Inadequate effectiveness of anticancer drug in treating renal cell carcinoma has been attributed to the overexpresssion of multidrug resistance gene (MDR1) and its product, membrane-bound P-glycoprotein. P-glycoprotein is known to actively pump
out
intracellular drug, which results in low intracellular anticancer drug concentration. Progesterone, which has been used in patients with advanced renal cell carcinoma is found to cause a three to four-fold increase in vinblastine accumulation in
the
P-glycoprotein-expressing murine macrophagelike cell line, we have studied to evaluate the MDR modulating action of medroxyprogesterone acetate(MPA) in renal cell caricinoma cell lines also with tamoxifen and verapamil.
A-498 of a high mdrl expressed cell line and Caki-2 of a mdrl expressed cell line were each placed in 96 multiwell plates. Vinblastine, in concentration from 0.01㎍/ml to 10㎍/ml was added to each well and verapamil, from 0.1μM to 10μM, MPA,
from
2.5μM to 25μM, or tamoxifen, from 0.1μM to 10μM was also added. The in vitro chemosensitivity of two renal cell carcinoma cell lines (Caki-2 and A-498) to vinblastine was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol
bromide(MTT)
colorimetric assay.
Growth of Caki-2 cells is inhibited by low doses of vinblastine(IC50: 0.27㎍/ml, but A -498 cells are highly resistant to the drug, with IC50 value of 0.47㎍/ml. The chomosensitivity of the A-498 cells is increased in response to 5 μM MPA, 1 μM
verapamil and 2 μM tamoxifen, which are known to partially reverse the MDR phenotype in other resistant tumors. The effective concentration of MPA for MDR reversal is in clinically achievable concentration but one of verapamil is not. The
chemosensitivity of Caki-2 cells does not change according to MDR modulating agents.
MPA is an effective MDR modulating agents to enhance the cytotoxicity of vinblastine in renal cell carcinoma cell line showing P-glycoprotein expression. It suggests that combination therapy of MPA and vinblastine is better than monotherapy with
MPA or
vinblastine alone.
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