Antitumor and toxicologic properties of the organometallic anticancer agent vanadocene dichloride

We report here on the antineoplastic, toxicologic, and transmembrane transfer properties of vanadocene dichloride (VDC), a representative metallocene dihalide. VDC is cytotoxic to HEp-2 human epidermoid carcinoma cells, in vitro, in a dose dependent manner, with a D_o value (dose increment reducing the survival fraction by 1/e) of 0.530 ± 0.005 μg/ml. Under similar experimental conditions, the D_o for cisplatin (CDDP) against these cells is 0.46 ± 0.08 μg/ml. In a murine mammary adenocarcinoma (TA3Ha) system, 125 μg/ml VDC inhibits the tumor-forming ability of 10⁵ cells upon i.p. inoculation into syngeneic Strain A mice. The transmembrane transfer rate constants for the metal uptake of VDC and CDDP by TA3Ha cells in vitro were found to be 3.3 ± 0.8 × 10^-4 min^-1 and 12 ± 2.0 × 10^t-4 min^-1, respectively. In vivo studies with TA3Ha cells show that two i.p. treatments of 20, 40, and 60 mg/kg VDC increase the host survival by 30, 50, and 90%, respectively. Under similar conditions, 2, 4, and 6 mg/kg CDDP (equitoxic dose levels) prolong the host survival 50, 75, and 83%, respectively. Morphological, blood urea nitrogen level, and serum creatinine level data for Strain A mice treated with 60 mg/kg VDC give no evidence of renal or small intestinal damage. However, changes in the liver consistent with fatty cell degeneration are observed in these mice.