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Biomedical subjects

Stephen H Thorne

Publications and source records attributed to Stephen H Thorne.

7 recordsLinked to original sources
PubMed2006

Selective intratumoral amplification of an antiangiogenic vector by an oncolytic virus produces enhanced antivascular and anti-tumor efficacy.

The development of effective cancer therapy will require the simultaneous targeting of multiple steps in tumor development. We have previously described an antiangiogenic gene therapy vector, Ad Flk1-Fc, which expresses a soluble VEGF receptor capable of inhibiting tumor angiogenesis and growth. We have also described an oncolytic virus, dl922/947, whose replication and subsequent cytotoxicity are restricted to cancer cells with a loss of the G1-S cell cycle checkpoint. Here we have optimized methods for combining these therapies, yielding significantly greater anti-tumor effects than the respective monotherapies. In cultured tumor lines, co-infection with both Ad Flk1-Fc and dl922/947 allowed replication and repackaging of the replication-deficient Ad Flk1-Fc and enhanced soluble VEGF receptor expression. Similar repackaging and increased gene expression were demonstrated in vivo using bioluminescence imaging studies. Finally, coadministration of these therapeutic viral therapies in vivo produced significantly enhanced anti-tumor effects in colon HCT 116 and prostate PC-3 xenografts in mice. This increased therapeutic benefit correlated with replication of Ad Flk1-Fc viral genomes, increased intratumoral levels of Flk1-Fc protein, and decreased microvessel density, consistent with enhanced antiangiogenic activity.

Adenocarcinoma↗
PubMed2006

New enzyme for reductive cancer chemotherapy, YieF, and its improvement by directed evolution.

Reductive prodrugs, mitomycin C and 5-aziridinyl-2,4-dinitrobenzamide (CB 1954), are nontoxic in their native form but become highly toxic upon reduction. Their effectiveness in cancer chemotherapy can be enhanced by delivering to tumors enzymes with improved prodrug reduction kinetics. We report the discovery of a new prodrug-reducing enzyme, YieF, from Escherichia coli, and the improvement of its kinetics for reducing mitomycin C and CB 1954. A YieF-derived enzyme, Y6, killed HeLa spinner cells with >or=5-fold efficiency than the wild-type enzymes, YieF and NfsA, at a variety of drug and enzyme concentrations and incubation times. With adhered HeLa cells and Salmonella typhimurium SL 7838 bacteria as enzyme delivery vehicle, at least an order of magnitude less of Y6-producing bacteria were required to kill >90% of tumor cells compared with bacteria expressing the wild-type enzymes, which at a comparable level killed < 5% of the cells. Thus, Y6 is a promising enzyme for use in cancer chemotherapy, and Salmonella strain SL 7838, which specifically targets tumors, may be used to deliver the prodrug-activating enzymes to tumors.

Antineoplastic Agents↗
PubMed2005

Oncolytic virotherapy: approaches to tumor targeting and enhancing antitumor effects.

The application of replicating viruses for the treatment of cancers represents a novel therapy that is distinct from traditional treatment modalities. It is apparent that the genetic changes that a virus produces within an infected cell in order to create an environment conducive to viral replication are often similar to the processes involved in cellular transformation. These include uncontrolled cellular proliferation, prevention of apoptosis, and resistance to host organism immune effector mechanisms. Deletions of viral genes involved in these processes have been exploited to produce viral mutants whose replication is selective for transformed cells. The use of tissue-specific transcriptional response or RNA stability elements to control the expression of critical viral genes has also resulted in targeted viruses. Work also is being undertaken to restrict or alter the tropism of viruses by altering their ability to infect certain cell types. Finally, the addition of exogenous genes can be used to increase the virus's lytic potential and/or bystander killing; to further induce the host's immune response against cancer cells; and/or to permit the controlled downregulation of viral replication if necessary. The combination of different tumor-targeting mutations in parallel with the expression of foreign genes has resulted in the evolution of second- and third-generation viruses that continue to become further distinct from their native parental strains. The movement of these viruses into the clinic has begun to demonstrate the potential of this approach in the treatment of cancers.

