Low-dose taxotere enhances the ability of sorafenib to induce apoptosis in gastric cancer models

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 12/2009; 15(2):316-26. DOI: 10.1111/j.1582-4934.2009.00993.x
Source: PubMed


Despite the low efficacy of conventional antitumour drugs, chemotherapy remains an essential tool in controlling advanced gastric and oesophageal cancers. We aimed to provide a biological rationale based on the sorafenib-taxotere interaction for the clinical treatment of gastric cancer. In vitro experiments were performed on four human gastric cancer cell lines (GK2, AKG, KKP and NCI-N87). Cytotoxicity was evaluated by sulforhodamine B (SRB) assay, cell cycle perturbations, apoptosis and mitotic catastrophe were assessed by flow cytometric and microscopic analyses, and protein expression was studied by Western blot. In the in vivo experiments, nude mice xenografted with the most resistant line were treated with sorafenib and docetaxel singly or in association. Sorafenib inhibited cell growth (IG(50) values ranged from 3.4 to 8.1 μM) and caused down-regulation of MAP-K/ERK phosphorylation and of mcl-1 and p-bad expression after a 48-hr exposure. Apoptosis induction was associated with caspase-3 and -9 activation and mitochondrial membrane depolarization. The drug combination enhanced apoptosis (up to 80%) and produced a synergistic interaction when low doses of the taxane preceded administration of the antityrosine kinase. This synergism was probably due to the induction of an anomalous multidiploid G0-G1 peak and to consequent mitotic catastrophe, which increased sensitivity to sorafenib. Consistent with in vitro results, the docetaxel-sorafenib sequence exhibited high therapeutic efficacy in NCI-N87 mouse xenografts producing tumour weight inhibition (> 65%), tumour growth delay (up to 25 days) and increased mouse survival (30%). Our findings suggest the potential clinical usefulness of treatment with sorafenib and docetaxel for advanced gastric cancer.

Download full-text


Available from: Anna Tesei,
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper provides a framework for understanding trade patterns in the Mashreq. An augmented gravity model is used to compare actual with expected levels of trade. Trade barriers, political uncertainty, and over-appreciation of domestic currencies seem to explain low levels of international trade. At the intra-regional level, specific trade barriers between Israel and other Mashreq countries reduce further levels of trade. Quite surprisingly, removing Israel from the sample leads to higher actual intra-regional trade than predicted. The analysis suggests that trade liberalization, correction of currency misalignments, reduction of political uncertainty, and improved trade relations with Israel would boost trade in the region.
    12/2001; 01(163). DOI:10.5089/9781451857931.001
  • [Show abstract] [Hide abstract]
    ABSTRACT: We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m(2)/q3 weeks), sorafenib was administered at 200 mg BID on days 2-19 (dose level 1), at 200 mg BID on days 1-21 (dose level 2), at 400 mg BID on days 2-19 (dose level 3), at 400 mg BID on days 1-21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety. Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months. Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1-21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.
    Cancer Chemotherapy and Pharmacology 07/2012; 70(2):293-303. DOI:10.1007/s00280-012-1914-y · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastric cancer represents one of the most common cancer worldwide. Unfortunately, the majority of patients still present in advanced stage and, despite advances in diagnostic and treatment strategies, outcome still remains poor with high mortality rate despite decreasing incidence. Although utility of classical chemotherapy agents has been widely explored, advances have been slow and the efficacy of these agents has reached a plateau of median overall survival not higher than 12 months. Therefore, researchers focused their attention on better understanding molecular biology of carcinogenesis and of acquisition of the cancer cell phenotype, as well on development of rationally designed drugs that would target specific molecular aberrancies in signal transduction pathways. These targets include cell surface receptors, circulating growth and angiogenic factors and other molecules involved in downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in gastric cancer are not so encouraging when compared to other solid organ malignanciessuch as breast and colorectal cancer. This article reviews the role of targeted agents in gastric cancer as single-agent therapy or in combination regimens, including their rational and emerging mechanism of action, current and emerging data. We focused our attention mainly on published phase III studies, therefore cornerstone clinical trials with trastuzumab and bevacizumab have been largely discussed. Phase III studies presented in important international meetings are also reviewed as well phase II published studies and promising new therapies investigated in preclinical or phase I studies. Todate, only trastuzumab has shown significantly increased survival in combination with chemotherapy in first-line and ramucirumab as single agent in second-line treatment, but - despite other disappointing results - these are the proof of principle that targeting the proper molecular aberration is the best way for implementing outcome of therapy.
    Current Medicinal Chemistry 11/2013; 21(8). DOI:10.2174/0929867321666131129124054 · 3.85 Impact Factor