The compound bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (
METVAN [VO(SO4)(Me2-Phen)2]), exhibits potent cytotoxicity against human
cancer cells at low micromolar concentrations. At concentrations > or = 1 microM,
METVAN treatment was associated with a nearly complete loss of the adhesive, migratory, and invasive properties of the treated
tumor cell populations.
METVAN did not cause acute or subacute toxicity in mice at dose levels ranging from 12.5 mg/kg to 100 mg/kg. Therapeutic plasma concentrations > or = 5 microM were rapidly achieved and maintained in mice for at least 24 h after i.p. bolus injection of a single 10 mg/kg nontoxic dose of
METVAN. At this dose level, the maximum plasma
METVAN concentration was 37.0 microM, which was achieved with a t(max) of 21.4 min. Plasma samples (diluted 1:16) from
METVAN-treated mice killed 85% of human
breast cancer cells in vitro.
METVAN was slowly eliminated with an apparent plasma t(1/2) of 17.5 h and systemic clearance of 42.1 ml/h/kg. In accordance with its potent in vitro activity and favorable in vivo pharmacokinetics,
METVAN exhibited significant antitumor activity and delayed
tumor progression in CB.17 severe combined immunodeficient (SCID) mouse xenograft models of human
glioblastoma and
breast cancer. In these experiments,
METVAN was administered in daily
injections of a single nontoxic 10 mg/kg i.p. dose on 5 consecutive days per week for 4 consecutive weeks beginning the day after the s.c. inoculation of U87
glioblastoma or MDA-MB-231
breast cancer cells. At 40 days after the inoculation of
tumor cells, the U87
tumor xenografts in the vehicle-treated control SCID mice were much larger than those of the mice treated with
METVAN (4560 +/- 654 mm(3) versus 1688 +/- 571 mm(3); P = 0.003). Similarly, the MDA-MB-231
tumors in SCID mice treated with
METVAN were much smaller 40 days after
tumor cell inoculation than those of the vehicle-treated control SCID mice (174 +/- 29 mm(3) versus 487 +/- 82 mm(3); P = 0.002). The favorable in vivo pharmacodynamic features and antitumor activity of
METVAN warrants further development of this novel oxovanadium compound as a potential new
anticancer agent.