wr-77913 and Cataract

The effect of some protective agents on cataract development is briefly reviewed and new evidence is presented on the efficacy of a phosphorothioate compound (Amifostine) in inhibiting the development of X-ray-induced cataract. Morphological studies showed that at the end of 4 months, lenses from X-irradiated rats which had not received any drugs showed liquefaction in the equatorial region and at the posterior pole, as well as a marked swelling of the fibers in the anterior cortex. Animals which received 1.16g/kg of WR77913 showed considerable protection against the development of radiation induced cataracts with morphological changes in the lens being less severe than in animals receiving no drugs. When animals were treated with 0.5g/kg of Amifostine (WR2721) the lenses showed much greater protection against cataract development than with WR77913. Amifostine appears to be more effective than WR77913 in inhibiting X-ray-induced cataract development.

Topics: Amifostine; Animals; Cataract; Cysteine; Galactose; Lens, Crystalline; Radiation Injuries, Experimental; Radiation-Protective Agents

Pantethine and the amino phosphorothioate, WR-77913, protected lenses against increased light scattering and opacification during cataract formation in five animal models: (1) radiation, (2) selenite, (3) galactose, (4) streptozotocin and (5) Royal College of Surgeons. In the radiation or selenite models, each test reagent was administered 15 to 30 min prior to initiation of cataract by a single injection of Na2SeO3 or a single exposure to 15 Gy (gray) gamma radiation. In the galactose, streptozotocin and Royal College of Surgeons models where the cataractogenic insult was continuous, repeated administrations of pantethine and WR-77913 were necessary. The results suggested that protein aggregation and lens opacification associated with a variety of physiological and biochemical mechanisms can be delayed or inhibited using a systemic administration of pantethine or WR-77913.

Topics: Amifostine; Animals; Cataract; Female; Galactose; Lens, Crystalline; Male; Pantetheine; Protein Denaturation; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Sodium Selenite; Streptozocin

Using two-dimensional (2-D) Fourier methods, we analysed the cellular microstructure of three rat lenses: normal transparent, selenite-induced cataractous and selenite-treated plus a phase separation inhibitor (PSI) to prevent cataract. 2-D Fourier analysis of electron micrographs of the lens cells quantified the dimensions of the spatial fluctuations in electron density of the lens cell microstructure. The 2-D Fourier spectra of the transparent normal and PSI-treated lens cells were remarkably similar while those of the opaque selenite-treated lens cells were dramatically different. In the opaque cells the contributions of large Fourier components (larger than half the wavelength of light) in the 2-D Fourier spectra were much greater than in the transparent cells. The results of the 2-D Fourier analysis of electron micrographs are consistent with the theory of transparency of the eye.

Topics: Amifostine; Animals; Cataract; Fourier Analysis; Image Processing, Computer-Assisted; Lens, Crystalline; Microscopy, Electron; Rats; Rats, Sprague-Dawley; Sodium Selenite

The radioprotective drug S-3-amino-2-hydroxypropylphosphorothioic acid (WR-77913) has been tested as an inhibitor of radiation cataractogenesis. Animals treated with 15 Gy whole-head 137Cs gamma radiation developed mature cataracts 10-12 weeks after irradiation. Intraperitoneal pretreatment with 815 mg/kg WR-77913 30 min before irradiation delayed the development of cataracts; mature cataracts required 42 weeks for development. Doses as low as 350 mg/kg, substantially below the toxic range, resulted in graded but incomplete protection and a significant delay in the development of cataracts. Drug treatment combined with radiation doses of 12.5 or 10 Gy showed less pronounced protection. The optimum time of drug delivery was found to be between 30 min and 2 h before irradiation; protective action diminished if longer times were used or if the drug was given after irradiation. These results are discussed in relation to those obtained with other chemical radioprotective agents and in terms of possible mechanisms of the action of the drug.

Topics: Amifostine; Animals; Cataract; Cesium Radioisotopes; Gamma Rays; Lens, Crystalline; Male; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats; Rats, Sprague-Dawley; Time Factors

A phase separation inhibitor, WR77913 [S-3(amino-2-hydroxypropyl) phosphorothioate], was tested for its effects on lens opacification in the radiation (RAD), selenite (SEL), galactose (GAL), streptozotocin (STZ), and Royal College of Surgeons (RCS) models for cataract. A single i.p. injection of WR77913, approximately 15 min before induction of cataract formation by RAD, SEL, STZ delayed or inhibited opacification. Repeated administration was necessary to delay or inhibit opacification in the GAL or RCS models for cataracts. The results suggest that phase separation inhibitors such as WR77913 have the potential to delay or inhibit lens opacification resulting from a variety of physiological or biochemical mechanisms.

