Toxicity of WR-2721 administered in single and multiple doses

Kligerman, Morton M.; Glover, Donna J.; Turrisi, Andrew T.; Norfleet, A.Lorraine; Yuhas, John M.; Coia, Lawrence R.; Simone, Charles B.; Glick, John H.; Goodman, Robert L.

doi:10.1016/0360-3016(84)90547-9

Cited by 111 publications

(32 citation statements)

References 3 publications

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“…These were severe enough to make the drug impractical for clinical use. 24 The experimental procedure of injecting high concentrations of vitamin E directly into the lumen cannot be duplicated clinically. Use of oral vitamin E as a radioprotectant could solve some of the problems encountered previously in the development of a practical pharmacologic regimen.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Radioprotection by Vitamin E (Alpha-Tocopherol)

et al. 1995

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Vitamin E has previously been shown to provide radioprotection in animal models: increased survival after whole-body irradiation, diminished absorptive malfunction, and modest diminution in postirradiation hemolysis. The lumenal route for intestinal radioprotection has not been tested. MethodsRat mid-small bowel was surgically exteriorized and segmented by ties into compartments, each of which was filled with a test solution 30 minutes before 1 100 cGy of x-irradiation was administered. After the rats were killed 5 days later, the various segments were evaluated for surviving crypts, mucosal height, and goblet cell preservation. Lumenal agents included alphatocopherol phosphate and alpha-tocopherol acetate. In a separate study, dietary supplements of alpha-tocopherol were given for 10 days before irradiation, and the same irradiation sequence was carried out. ResultsSmall bowel crypt cell numbers, mucosal height, and goblet cell numbers were significantly protected from radiation effects by dietary alpha tocopherol pretreatment and by lumenal application of the vitamin. ConclusionsThese studies indicate that vitamin E can serve as a partial protectant against acute irradiation enteritis, whether given as chronic oral systemic pretreatment or as a brief topical application. 504Therapeutic irradiation regimens are designed to maximize tumoricidal effects while causing minimal damage to normal organs. Radiation to abdominal or pelvic malignancies unavoidably injures the intestine. Largely because of rapid cell turnover, the intestine is highly sensitive to radiation injury and is therefore the limiting factor in the permissible dosage for abdominal and pelvic irradiation. An early clinical consequence of intestinal

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Section: Discussionmentioning

confidence: 99%

Intestinal Radioprotection by Vitamin E (Alpha-Tocopherol)

et al. 1995

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“…Considerable interest has recently been expressed in the use of phosphorylthioate drugs as adjuvants to radiotherapy (Kligerman et al, 1980(Kligerman et al, , 1984Takahasi et al, 1986). This interest is based upon an early observation by Yuhas and Storer, (1969) that WR-2721 differentially protects normal as compared to tumour cells.…”

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confidence: 99%

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

Sigdestad¹,

Treacy²,

Knapp³

et al. 1987

Br J Cancer

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Summary Radiation induced DNA double strand breaks are believed to be important lesions involved in processes related to cell killing, induction of chromosome aberrations and carcinogenesis. This paper reports the effects of the radioprotector 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation-induced DNA damage and repair in V79 cells using the neutral elution method performed at pH 7.2 or pH 9.6. WR-1065 (4mM) was added to the culture medium either 30 minutes prior to and during irradiation with Cobalt-60 gamma rays (for dose response experiments) or during the repair times tested (for DNA rejoining experiments). The results indicate that WR-1065 is an effective protector against the formation of radiationinduced double-strand breaks in DNA as measured using a neutral elution technique at either pH. The protector reduced the strand scission factors by 1.44 and 1.77 in experiments run at pH 9.6 and pH 7.2, respectively.The kinetics of DNA double-strand rejoining were dependent upon the pH at which the neutral elution procedure was performed. Unlike the results obtained with alkaline elution, rejoining of DNA breaks was unaffected by the presence of WR-1065 at either pH.

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“…Interactions of free radicals with DNA can induce genetic damage, leading to mutagenesis and carcinogenesis [Reily, 1994]. With respect to the potential application of ionizing radiation in medical practices (e.g., radiotherapy and nuclear medicine), the development of effective radiomodifiers is highly desired [Hosseinimehr, 2007]; for example it has shown that Amifostine, a thiol synthetic compound, is a powerful radioprotective agent compared to other agents [Kligerma et al, 1984;Hosseinimehr et al, 2002]. However, due to its side effects and toxicity, the use of this drug is limited in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Radioprotective effects of Daflon against genotoxicity induced by gamma irradiation in human cultured lymphocytes

Hosseinimehr¹,

Ahmadi²,

Mahmoudzadeh³

et al. 2009

Environ and Mol Mutagen

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The ability of Daflon to protect against genotoxicity induced by gamma irradiation has been investigated in vivo and in vitro in cultured lymphocytes from healthy human volunteers. Peripheral human blood samples were collected predose (10 min before) and 1, 2, and 3 hr after a single oral ingestion of 1000 mg of Daflon. At each time point, whole blood was exposed in vitro to 150 cGy of cobalt-60 gamma rays, and then the lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis-blocked binucleated cells. For each volunteer, the results showed a significant increase in the incidence of micronuclei after exposure to gamma irradiation as compared to control unexposed samples. As early as 1 hr after Daflon administration, a significant decrease in the incidence of micronuclei was observed in comparison with similarly irradiated lymphocytes collected before administration. The maximum protection was reached 1 hr after administration of Daflon with a significant decrease in the frequency of micronuclei of 40%. These findings suggest the possible application of Daflon for the protection of human lymphocytes from the genetic damage and side effects induced by gamma irradiation.

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Toxicity of WR-2721 administered in single and multiple doses

Cited by 111 publications

References 3 publications

Intestinal Radioprotection by Vitamin E (Alpha-Tocopherol)

Intestinal Radioprotection by Vitamin E (Alpha-Tocopherol)

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

Radioprotective effects of Daflon against genotoxicity induced by gamma irradiation in human cultured lymphocytes

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