Antiarthritic effects of two acyclic nucleoside phosphonates, 9-(2-phosphonomethoxyethyl)adenine (PMEA; Adefovir) and 9-(2-phosphonomethoxypropyl)adenine (PMPA), as well as their more bioavailable prodrugs, bis(pivaloyloxymethyl)ester of PMEA [bis(POM)-PMEA; Adefovir Dipivoxil] and bis(isopropyloxycarbonyloxymethyl)ester of PMPA [bis(POC)-PMPA], were investigated in a model of adjuvant-induced arthritis in Lewis rats. The drugs were injected subcutaneously at doses of 5-50 mg/kg. PMEA and its prodrug inhibited by > 80% arthritic paw swelling, splenomegaly and fibroadhesive perisplenitis. Both prophylactic and therapeutic dosing regimens were effective. Neither PMPA nor bis(POC)-PMPA suppressed development of arthritic lesions. Substantially reduced nitrite + nitrate levels were detected in serum and urine of PMEA-treated animals as compared to those of untreated diseased controls. Also, complete suppression of the disease-associated, greatly enhanced systemic levels of the chemokine, RANTES (regulated upon activation, normal T cell expressed and secreted), was observed in rats injected with PMEA. Additional in vitro studies showed that PMEA does not change, PMPA enhances, and both prodrugs inhibit the immune-activated NO production. Under the same conditions PMEA inhibits, while PMPA slightly stimulates, secretion of RANTES. Collectively, these data suggest that the in vivo-inhibited production of nitric oxide (NO) is a consequence rather than a mechanism of antiarthritic action of PMEA. Possible mechanisms for the anti-RANTES activity of PMEA remains to be firmly established.