ABSTRACT
Tamoxifen dosage is based on the one-dose-fits-all approach. The anticancer effect of tamoxifen is believed to be due to the metabolites, 4-hydroxytamoxifen (4OHtam), and 4-hydroxy-N-desmethyltamoxifen (4OHNDtam/endoxifen). These demethylated metabolites of tamoxifen have been associated with its side effects, whereas the effect mediated by tamoxifen-N-oxide (tamNox) is still poorly understood. Our objective was to improve the therapeutic index of tamoxifen by personalizing its dosage and maintaining serum tamoxifen metabolite concentrations within a target range. We examined the levels of tamoxifen, 4OHtam, 4OHNDtam, N-desmethyltamoxifen (NDtam), N-desdimethyltamoxifen (NDDtam), and tamNox in serum and in breast tumors specimens of 115 patients treated with 1, 5 or 20 mg/day of tamoxifen for 4 weeks before surgery in a randomized trial. Furthermore, the metabolism of tamNox in MCF-7 breast cancer cells was also studied. The concentrations of tamoxifen and its metabolites in tumor tissues were significantly correlated to their serum levels. Tumor tissue levels were 5-10 times higher than those measured in serum, with the exception of tamNox. In MCF-7 cells, tamNox was converted back to tamoxifen. In contrast to the tissue distribution of tamNox, the concentrations of 4OHtam and 4OHNDtam in tumor tissues corresponded to their serum levels. The results suggest that implementation of therapeutic drug monitoring may improve the therapeutic index of tamoxifen. Furthermore, the tissue distribution of tamNox deviated from that of the other tamoxifen metabolites.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacokinetics , Breast Neoplasms/drug therapy , Tamoxifen/analogs & derivatives , Aged , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Middle Aged , Randomized Controlled Trials as Topic , Statistics, Nonparametric , Tamoxifen/adverse effects , Tamoxifen/pharmacokinetics , Tamoxifen/therapeutic use , Tissue DistributionABSTRACT
PURPOSE: Nuclear receptor coactivator expression and activity may partly explain the complex agonist/antagonist effects of tamoxifen at clinical level. In a preoperative trial, dose reduction from 20 to 1 mg tamoxifen was associated with retained antiproliferative effect on breast cancer. Here, we assessed the gene expression of the steroid receptor coactivators SRC-1, SRC-2/transcription intermediary factor 2, and SRC-3/amplified in breast cancer 1 (AIB1) and the growth factor receptor HER-2/neu under three tamoxifen dose regimens. EXPERIMENTAL DESIGN: Surgical specimens from estrogen receptor-positive breast cancer and adjacent normal breast tissue from 64 patients treated 4 weeks preoperatively with 20, 5, or 1 mg/d tamoxifen and 28 nontreated breast cancer controls were analyzed for coactivator and HER-2/neu mRNA expression using real-time reverse transcription-PCR. The gene expression levels were related to immunohistochemical expression of Ki67, serum levels of insulin-like growth factor I and sex hormone binding globulin, other prognostic factors, and clinical outcome. RESULTS: The coactivators and HER-2/neu mRNA levels were higher in malignant compared with normal tissue (P < 0.001). Tamoxifen significantly increased the expression of coactivators in normal and malignant tissue irrespective of dose, especially for SRC-3/AIB1 (P < 0.001 tamoxifen-treated versus nontreated subjects). SRC-3/AIB1 and HER-2/neu mRNA levels were positively correlated (P = 0.016), but the coactivators could not explain the variability of Ki67, insulin-like growth factor I, and sex hormone binding. Although not significant, SRC-3/AIB1 tended to be higher in subjects with poor clinical outcome and unfavorable prognostic factors. CONCLUSIONS: Increased coactivator mRNA levels seem to be an early response to tamoxifen without dose-response relationship in the 1- to 20-mg range. Clinical and molecular effects of low-dose tamoxifen should be further explored.
Subject(s)
Breast Neoplasms/drug therapy , Breast/drug effects , Carcinoma/drug therapy , Nuclear Receptor Coactivator 3/genetics , Tamoxifen/administration & dosage , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Breast/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinoma/genetics , Carcinoma/metabolism , Dose-Response Relationship, Drug , Double-Blind Method , Drug Resistance, Neoplasm/genetics , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic/drug effects , Humans , Middle Aged , Nuclear Receptor Coactivator 3/metabolism , Randomized Controlled Trials as Topic , Tamoxifen/pharmacologyABSTRACT
Tetradecylthioacetic acid (TTA) is a hypolipidemic modified fatty acid and a peroxisome proliferator-activated receptor (PPAR) ligand. The mechanisms of TTA-mediated effects seem to involve the PPARs, but the effects have not been assigned to any specific PPAR subtype. PPARalpha-/- mice were employed to study the role of PPARalpha after TTA treatment. We also performed in vitro transfection assays to obtain mechanistic knowledge of how TTA affected PPAR activation in the presence of PPARgamma coactivator (PGC)-1 and steroid receptor coactivators (SRC)-1 and SRC-2, which are associated with energy balance and mitochondrial biogenesis. We show that TTA increases hepatic fatty acid beta-oxidation in PPARalpha-/- mice. TTA acts as a pan-PPAR ligand in vitro, and PGC-1, SRC-1 and SRC-2 have cell type and PPAR-specific effects together with TTA. In the absence of exogenous ligands, SRC-1 did not induce PPAR activity, while PGC-1 was the most potent PPAR coactivator. When the coactivators were overexpressed, pronounced effects of TTA were observed especially for PPARdelta and PPARgamma. We conclude that PPARalpha is involved in, but not required for, the hypolipidemic mechanisms of TTA. It appears that the activity of PPARdelta, with substantial contribution of nuclear receptor coactivators, PGC-1 in special, is conducive to TTA's mechanism of action.
