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 metast asis was studied. Murine colon 38 tumor cells (1 x 10(5)) were inocula ted via the superior mesenteric vein. Mice were grouped depending on C sA dosage and time schedules: Group A: CsA 30 mg/kg body weight on the 7, 8 and 9th post tumor inoculation days by gavage; Group B: CsA 15 m g/kg body weight 30 min before tumor inoculation and 2 times more at 2 4 h intervals; Group C: CsA 30 mg/kg body weight at the same dose timi ng as Group B. Measurement of the diameter of the largest tumor serial ly by weekly laparotomy up to 4 weeks revealed that the tumor growth r ates 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 c ontrol, 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 hepat ic 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 d ifferences (Groups B and C vs. A or control, P < 0.05). In vitro MTT a ssay showed that cell viability rates were greater than 100% in the me dium containing CsA concentrations of less than 10(-7) mol/liter. Howe ver, 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 t he liver. The mechanism of cytoproliferative effect of CsA is unknown but may involve multiple factors.