Enhancement of Tumor Proliferation by Cyclosporine A in Early Phase of Experimental Hepatic Metastasis

The effect of cyclosporine A (CsA) on in vivo growth of hepatic metastasis was studied. Murine colon 38 tumor cells (1 × 10(5)) were inoculated via the superior mesenteric vein. Mice were grouped depending on CsA dosage and time schedules: Group A: CsA 30 mg/kg body weight on the 7, 8 and 9th post tumor inoculation days hy gavage; Group B: CsA 15 mg/kg body weight 30 min before tumor inoculation and 2 times more at 24 h intervals; Group C: CsA 30 mg/kg body weight at the same dose timing as Group B. Measurement of the diameter of the largest tumor serially by weekly laparotomy up to 4 weeks revealed that the tumor growth rates were significantly greater in Groups B and C than those in Group A or the control (without CsA). The mean tumor doubling times in the control, and Groups A, B and C were 2.2±1.3, 2.0±0.5, 1.5±0.4 and 1.3±0.8 days, respectively. The mean tumor numbers of hepatic metastasis were 13.2±8.3, 11.3±7.3, 19.4±8.7 and 19.6±6.8, respectively. Values of tumor proliferation index obtained by bromodeoxyuridine immunohistochemistry were 10.0±6.1%, 14.9±8.0%, 28.6±8.2% and 30.1±12.4%, respectively, with significant differences (Groups B and C vs. A or control, P<0.05). In vitro MTT assay showed that cell viability rates were greater than 100% in the medium containing CsA concentrations of less than 10(−7) mol/liter. However, a cytostatic effect of CsA was apparent at higher concentrations. In contrast to the previous in vivo finding of a cytostatic effect of CsA on tumor cells, we found a cytoproliferative action when CsA was administered early in the course of metastatic tumor implantation in the liver. The mechanism of cytoproliferative effect of CsA is unknown but may involve multiple factors.