valproic acid + FEC100

The combination of valproic acid and FEC100 is a therapeutic regimen that has been studied in clinical trials for cancer treatment, particularly breast cancer. This combination leverages the histone deacetylase (HDAC) inhibitory properties of valproic acid alongside the cytotoxic effects of the FEC100 chemotherapy regimen. ## Drug Components Valproic acid is an eight-carbon, branched-chained fatty acid that has been used for over 50 years as an anticonvulsant and mood stabilizer[2]. In cancer therapy, it functions as a histone deacetylase inhibitor (HDACi)[1][2]. FEC100 is a chemotherapy regimen consisting of three drugs: 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (500 mg/m²), administered intravenously every 21 days[6][8]. ## Clinical Evidence A phase I/II trial investigated this combination in patients with solid tumors. The study had two parts: - Phase I: 44 patients with solid tumors received escalating doses of valproic acid followed by epirubicin alone or in combination with FEC100[1][2]. - Phase II: A disease-specific cohort of 15 breast cancer patients received 120 mg/kg/day valproic acid plus the FEC100 regimen[1][2]. The maximum tolerated dose (MTD) for valproic acid was determined to be 140 mg/kg/day[2]. During the phase I part, partial responses were observed in 9 of 41 (22%) patients[1]. In the breast cancer cohort, 9 of 14 (64%) evaluable patients showed objective responses, with a median of 6 administered cycles[1]. ## Mechanism of Action The combination works through multiple mechanisms: 1. Valproic acid acts as a histone deacetylase inhibitor, which affects gene expression and can induce differentiation and sensitization of cancer cells to chemotherapy[1][2]. 2. FEC100 components work through different mechanisms: - 5-fluorouracil: Interferes with DNA synthesis - Epirubicin: Intercalates with DNA and inhibits topoisomerase II - Cyclophosphamide: Alkylating agent that cross-links DNA Preclinical studies have shown that HDACi, including valproic acid, induces synergistic antitumor effects in combination with fluoropyrimidines in colorectal cancer models[2]. Additionally, valproic acid has been shown to induce differentiation and sensitization of colorectal cancer stem cells to oxaliplatin[2]. ## Side Effects The predominant toxicities observed in clinical trials were: - Valproic acid-associated somnolence[1][2] - Epirubicin-induced myelosuppression[1] - Neutropenia (grade 3/4 in 51.3% of patients in one study)[10] Valproic acid plasma levels were associated with short-term, reversible depletion of white blood cells and neutrophils within 48 hours[1]. ## Biomarkers Histone acetylation in tumor samples and in peripheral blood mononuclear cells (PBMCs) correlated with valproic acid levels and was linked to baseline HDAC2 but not to HDAC6 expression[1][2]. This suggests that PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies, and HDAC2 should be considered as a relevant therapeutic target[1]. This combination represents an innovative approach to cancer treatment by combining epigenetic modulation with conventional chemotherapy, potentially enhancing the efficacy of standard treatments.

Other names

Valproic Acid + FEC100VPA + FEC100