METVAN: A Novel Anticancer Agent

DESCRIPTION (provided by applicant): The goal of this proposal is to facilitate the design of innovative treatment regimens employing METVAN for breast cancer and brain tumor patients. Among the 25 bis(cyclopentadienyl)vanadium(IV) and 15 oxovanadium(IV) compounds synthesized and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) [METVAN] was identified as the most promising multitargeted anticancer vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations, METVAN induces apoptosis in human leukemia cells, multiple myeloma cells, and solid tumor cells derived from breast cancer, glioblastoma, ovarian, prostate, and testicular cancer patients. It is highly effective against cisplatin-resistant brain, ovarian and testicular cancer cell lines. METVAN is much more effective than standard chemotherapeutic agents dexamethasone and vincristine in inducing apoptosis in cancer cells. Treatment of breast cancer or brain tumor cells with METVAN at concentrations >1muM is associated with a nearly complete loss of the adhesive, migratory, and invasive properties of the treated cancer cell populations. METVAN shows favorable pharmacokinetics in mice and does not cause acute or subacute toxicity in mice at dose levels tested (12.5 - 100 mg/kg). Therapeutic plasma concentrations greater than or equal to 5muM, which are highly cytotoxic against human cancer cells, can be 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. METVAN exhibits significant antitumor activity, delays tumor progression and prolongs survival time in severe combined immunodeficiency (SCID) mouse xenograft models of human malignant glioblastoma and breast cancer. The broad-spectrum anticancer activity of METVAN together with favorable pharmacodynamic features and lack of toxicity warrants further development of this novel oxovanadium compound as a new anticancer drug. The further development of METVAN as an anticancer agent will depend on in vivo efficacy and pharmacokinetic studies in relevant animal models. We are now proposing to use the SCID mouse model for detailed in vivo anticancer activity and pharmacokinetic analysis to determine the systemic exposure levels of METVAN, which would yield the best therapeutic index in SCID mice challenged with human breast cancer and brain tumor cells. Our specific aims are: (i) To study the in vivo anticancer activity of METVAN as a single agent and in combination with standard chemotherapeutic drugs in SCID mouse xenograft models of metastatic human breast cancer and malignant glioblastoma. (ii) To study the in vivo pharmacokinetic features of METVAN in SCID mouse xenograft models of metastatic human breast cancer and malignant glioblastoma. The knowledge gained from these studies described under Specific Aims 1-2 is expected to facilitate the design of innovative treatment regimens employing METVAN for metastatic breast cancer and brain tumor patients.