protects against chronic lung fibrosis caused by radiation at least as well as against the earlier appearing pneumonitis after single doses of radiation. Thus, if WR-2721 is dose modifying and if late tissue complications are dose limiting in clinical radiotherapy, then a therapeutic benefit would be obtained by the use of this drug in clinical radiotherapy, provided that the radioprotection of tumors did not exceed a factor of 1.5-1.6.

Radioprotection of two mouse tumors by WR-2721 in single and fractionated treatments

The radioprotective effect of WR-2721 has been studied in two murine tumors using single doses or five daily fractions. Single dose irradiations of the SA FA resulted in a highly variable radio-protective response. In one experiment large protection factors (1.2–2.5) were obtained, with the greatest protection at low X ray doses. In later experiments with the same tumor, there was little or no radioprotection. The Ca MT was significantly protected against single dose irradiation with both 250 mg/kg and 400 mg/kg of the drug. In a five fraction schedule the extent of radioprotection for CA MT was greater than with single X ray doses for the same drug dose per fraction. Tumor protection factors from the present work and from the literature are compared with published protection factors for normal tissues. Significant tumor radioprotection is seen in most studies. The data indicate more variability in the extent of tumor protection for a given drug dose than is seen in normal tissues. Tumor protection is often greatest at low X ray doses which may be a result of preferential protection of the better-oxygenated tumor cells.

Short-Term Radioprotective Effects of WR-2721 on the Rat Parotid Glands

The radioprotective capacity of the chemoprotector WR-2721 was assessed in the rat parotid gland using gland weight and amylase content as the indicators of effect over the 9-day period following x irradiation with 1.6, 3.2, and 6.4 kR of acute x rays. The decline and recovery of weights and amylase content were measured and compared in animals which had and had not received WR-2721 just prior to irradiation. Analysis of the dose-response curves for the WR-2721 protected vs nonprotected animals yielded dose modification factors of 2.5 for gland weight, 1.7 for amylase concentration, and 1.8 for total gland amylase. Thus, WR-2721 was found to be effective in yet another tissue and to a degree consistent with that of other organs and systems.

The Radioprotective Effect of WR-2721, WR-638, MEA and AET on the Intestinal Epithelium

The Radioprotective Effect of WR-2721, WR-638, MEA and AET on the Intestinal Epithelium