Protection by WR-2721 against radiation plus cis-diamminedichloroplatinum II caused injury to colonic epithelium in mice.

PURPOSE

The study was designed to investigate the ability of S-2-(3-aminopropylamino) ethylphosphorothioic acid (WR-2721) to protect mouse colon mucosa against damage produced by the combined radiation plus cis-diamminedichloroplatinum II (cis-DDP) treatment.

METHODS AND MATERIALS

The mucosal damage was quantified by using microcolony assay, which measures the survival of epithelial cells in colon crypts. Radiation doses ranged from 8-24 Gy gamma rays. Cis-diamminedichloroplatinum at a dose of 13 mg/kg and WR-2721 at a dose of 400 mg/kg body weight were given IP before or after irradiation.

RESULTS

Addition of cis-DDP to radiation within 24 h before and 48 h after irradiation reduced the number of crypt cells more than did radiation alone. The highest reduction was seen when the drug was given 2 or 6 h before irradiation: the damage was increased by a factor of 1.5. Protective effects of WR-2721 were tested in the radiation plus cis-DDP combination in which cis-DDP was given 2 h before or 2 h after radiation. In the former sequencing, WR-2721 was given 30 min before radiation (90 min after cis-DDP); damage was reduced more than the amount of damage contributed by cis-DDP (PF = 1.6). When cis-DDP was given 2 h after irradiation, WR-2721 was administered 30 min either before irradiation or 30 min before cis-DDP. Here, the protective effect was achieved only when WR-2721 was given before radiation: the PF was 1.3 in that case and only 1.1 when WR-2721 was given before cis-DDP. Thus, WR-2721 must be given before irradiation, but even then the degree of protection achieved depends on whether cis-DDP is applied before or after irradiation, with the protection being greater in the former situation.

CONCLUSION

Our observations showed that WR-2721 is a potent protector against the injury of mouse colon mucosa produced by the combined radiation plus cis-DDP treatment. They have important implications in the clinic, indicating that proper timing of WR-2721 administration is crucial for preventing side effects of the cis-DDP and radiotherapy combination, where damage to mucosal epithelial cells is dose limiting.