Ramón Alemany

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

Persistence of adenovirus type 5 in blood has implications for the pathogenicity of the virus infection and for the use of this virus in oncolysis and gene therapy. In this study, the kinetics of adenovirus clearance from blood in mice has been evaluated. After a single inoculation of concentrated virus into the vena cava, virus half-life was less than 2 min. Depletion of Kupffer cells (KC) resulted in increased viraemia. After tail-vein injection, virus and latex beads co-localized within KC. An important factor in clearance by KC is the negative charge of particles. Deletion of the hexon hypervariable region 1 acidic stretch decreased the negative charge of the virion but it did not increase blood persistence. Coating with PEG ('PEGylation') reduced the clearance rate but also reduced infectivity.

BACKGROUND: Oncolytic adenoviruses are promising therapies for the treatment of gliomas. However, untargeted viral replication and the paucity of coxsackie-adenovirus receptors (CARs) on tumor cells are major stumbling blocks for adenovirus-based treatment. We studied the antiglioma activity of the tumor-selective Delta-24 adenovirus, which encompasses an early 1 A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, and of the Delta-24-RGD adenovirus. Delta-24-RGD has an RGD-4C peptide motif inserted into the adenoviral fiber, which allows the adenovirus to anchor directly to integrins. METHODS: CAR and integrin expression were examined by flow cytometry in six glioma cell lines and in normal human astrocytes (NHAs). Adenoviral vectors containing green fluorescent protein (GFP) (AdGFP and AdGFP-RGD) were used to infect glioma cell lines with high or low CAR expression. Viability of glioma cells infected with different adenoviruses was assessed by trypan blue staining. Adenovirus replication was quantified with the infection-dose replication assay. Athymic mice carrying glioma xenografts received intratumoral injections of Delta-24-RGD or Delta-24 and were followed for survival, which was analyzed by the Kaplan-Meier method and the log-rank test. All statistical tests were two-sided. RESULTS: Half the glioma cell lines expressed low levels of CAR (defined as <50% of cells expressing detectable CAR); all lines expressed integrins in more than 50% of cells. Infection of U-87 MG cells (a low-CAR-expressing line) with AdGFP-RGD resulted in approximately six times more GFP-positive cells than infection with AdGFP. Delta-24-RGD was more cytopathic to both low- and high-CAR-expressing glioma lines than Delta-24, and it replicated more efficiently in both cell lines. In the xenografted mice, intratumoral injection of Delta-24-RGD was associated with longer survival than intratumoral injection of Delta-24 (P<.001, log-rank test). Furthermore, 60% of Delta-24-RGD-treated mice but only 15% of Delta-24-treated mice survived more than 4 months (difference = 45%, 95% CI = 21% to 68%). CONCLUSIONS: The antitumor activity of Delta-24-RGD suggests that it has the potential to be an effective agent in the treatment of gliomas.