Abstract 2575: Pharmacodynamic evaluation of the combination of carboplatin and paclitaxel associated with either pioglitazone or hydroxyurea, within a randomized phase 1 dose escalation clinical trial in patients with advanced solid tumors

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Abstract Background: Hidroxyurea acts synergistically with DNA alkylating agents; pioglitazone is a ligand of PPAR-gamma, a nuclear receptor with great potential in controlling oncogenic mechanisms unexplored in clinic, upregulated after exposure to several cytotoxic agents. Purpose: To evaluate pharmacodynamic effects of the combination of carboplatin and paclitaxel, associated with either hydroxyurea or pioglitazone, within a phase 1-2 clinical study. Material and Methods: Patients with unresectable, advanced solid tumors, refractory to standard therapies were considered eligible for this randomized, dose escalating trial. Patients received weekly administration of carboplatin (AUC = 2) and paclitaxel (80 mg/m2) on days 1, 8, 15 q 28d. Patients were randomly allocated to additionally receive either pioglitazone (P) or hydroxyurea (H). The doses of P were 30, 45 and 60 mg/d, whereas the doses of H were 1000 and 1500 mg/d. The comet assay was chosen as a tool to assess the added effects of hydroxyurea, whereas UCP-2 (Uncoupling Protein 2) was selected for the evaluation of the effects of pioglitazone. These events were determined in mononuclear cells from peripheral blood, at baseline and at week 4. Alkaline comet assays were performed using a single-cell electrophoresis protocol and comet lengths were measured with the ImageJ software. UCP-2 was determined by quantitative RT-PCR. For these results, intrapatient and intercohort variations were analyzed. Results: The UCP-2 gene expression was increased after treatment in the majority of patients in our cohort. The increased expression of UCP-2 was lower in patients treated with pioglitazone versus hydroxyurea, however there were no significant differences between treatments. The rate of affected cells with double-strand breaks after treatment, was significantly higher in patients treated with hydroxyurea than in patients treated with pioglitazone (27.1% vs. 16.3% of cells affected, P<0.05). Conclusions: Our study has the limitations of a small sample size, but we have seen that the use of hydroxyurea can lead further damage to cellular DNA. UCP-2 expression was increase after both treatments, and we can not attribute it to one drug in particular. We should note that we could not discriminate between the different drug doses administered to patients due to small sample. A correlation between these effects and tumor response will be analyzed and shown. Citation Format: M. Teresa Agulló-Ortuño, Carlos Pérez, C. Vanesa Díaz-García, Blanca Homet, Alba Agudo-López, Analia Rodríguez Garzotto, Elena Prieto-García, Jorge Adeva, María C. Riesco, Raquel Rodríguez, M. Luisa Durán, Elena Laguna, Carmen Montalbán, Hernán Cortés-Funes, José A. López-Martín. Pharmacodynamic evaluation of the combination of carboplatin and paclitaxel associated with either pioglitazone or hydroxyurea, within a randomized phase 1 dose escalation clinical trial in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2015-2575

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