Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
Once a nascent tumor attains a millimeter or two in size, it reaches out for its own blood supply, which will ferry in oxygen and nutrients to fuel its future growth. This well-known fact of angiogenesis has generated a tidal wave of interest among not only oncologists but investors as well.
Since the mid-1990s, numerous injectable anti-angiogenesis compounds have entered preclinical and clinical trials with the aim of throttling tumors at birth, as it were, by preventing infusion of blood vessels into wannabe tumors. So far, these clinical efforts have their own drawbacks, and the search continues for effective anti-angiogenic therapies.
Now immunologists and cell biologists at the Scripps Research Institute in La Jolla, Calif., have engineered an oral vaccine that counteracts cancer in mice by choking off the angiogenic spread of new blood vessels. They report their feat in an online article in Nature Medicine, dated Nov. 4, 2002, and titled: "A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth." The journal has scheduled print publication in its December 2002 issue.
This Scripps approach, the paper points out, has the advantage of being potentially effective against a wide range of tumor types. The co-authors targeted a protein produced in new blood vessels rather than tumor cells. It's called vascular endothelial growth factor (VEGF) receptor 2 - FLK-1 for short.
The authors engineered DNA encoding the FLK-1 protein into a non-infectious strain of the bacterium Salmonella typhimurium, and administered this live vaccine to mice. These animals showed reduced blood vessel growth and were able to fend off tumor challenges in models of three different types of malignancy - melanoma, colon cancer and lung carcinoma cells - while suffering no ill effects.
Many current strategies for shutting off tumor blood supply rely on specific inhibitors that often require constant administration at relatively high doses. In contrast, the FLK-1 vaccine protected mice even 10 months after their last dose. DNA vaccines based on other proteins are already being tested in clinical trials. Whether an FLK-1 vaccine could work in humans remains to be seen. It might be particularly effective in combination with treatments that promote cell death or affect other aspects of tumorigenesis. Such a vaccine has the greatest potential in preventing or delaying the onset of recurrent malignancies, especially in cases of minimal residual disease following other therapies.
"Our strategy circumvents problems in targeting of genetically unstable tumor cells," the paper observed, concluding that "this approach may provide a new strategy for the rational design of cancer therapies."
X-Ray Crystallography Trumps Staph aureus' Drug- Resistant Ace With Potential Inhibitory Alternatives
With more and more infectious pathogens throwing a drug-resistance loop against the antibiotic likes of penicillin, one of the most widespread and clinically troublesome examples of multiple-drug resistance is now being seen in methicillin-resistant clinical samples of Staphylococcus aureus.
The germ is a major cause of hospital- and community-acquired infections worldwide. Its clinical isolates account for 34 percent of antibiotic resistance in the U.S., much higher in parts of Asia and Europe. These deadly bacterial strains can survive even in the presence of powerful beta-lactam antibiotics such as penicillin and its weaker chemical cousin, methicillin. Just one year after its introduction, methicillin multidrug resistance turned up in an S. aureus strain. The bug's resistance comes from the presence of a newly discovered bacterial penicillin-binding protein, PBP2a, which is vital to the maintenance of S. aureus' cell wall.
From the University of British Columbia in Vancouver, a paper in the November 2002 issue of Nature Structural Biology reports: "Structural basis for the b-lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus." It reports the crystal structures of one form of PBP2a, bound to several beta-lactam antibiotics.
"It provides a single target," the paper points out, "for the development of specific inhibitors against the resistant bacterial strain, which will be greatly facilitated by the structural information on the active-site cavity presented here." The co-authors' results "reveal the structural basis for the remarkable beta-lactam resistance of S. aureus, and will be useful for designing new effective therapeutics."
Excessive Radiation Therapy For Brain Tumors Carries A Price Of Decline In Cognitive Function
Dutch authors of a paper in The Lancet, released online Nov. 1, 2002, caution against the use of high-level radiation to treat low-grade brain tumors. Such therapy, they find, does not improve survival and may contribute to cognitive deterioration. They also observe that the tumor itself is the main cause of cognitive impairment, and that other factors - notably the use of antiepileptic drugs - may play a role in reducing cognitive performance.
Their paper makes the point, "Survival benefits of treatments for gliomas with radiotherapy are questionable, as such treatment can cause substantial damage to the brain over time. Consequently," they note, "the optimal therapeutic strategy is unclear."
Neurosurgeons at Vrije University in Amsterdam report in The Lancet that "High-dose radiotherapy could reduce cognitive function for people with low-grade brain tumors." They compared 105 patients, half of whom had received radiotherapy one to 22 years previously, to 100 patients who had non-Hodgkin's lymphoma or chronic lymphatic leukemia, with 195 healthy controls. Patients with low-grade gliomas had lower ability in all cognitive areas - such as perception/psychomotor speed, memory and attention - than subjects with hematological cancer. Their cognitive ability was further reduced compared with controls. Recipients of high-dose radiotherapy had greater memory deficits than patients not exposed to radiotherapy.
Antiepileptic drug use was strongly associated with disability in attention and "executive function" - the capacity for formulating and carrying out goals.