We have established a model of human
renal cell carcinoma, Kgg2, transplanted into athymic nude mice which expressed
P-glycoprotein (P-gp) (detected by flow cytometry) and a high level of
mRNA transcript of mdr1 gene (Northern blot analysis). We have evaluated the antitumor activity of a new highly potent vinca-
alkaloid derivative,
S 12363, in comparison with the activity of the reference compound
vinblastine (VLB), when used alone or in combination with
verapamil (VRP). The influence of the
calcium influx blocker
verapamil on the activity of the combination of
S 12363 with
adriamycin (ADR) was also determined. The results showed that
S 12363 at a dose of 0.05 mg/kg/day, administered alone by intraperitoneal route daily on days 1 to 5, induced a tumoral regression of 50% during the first days
after treatment. This effect was potentialized by simultaneous treatment with
verapamil at 20 mg/kg/day for 5 days, leading to a long-term reduction of 70% of
tumor growth.
Vinblastine at a dose of 0.4 mg/kg/day administered alone or in combination with
verapamil, using the same protocol, was less efficient. The association of
S 12363 at 0.075 mg/kg/day (on days: 1-5, 11, 21 and 31),
adriamycin at 2 mg/kg/day (on days: 11, 21 and 31) and
verapamil at 20 mg/kg/day (on days: 0-5, 11, 21 and 31) induced an important reduction of
tumor growth of 80% at the end of the experiment. In conclusion, the new vinca-
alkaloid derivative
S 12363 could present a therapeutic advantage over the reference compound
vinblastine in the treatment of
renal cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)