Abstract 2535: PrevOnco® exhibits anti-tumor activity in in vitro and in vivo human tumor models: Combination therapy (PrevOnco® / Doxorubicin) demonstrates a better efficacy profile with enhanced survival rate in a liver cancer model

Background: The investigational anti-neoplastic agent PrevOnco® (know as Prevacid® /Lansoprazole®) is entering Phase II clinical trials in the US for hepatocellular carcinoma. Objectives: This study examined the efficacy of PrevOnco® in both in vitro and in vivo human tumor models. The optimal oral formulation, pharmacokinetic parameters and its combination therapy with doxorubicin were evaluated. Methods: Cytotoxicity was assessed in vitro by MTT analysis. In vivo efficacy was assessed in nude mice in 2 survival models of the pediatric kidney-derived G401 and SR leukemia, and one ectotopic HepG2 model. Results: In MTT assays, PrevOnco® demonstrated a concentration-dependent cytotoxic effect against a number of cancer cell lines (MC116, HOP-62, MOLT4, HCT-15, JMI, RPMI6666, RS 1184, STA 486, SF539, U251, SF295, UACC-62). Synergistic activity was observed with doxorubicin but not with cisplatin. PrevOnco® was significantly more effective than Omeprezole or SCH-28080. Pharmacokinetic analysis in nude mice showed 10% PEG400 to be a better vehicle than carboxy-methyl cellulose. A mean maximum concentration (Cmax) of 20,242 ng/mL was detected at 0.5 hours (Tmax) with the mean dose adjusted area under the curve (AUC) determined to be 846.5 nM*hr/mg. The half life (T1/2) of the compound was 0.9 hours. PrevOnco® at 100 mg/kg given orally significantly prolonged the survival rate in the G401 kidney xenograft by 60% at day 70 whereas all mice in vehicle treaded group died. At study end (day 83) 26% of the mice remained alive in the treated group. SR leukemia xenograft treated with PrevOnco® survived through the end of the study with >80% of the mice remaining alive. PrevOnco® induced a dose-dependent reduction in tumor growth in hepG2 model. A synergestic antitumoral effect was obtained with the combination treatment of PrevOnco® at 30 mg/kg and doxorubicin at10 mg/kg. PrevOnco® levels in hepG2 tumors following 100 mg/Kg BID treatment for 3 consecutive days indicated accumulation of the drug into tumor tissue. Conclusion: PrevOnco® exhibited anti-neoplastic activity in both in vitro and in vivo, enhancing survival and inhibiting tumor growth. Synergistic activity was obtained with doxorubicin in xenograft model of liver cancer, suggesting a potential new combination therapy for the treatment of liver cancer with less toxicological liability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2535. doi:10.1158/1538-7445.AM2011-2535