In vivo antitumor activity of bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) {METVAN [VO(SO4)(Me-2-Phen)(2)]}

Citation
Rk. Narla et al., In vivo antitumor activity of bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) {METVAN [VO(SO4)(Me-2-Phen)(2)]}, CLIN CANC R, 7(7), 2001, pp. 2124-2133
Citations number
60
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
7
Issue
7
Year of publication
2001
Pages
2124 - 2133
Database
ISI
SICI code
1078-0432(200107)7:7<2124:IVAAOB>2.0.ZU;2-H
Abstract
The compound bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) { METVAN [VO(SO4)(Me-2-Phen)(2)]}, exhibits potent cytotoxicity against human cancer cells at low micromolar concentrations. At concentrations greater t han or equal to1 muM, METVAN treatment was associated with a nearly complet e loss of the adhesive, migratory, and invasive properties of the treated t umor cell populations. METVAN did not cause acute or subacute toxicity in m ice at dose levels ranging from 12.5 mg/kg to 100 mg/kg, Therapeutic plasma concentrations greater than or equal to5 muM were rapidly achieved and mai ntained 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 METV AN concentration was 37.0 muM, which was achieved with a t(max) of 21.4 min . Plasma samples (diluted 1:16) from METVAN-treated mice killed 85% of huma n breast cancer cells in vitro. METVAN was slowly eliminated with an appare nt plasma t(1/2) of 17.5 h and systemic clearance of 42.1 ml/h/kg. In accor dance with its potent in vitro activity and favorable in vivo pharmacokinet ics, METVAN exhibited significant antitumor activity and delayed tumor prog ression in CB.17 severe combined immunodeficient (SCID) mouse xenograft mod els of human glioblastoma and breast cancer, In these experiments, METVAN w as 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 a fter the s.c. inoculation of U87 glioblastoma or MDA-MB-231 breast cancer c ells. At 40 days after the inoculation of tumor cells, the U87 tumor xenogr afts in the vehicle-treated control SCID mice were much larger than those o f 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 M ETVAN 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 m m(3); P = 0.002). The favorable in vivo pharmacodynamic features and antitu mor activity of METVAN warrants further development of this novel oxovanadi um compound as a potential new anticancer agent.