Philippe Collery

Biological study of the effect of water soluble [N-(2-hydroxybenzyl)-l-aspartato] gallium complexes on breast carcinoma and fibrosarcoma cells

Two water soluble gallium complexes described as [Ga(III)LCl], where l is the deprotonated form of N-2-hydroxybenzyl aspartic acid derivatives, were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, mass spectrometry, and elemental analysis. The 2-(5-chloro-2-hydroxybenzylamino)succinic acid derivative (GS2) has been found to be a promising anticancer drug candidate. This compound was found to be more cytotoxic against human breast carcinoma MDA-MB231 and fibrosarcoma HT-1080 cell lines than the unsubstituted derivative and GaCl3. GS2 was able to induce apoptosis through downregulation of AKT phosphorylation, G2M arrest in cell cycle, and caspase 3/7 pathway. This gallium complex was found to induce an increase in mitochondrial ROS level in HT-1080 cells but not in MDA-MB231 cells. This suggests that the mechanism of action of GS2 would not be mediated by the drug-induced oxidative stress but probably by directly and indirectly inhibiting the AKT cell-signaling pathway.Graphical abstract

Abstract C129: Relation between long‐term blood pharmacokinetics, pharmacogenomics, and severe neurotoxicity in patients undergoing an oxaliplatin‐based regimen

The aim of the study was to investigate the residual blood level of O before each cycle of various oxaliplatin (O) based protocols, and to explore its predictive value for potential occurrence of a severe neurotoxicity. Methods: Between 11/2005 and 06/2008, 220 Pts were included in a prospective cohort, in 7 French centers. Patients received a minimum of 7 cycles of O. Blood samples were taken before each cycle with a maximum of 12 cycles. In parallel neurotoxicity was assessed by the modified Levi score (grade 0 to 3) and by the Von Frey filament exam. Saliva was collected before the first cycle for genomics analysis. The O concentration was obtained by Atomic Absorption Spectrometry assay after nitric digestion of total blood. Polymorphism of different targets were investigated (carrier proteins: MRP2, OCT1, OCT2, GSTP1, adducts repair system: ERCC1, ERCC2). Time to first severe neurotoxicity occurrence (TTSN Events: Grade 2 or3) was estimated using Kaplan‐Meier. Predictive value of severe neurotoxicity was explored using univariate and multivariate logistic or Cox regressions. Harrel C index was produced. Results: 206 pts with gastro‐intestinal cancer had, at the time of analysis, completed follow‐up and 201 pts (91.3%) were eligible for pharmacokinetics. (85%) received FOLFOX regimen (85mg/m2every 2 weeks), the others GEMOX or XELOX (100mg/m2 every 3 weeks). The mean total dose of O received for all pts was 1.18 ± 0.4 g. After cycle 1, 2 and 10, median residual level of O was respectively 0.31 mg/L, 0.43 mg/L and 0.60 mg/L. The maximal concentration was obtained between cycle 5 and cycle 9. Respectively 89 Pts (44%) and 15 pts (7%) had a Gr2 and a Gr3 neurotoxicity. Median time TTSN was 141 days (95% CI: 132 – 161). O concentration before 2nd cure (HR = 1.39, p Conclusions: 1. The mean residual blood level of O before the second cure is correlated with the occurrence of Gr2 or Gr3 neurotoxicity (p Mann‐Whitney = 0.0007) 2. The residual blood level of O before the second O cure is correlated with the delay of occurrence of a Gr2 or Gr3 neurotoxicity in patients receiving an O based‐regimen (Harrel C=0.54, p=0.021). Further statistical analyses will be done to analyse the data from the Von Frey filaments and the gene polymorphism and will be presented at the meeting. An O posology adaptation or infusion duration modification based on Platinum residual level of cure 1 have to be considered in future clinical trial in order to avoid severe Gr2 or Gr3 neurotoxicity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C129.