Topics: Amifostine; Animals; Cataract; Disease Models, Animal; Female; Galactose; Lens, Crystalline; Male; Radiation Injuries, Experimental; Radiation-Sensitizing Agents; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Sodium Selenite; Streptozocin

The variation of the phase-separation temperature (Tc) was studied in lenses during formation of cataracts induced by a subcutaneous injection of sodium selenite. In normal control animals, the Tc decreased monotonically with increasing age. Approximately 2 days after administration of the selenite the Tc decreased sharply to a minimum, and then at day 4 the Tc increased dramatically toward body temperature. Mature irreversible cataracts formed approximately 6 days after injection of the selenite. Intraperitoneal administration of WR-77913, a phase-separation inhibitor, prevented the abnormal variation of Tc in vivo. When injected into control animals without selenite, WR-77913 produced no abnormal variation in Tc. The results confirm that Tc is a sensitive measure of early changes in the lens and that opacification associated with abnormal variation in Tc can be prevented in vivo by using a phase-separation inhibitor.

Topics: Amifostine; Animals; Cataract; Chemical Phenomena; Chemistry, Physical; Lens, Crystalline; Rats; Rats, Inbred Strains; Selenium; Sodium Selenite; Temperature

Galactose, and the phosphorothioates, WR-77913 and WR-2721, which inhibit cataract produced by X-irradiation, were evaluated for their effects on the phase separation temperature, Tc, of calf lens homogenate. The reagents were added to nuclear homogenate and the change in Tc per mol, dTc/dC, was measured. Galactose decreased Tc, -65 degrees C mol-1, WR-77913 decreased Tc, -28 degrees C mol-1 and WR-2721 decreased Tc, -76 degrees C mol-1. These are the first phase separation inhibitors that can be used in vivo to study the inhibition of lens opacification.

Topics: Amifostine; Animals; Cataract; Cattle; Galactose; Lens, Crystalline; Organothiophosphorus Compounds; Radiation-Sensitizing Agents; Temperature

Protection by WR-77913 against radiation-induced cataract formation in rats was observed following intraperitoneal (i.p.) administration of drug (1160 mg/kg) 15-30 min before exposure to 15.3 Gy of Cs-137 whole head irradiation. Control groups included irradiated, non-protected animals, and sham-irradiated aging controls. Protection was documented photographically and by analysis of eye lens constituents. All non-protected irradiated animals developed dense cataracts throughout the lens between 90-120 days post-irradiation, while WR-77913 protected animals developed minimal lens opacification through 200 days post-irradiation. No opacification in aging controls was seen. Lens protein analysis by Lowry assay and size exclusion HPLC showed radioprotected and aging control animals were similar in protein content, distribution of total and soluble protein, and degree of lens hydration. This contrasted significantly with cataractous lenses of non-protected animals. In cataractous lenses, the soluble protein concentration in the 25-43 K dalton range was approximately 10% of that found in radioprotected or aging control lenses. Hydration was substantially higher in cataractous lens. These results indicate that WR-77913 protects against lens opacification, protein insolubilization, and hydration in lenses of irradiated animals. Biodistribution studies with [S-35]-WR-77913 showed ocular uptake of drug within 15 minutes after i.p. injection, which remained relatively constant through 60 min. The relative order of drug concentration for individual eye components was: globe greater than total eye approximately equal to humor greater than lens. Although the mechanism of radioprotection observed remains to be elucidated, WR-77913 clearly prevents radiation-induced cataracts in rats. The potentially significant clinical use for this radioprotective compound is being investigated further.

Topics: Amifostine; Animals; Cataract; Cesium Radioisotopes; Gamma Rays; Organothiophosphorus Compounds; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats

Radiation induced cataracts are models for studying mechanisms of lens opacification. WR-77913, S-3-(amino-2-hydroxypropyl) phosphorothioate (NCS-318809), has been identified as a radioprotective agent. Injection of WR-77913 (1160 mg/kg, i.p.) 15 to 30 min before exposure to 15.3 gray of x-irradiation inhibited rat lenses from developing radiation cataracts. Irradiated rats which did not receive the drug developed dense cataracts. Lenses from control rats which received no radiation remained transparent. Individual lenses were weighed, homogenized, and assayed for protein content using the Lowry method. The molecular weight distribution of soluble protein was determined by HPLC. Mean lens weights were: controls 48.2 mg; irradiated, drug-treated 45.9 mg; and irradiated, nontreated 45.5 mg. Protein accounted for over 40% of the lens weight in control and drug-treated rats and less than 20% for the nontreated cataractous lenses. Water was less than 60% of the lens weight in control and drug-treated rats and over 80% in cataractous lenses. Insoluble protein ranged from 12 to 17% of the total lens weight for each group. The ratio of insoluble to soluble lens protein was 0.40 for control, 0.65 for drug-treated, and 11.28 for cataractous rat lenses. HPLC confirmed a dramatic loss of soluble protein and a complete absence of protein below 25K daltons in cataractous lenses. Proteins below 25K daltons accounted for over 25% of the soluble protein in control and drug-treated rat lenses. WR-77913 stabilizes protein composition and appears to be an effective inhibitor of radiation cataractogenesis.

Topics: Amifostine; Animals; Body Water; Cataract; Crystallins; Lens, Crystalline; Male; Organothiophosphorus Compounds; Osmolar Concentration; Photography; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Time Factors; Tissue Distribution