EFFECT OF THE CHEMOPROTECTIVE AGENT WR-2721 ON DISPOSITION AND BIOTRANSFORMATIONS OF ORMAPLATIN IN THE FISCHER-344 RAT BEARING A FIBROSARCOMA

The effects of the phosphorothioate agent, WR-2721, have been investigated with respect to the biotransformations of ormaplatin in the Fischer 344 rat bearing a transplanted fibrosarcoma. A number of different paradigms of dosing route and schedule for the administration of the two agents have been investigated. In the first group of experiments, WR-2721 (200 mg/kg, i.p.) was administered 30 min before ormaplatin (12.5 mg/kg, i.p.), and then peritoneal fluid, plasma, and tissues were harvested at 30 min after the ormaplatin administration. Our results suggest that a significant interaction between WR-2721 and ormaplatin is occurring in the peritoneal cavity. The interaction was evident in terms of both effects on distribution and disposition of total platinum and in alterations of the profiles of biotransformation products formed in the various tissues and fluids. Plasma protein binding of ormaplatin was decreased by 50% in the presence of WR-2721. Total platinum in the spleen was decreased by 66% and in the liver by 50%. There were no trends among the findings that would indicate any selectivity between tumor and nontumor tissue with respect to the effects of WR-2721 on the parameters measured. Subsequent investigations examined the effects of dosing the WR-2721 by the i.v. route while continuing with the i.p. administration of the ormaplatin. WR-2721 was administered either 30 or 5 min before the ormaplatin, and the plasma and tissues were harvested at 15, 30, or 60 min after ormaplatin administration. The reverse-phase HPLC peak, which behaved chromatographically as a Pt(dach)(WR-1065) standard, was less prominent after the i.v. administration of WR-2721 than it was after i.p. administration under any of the paradigms tested. There was again no evidence for selectivity between tumor and nontumor tissue in the findings from any of the paradigms. It is concluded that if WR-2721 is capable of selectively protecting nontumor tissue from the toxicities of platinum-based chemotherapy, it is doing so by some mechanism other than its selective uptake into normal tissue and subsequent nonspecific inactivation of any reactive cytosolic platinum species formed. Other possible mechanisms are briefly discussed.