By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-related research.
One basic difference between cancerous cells and normal cells is that tumors can live and grow by burning sugar without oxygen. This seemingly paradoxical phenomenon was discovered 75 years ago by a German biochemist, Otto Warburg (1883-1970), who won a Nobel Prize in 1931 for his finding.
Just how cancers pull off this neat metabolic trick, immortalized in medical literature as ¿the Warburg effect,¿ remained a mystery from that day to this.
Now, a report in the Proceedings of the National Academy of Sciences (PNAS), dated Mar. 16, 1999, announces identification of a novel respiratory enzyme, which acts as a molecular switch, enabling tumor cells to make lactic acid and metabolize sugars, notably glucose, without benefit of oxygen. The research paper, by scientists at the Picower Institute for Medical Research, Manhasset, N.Y., bears the title: ¿An inducible gene product for 6-phosphofructo-2-kinase [FFK] with an AU [adenine-uridine] ¿ rich instability element: Role in tumor cell glycolysis and the Warburg effect.¿
As so often in research, serendipity stepped in to reveal the never-before-seen FFK enzyme. The paper¿s lead author, biochemist Jason Chesney, was hunting for a chemical in human cells that fights infections. Instead, he came up with the tumor-fueling FFK enzyme.
It took him and his co-authors many months to determine that FFK works like a switch that¿s always in the ¿on¿ position, thus controlling generation of energy in eight human tumor cell lines.
In a pivotal preclinical in vivo experiment, the group inoculated nude mice with human leukemia cells. Within a week the animals had grown tumors averaging a sizeable 0.4 grams. Then, they implanted FFK-specific antisense oligonucleotides into these tumors, which had shrunk significantly two days later.
Picower has licensed this technology to its biotech affiliate, Seattle-based Cytokine Networks Inc., to develop compounds that inhibit the FFK family of tumor-nurturing enzymes.
A Pill For Multiple Sclerosis? Israelis Test Oral MS Vaccine Successfully In Rats, Mice
Myelin is a fatty protein that wraps around nerve cells in the brain and spinal cord. It protects them from dissipation of their messages, and is compared to plastic insulation around electric wires.
When autoimmune antibodies attack and destroy myelin basic protein (MBP), multiple sclerosis (MS) ensues. One promising therapeutic agent is a synthetic, myelin-simulating molecule called copolymer 1 (Cop 1), which consists of four combined amino acids. Injections of Cop 1 have brought therapeutic benefits to MS patients, but unlike insulin for diabetics, is not practical for self-injection. What¿s needed is a pill instead of a needle, to administer the drug orally.
This need is reportedly met by an orally available form of Cop 1, which worked well in a mouse model of MS. Because the human disease syndrome is so protean and unpredictable, researchers at the Weizmann Institute of Science, in Rehovot, Israel, tested their proto-pill molecule in another demyelinating disorder, experimental autoimmune encephalomyelitis (EAE), which closely mimics MS in rodents.
Their report in the current Proceedings of the National Academy of Sciences (PNAS), dated March 30, 1999, is titled ¿Immunomodulation of experimental autoimmune encephalomyelitis.¿
Low doses of Cop 1 fed to rats cut their EAE incidence and severity by more than half, and worked nearly as well in mice. It proved more efficacious than orally administered MBP itself. What¿s more, the Israeli immunologists found that Cop 1 activated special helper T cells to trigger certain anti-inflammatory chemicals, which suppressed the anti-myelin autoimmune response.
Oral immunization reflects that fact that some 70 percent of the body¿s immune reactive cells occur in the intestines. (See BioWorld Today, April 6, 1999, p. 1.)
Neurologist Howard Weiner, of Harvard Medical School, wrote a commentary accompanying the Weizmann article in PNAS. He observed that, ¿although oral tolerance has been shown to be effective in a large number of animal models, it has not yet led to the development of an approved drug for the treatment of a human autoimmune disease. Weiner also suggested that ¿Because Cop 1 can be given safely by injection its oral effect could be enhanced or boosted by periodic injections that would serve to boost the helper T-cell responses. This approach then would be a true vaccination paradigm for the treatment of autoimmune disease.¿
Two-Edged Clot-Busting Heparin Loses Its Side Effects In French-Synthesized Molecular Mimic
From a Band-Aid to a tourniquet, Nature¿s way of binding up a wound is obliging the blood to clot.
In forming this natural bandage, the key mechanism is coagulation. This blood-thickening process recruits a cascade of cells that literally knit a mat of fibrin, an elastic, filamentous protein that entraps red blood cells, platelets and other factors to create the impervious clot, or thrombus.
Thrombi are clots that build up inside blood vessels. When such a plaque plugs a coronary artery, blood can¿t deliver oxygen to the heart muscle. Result: a myocardial infarction. For such a life-threatening event, cardiovascular surgeons administer a tissue plasminogen activator (TPA), such as alteplase, South San Francisco-based Genentech Inc.¿s blockbusting recombinant TPA.
The surgeons usually boost that clot-busting treatment by adding heparin, a blood-thinning polysaccharide compound. But dosing heparin is devilishly tricky. Too much can induce hemorrhaging or thrombocytopenia ¿ a dearth of platelets in the blood.
Heparin by itself is the drug of choice for treating deep venous thrombosis, in which clots cut off circulation to a calf or leg. Besides the danger of losing the limb to gangrene, an even more life-threatening fear is that the clot will break loose and travel to the lung.
A large, inchoate molecule, heparin is a standing challenge to the pharmaceutical industry to come up with a tidier, more specific substance, free of its twin dire side-effects, hemorrhage and heparin-induced thrombocytopenia. Now a French molecular biology firm, Sanofi Recherche, of Toulouse, reports having synthesized just such a molecule.
Its account, in a Nature paper, dated April 1, 1999, is titled ¿Synthesis of thrombin-inhibiting heparin mimetics without side effects.¿ Sanofi¿s strategy was the opposite of other attempts to isolate heparin¿s active portion by breaking away ancillary fragments. Instead, the French chemists started from scratch to put together the minimal active product.
It took them 11 false starts before hitting bingo with their 12th synthesis. ¿Breakthroughs in oligosaccharide chemistry,¿ the co-authors pointed out, ¿made possible the total synthesis of the pentasaccharide antithrombin binding site of heparin.¿