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Wednesday, November 19, 2003

http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrc/journal/v1/n2/full/nrc1101-130a_fs.html


CANCER GENE THERAPY: FRINGE OR CUTTING EDGE?

Frank McCormick about the author

University of California San Francisco, Cancer Research Institute, 2340 Sutter Street, San Francisco, California 94115, USA.
mccormick@cc.ucsf.edu


Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally — a challenge that has been successfully addressed.

Gene therapy offers tremendous promise for the future of cancer treatment. This technology, more than any other, takes direct advantage of our new understanding of cancer at the molecular level and has been exploited to develop new strategies for killing cells selectively or arresting their growth. However, despite the promise of safe and rational treatment, many researchers have serious doubts as to whether this is a viable approach. Is this view accurate? Or does gene therapy have a future in mainstream clinical oncology?
Nature Reviews Cancer - Review: "CANCER GENE THERAPY: FRINGE OR CUTTING EDGE?

Frank McCormick about the author
University of California San Francisco, Cancer Research Institute, 2340 Sutter Street, San Francisco, California 94115, USA.
mccormick@cc.ucsf.edu

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally � a challenge that has been successfully addressed."
Nature Reviews Cancer - Review: "CANCER GENE THERAPY: FRINGE OR CUTTING EDGE?

Frank McCormick about the author
University of California San Francisco, Cancer Research Institute, 2340 Sutter Street, San Francisco, California 94115, USA.
mccormick@cc.ucsf.edu

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally � a challenge that has been successfully addressed."
Virus therapy attacks cancer cells

Researchers have come up with an ingenious means of engineering a virus so that it selectively replicates in and destroys tumor cells. Because the virus is unable to attack normal cells, it may prove useful as a supplement to traditional cancer treatments, which do not discriminate between normal and tumor cells and often cause debilitating side effects. The new type of adenoviruses, described by Richard Vile and coworkers in the July issue of Nature Biotechnology, replicates in cells with cancer-associated genetic mutations.

Vile and his team engineered into their virus a special type of mRNA ‘stability’ sequence that causes a gene (E1A) essential for viral replication to be degraded in normal cells, thus inhibiting reproduction of the virus. Because mRNA stability is improved in the presence of a protein called RAS—which is less abundant in normal cells, but common in certain cancer cells—the researchers hypothesized that their virus would, however, selectively replicate in and destroy tumor cells. Sure enough, when they injected the virus into tumors implanted in mice, it replicated and reduced tumor growth. The approach provides a step towards generating truly selective viral therapies against cancer.
Nature Cancer Update - Hot off the Press - Virus therapy attacks cancer cells: "Vile and his team engineered into their virus a special type of mRNA �stability� sequence that causes a gene (E1A) essential for viral replication to be degraded in normal cells, thus inhibiting reproduction of the virus. Because mRNA stability is improved in the presence of a protein called RAS�which is less abundant in normal cells, but common in certain cancer cells�the researchers hypothesized that their virus would, however, selectively replicate in and destroy tumor cells. Sure enough, when they injected the virus into tumors implanted in mice, it replicated and reduced tumor growth. The approach provides a step towards generating truly selective viral therapies against cancer."
Nature Reviews Cancer - ReviewuPA and uPAR as targets in cancer therapy. Selective inhibition of the complex interaction between uPA and uPAR is considered to be a feasible approach for the treatment of malignant brain tumours. Recent reports indicate that uPA antisense oligodeoxynucleotides given through catheters or intratumorally in rats with intracerebral C6 tumours are tolerated well, with no evidence of toxicity, at levels that are expected to be therapeutic27. Furthermore, phenylbutyrate — a differentiation-inducing and cytotoxic compound — inhibits glioma-cell proliferation, morphology, migration and invasiveness, and decreases levels of both c-MYC and uPA28. Recent studies have shown that a combination of cisplatin and A6 — an octamer-capped peptide derived from the non-receptor-binding region of uPA — inhibits glioblastoma tumour growth and angiogenesis in vivo29. Our recent studies have shown that the expression of uPA can be downregulated by antisense uPA cDNA in glioblastoma cells. The stable antisense-expressing clones were less invasive, and tumour formation was inhibited in both in vitro and in vivo models30. We also showed that clones stably expressing an amino-terminal fragment of uPA (ATF-uPA) showed markedly less invasion and no tumour growth in both in vitro and in vivo models31. The downregulation of uPAR expression by glioblastoma cells by expression of an antisense-uPAR vector significantly decreased cell migration and invasiveness in vitro32. Furthermore, glioblastoma cells in which uPAR expression was downregulated by antisense-uPAR cDNA or by transfection with an adenovirus that encoded an antisense-uPAR sequence (Ad-uPAR) did not form tumours after intracerebral injection in nude mice33, 34. In addition, injection of the Ad-uPAR construct into previously established, subcutaneous U87MG tumours in nude mice caused tumour regression34. These findings support the therapeutic potential of targeting the uPA–uPAR system for the treatment of gliomas.

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