BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.
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.
Leblond
Lorraine
L
Shire BioChem, Inc., Laval, Quebec, H7V 4A7 Canada. lleblond@ca.shire.com
Attardo
Giorgio
G
Hamelin
Bettina
B
Bouffard
David Y
DY
Nguyen-Ba
Nghe
N
Gourdeau
Henriette
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010721:Phosphinic Acids / Q000493:pharmacokinetics*; D013997:Time Factors; D014407:Tumor Cells, Cultured
C119423:2-dihydroxyphosphinoyl-5-(guanin-9'-ylmethyl)tetrahydrofuran; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D010721:Phosphinic Acids; D006147:Guanine; D004256:DNA Polymerase I