TAMOXIFEN MODULATION OF CARBOPLATIN CYTOTOXICITY IN A HUMAN U-138 GLIOMA CELL-LINE

Glioma cells express high protein kinase C (PKC) activity, which may r epresent an important therapeutic target. Tamoxifen (TAM) has moderate PKC-inhibiting activity, blocking DNA synthesis and cellular prolifer ation in human glioma cells at concentrations that can be achieved the rapeutically. Carboplatin (CBDCA), a second-generation platinum deriva tive, induces intra- and interstrand DNA-protein crosslinks producing inhibition of tumor-cell growth. In the present study, the effect of T AM. CBDCA, and the combination of both was evaluated against the human established U-138 glioma cell line during the exponential growth phas e (48-72 h) by means of both the Biorad protein assay (BPA) method and Trypan blue exclusion study (TBES). Both TAM and CBDCA reduced the ce llular growth rate, with a median 50%-inhibiting concentration (IC50) of 12.5 mu M for TAM and 350 mu M for CBDCA. The U-138 glioma cell lin e showed a moderate response to 100 mu M Of CBDCA, with less than or e qual to 10% reduction of the growth rate. The association of both chem otherapeutic agents induced a 98% reduction of the IC50 dose of TAM (0 .1 mu M), and a 71% reduction of the IC50 dose of CBDCA (100 mu M). Du ring the combinational TAM-CBDCA exposure we observed a cytotoxic effe ct of TAM at concentrations lower than 0.1 mu M, not recognized using it as a single drug. The differences observed among the IC50 doses (TA M, CBDCA, TAM-CBDCA) and among treated and untreated matched control c ells were statistically significant (P < 0.01). Our results confirm pr evious observations about the efficacy in vitro of TAM against human g lioma cell lines and show a marked enhancement of this activity by CBD CA. (C) 1998 Elsevier Science B.V. All rights reserved.