Tamoxifen modulation of carboplatin cytotoxicity in a human U-138 glioma cell line.
Glioma cells express high protein kinase C (PKC) activity, which may represent an important therapeutic target. Tamoxifen (TAM) has moderate PKC-inhibiting activity, blocking DNA synthesis and cellular proliferation in human glioma cells at concentrations that can be achieved therapeutically. Carboplatin (CBDCA), a second-generation platinum derivative, induces intra- and interstrand DNA-protein crosslinks producing inhibition of tumor-cell growth. In the present study, the effect of TAM, CBDCA, and the combination of both was evaluated against the human established U-138 glioma cell line during the exponential growth phase (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 cellular growth rate, with a median 50%-inhibiting concentration (IC50) of 12.5 microM for TAM and 350 microM for CBDCA. The U-138 glioma cell line showed a moderate response to 100 microM of CBDCA, with < or = 10% reduction of the growth rate. The association of both chemotherapeutic agents induced a 98% reduction of the IC50 dose of TAM (0.1 microM), and a 71% reduction of the IC50 dose of CBDCA (100 microM). During the combinational TAM CBDCA exposure we observed a cytotoxic effect of TAM at concentrations lower than 0.1 microM, not recognized using it as a single drug. The differences observed among the IC50 doses (TAM, CBDCA, TAM-CBDCA) and among treated and untreated matched control cells were statistically significant (P < 0.01). Our results confirm previous observations about the efficacy in vitro of TAM against human glioma cell lines and show a marked enhancement of this activity by CBDCA.
Mastronardi
L
L
Civilian Hospital of Terni, Department of Neurological Sciences Neurosurgery, Italy. mastro@tin.it
Farah
J O
JO
Puzzilli
F
F
Ruggeri
A
A
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005910:Glioma / Q000473:pathology*; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D016190:Carboplatin; D011493:Protein Kinase C