POTENT ANTITUMOR-ACTIVITY OF THE ACYCLIC NUCLEOSIDE PHOSPHONATE 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE IN CHORIOCARCINOMA-BEARING RATS

The acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective antiretroviral agent which is curren tly evaluated in its oral prodrug form, bis(POM)PMEA (adefovir dipivox il), in phase II and III clinical trials in human hepatitis B virus (H BV)- and human immunodeficiency virus (HIV)-infected individuals, resp ectively. We have now found that PMEA is also a potent inhibitor of gr owth of the highly aggressive choriocarcinoma tumor arising from rat c horiocarcinoma RCHO cells grafted under the kidney capsule of syngenei c WKA/H rats. In untreated rats, massive invasive RCHO tumors, coverin g the whole surface of the kidney and resulting in a marked enlargemen t of the kidney, were observed at day 10 after tumor cell grafting. Da ily treatment with PMEA at 25 mg/kg/ day afforded a marked reduction i n tumor size (i.e., smaller tumors and slight, if any, enlargement of the kidney). Increasing the PMEA dose to 50, 100 or 250 mg/kg/day resu lted in a gradual increase of the antitumor effect of the compound. At the highest dose tested, i.e., 250 mg/kg/day, PMEA completely suppres sed tumor growth. The antitumor activity of PMEA persisted for at leas t 10 days after termination of drug treatment. In addition, delayed tr eatment with PMEA at a dose of 200 mg/kg/day, started at a time point where choriocarcinoma tumors had already developed, stopped further gr owth and even induced regression of the tumors. PMPA, a closely relate d structural analogue of PMEA, failed to inhibit choriocarcinoma tumor growth. This observation points to the specificity of PMEA as an anti tumor agent. In view of our findings, the therapeutic potential of PM EA for the treatment of neoplastic diseases appears to merit further i nvestigation. (C) 1998 Wiley-Liss, Inc.