Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of
antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a
tetrahydrofuran phosphonate analogue of
guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl)
tetrahydrofuran (BCH-1868), previously reported as having
antiviral activity, also displays antitumor activity. In vitro,
BCH-1868 inhibited the proliferation of several murine and human
cancer cell lines with IC50s in the microM range independently of the tissue type or the presence of multidrug resistance
protein MRP/gp190. In vivo,
BCH-1868 was active against a variety of human
tumor xenograft models (Caki-1, HT-29, DU 145, COLO 205, and CCRF-CEM). In all
tumors tested, a significant
tumor growth inhibition was noted at 40-50 mg/kg (daily x 5), but no
tumor regression was observed in the settings used. To better understand these results, we partially characterized, at the cellular level, the mechanism of action of this new cyclic
nucleoside phosphonate and investigated its pharmacokinetic characteristics in mice. We showed that
BCH-1868 exerts its antitumor activity by an inhibitory mechanism at the level of
DNA polymerase a, resulting in arrest of
DNA synthesis and a block of cell division at the S phase of the cell cycle. Low-circulating plasma concentration (Cmax = 87 microM; area under the curve = 1138 micromol x min/liters; after a bolus i.v. injection of 10 mg/kg) and rapid clearance of the
drug (terminal half-life, t1/2 = 16 min) may contribute to the modest antitumor efficacy observed in vivo.