Apoptosis↗
PubMed2005

Effects of febrile temperature on adenoviral infection and replication: implications for viral therapy of cancer.

We previously conducted a phase I/II study using arterial infusions of ONYX-015 (dl1520), a replication-selective adenoviral vector, with E1b deleted, for patients with metastatic colorectal cancer. No dose-limiting toxicities occurred, but >90% of the patients experienced fever. The effects of temperature on the replication of dl1520 in normal and transformed cells had not been studied. Therefore, replication and cell viability assays were performed with a panel of nontransformed and transformed cell lines cultured at 37 and 39.5 degrees C and treated with adenovirus type 5 (Ad5) or dl1520. Ad5-mediated cytolytic effects were inhibited and production of infectious particles decreased by >1,000-fold in the nontransformed cells at 39.5 degrees C. Seven of nine of the tumor cell lines retained significant cell-killing effects when treated with Ad5 at 39.5 degrees C. When dl1520 was used, no cytolytic effects were observed at 39.5 degrees C in the nontransformed cell lines; however, cytolytic effects occurred in six of nine tumor cell lines at 39.5 degrees C. Notably, a subset of the tumor cell lines demonstrated increased dl1520-mediated cytolytic effect and replication at 39.5 degrees C. Suppression of Ad5 and dl1520 replication at 39.5 degrees C was not related to p53 status or HSP70 expression. Also, at 39.5 degrees C, E1a expression was inhibited in nontransformed cells but was still abundant in the transformed cells, indicating that a novel early block in viral replication occurred in the nontransformed cells. Fever may therefore augment the therapeutic index of oncolytic viruses by inhibiting replication in normal cells while permitting or enhancing viral replication in some tumor cells.

Adenovirus E1B Proteins↗
PubMed2005

The use of oncolytic vaccinia viruses in the treatment of cancer: a new role for an old ally?

The use of genetically engineered, tumor-targeting viruses as oncolytic agents has recently emerged as a promising new area for the development of novel cancer therapies. The first viruses to enter the clinic, such as ONYX-015 (an oncolytic adenovirus), provided evidence both for the safety and for the anti-tumor potential of this approach. The results of these early trials have also allowed investigators to examine the limitations of these viruses and to develop potentially far more effective approaches. In this review the development of such next generation viruses, in particular the potential use of strains of vaccinia virus, will be discussed. Vaccinia has an enormous history of use in humans and possesses many of the features felt to be beneficial for the creation of a successful virotherapy agent. It causes no known disease in humans, yet is capable of infecting almost all cell types with a subsequent rapid and lytic infection, which subsequently induces a vigorous local CTL immune response at the site of infection. Vaccinia also displays natural tumor tropism, and several approaches have been used to further limit viral replication to tumor cells and to optimize the immune response induced at the site of the tumor. Finally, the large cloning capacity of vaccinia allows for the addition of multiple foreign genes into the viral genome. This has been exploited to increase the bystander effect of the virus by immune modulation or by expression of pro-drug converting enzymes as well as to incorporate safety controls and reporters for in vivo molecular imaging. Initial clinical trials with these viruses further highlights their potential as the next generation of oncolytic agents and as highly effective future cancer therapies.

Antigens, Neoplasm↗
PubMed2005

Vaccinia virus and oncolytic virotherapy of cancer.

Vaccinia viruses possess many of the key attributes necessary for an ideal viral backbone for use in oncolytic virotherapy. These include a short lifecycle, with rapid cell-to-cell spread. strong lytic ability, a large cloning capacity and well-defined molecular biology. In addition, although capable of replicating in human cells, they are not considered a natural health problem and are especially well characterized. having been delivered to millions of individuals during the campaign to eradicate smallpox. A variety of tumor-targeting mutations have been described in several different vaccinia strains and the expression of a variety of different transgenes has been studied. Early clinical results using either vaccine strains or genetically modified vaccinia strains have demonstrated antitumor effects. Future prospects for the development of these viruses will be discussed.

Antineoplastic Agents↗