David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
When President Nixon declared war on cancer three decades ago, the weapon systems deployed were conventional armaments - surgery to cut out malignant tumors, ionizing radiation to mop up residual pockets of malignancy, chemotherapy to attack invasive or metastasizing cancer cells.
That armamentarium hasn't stopped cancer from remaining the second-leading cause of death in the U.S., exceeded only by heart disease. The American Cancer Society estimates that 1,220,100 cases of cancer are expected to surface in this first year of the new millennium, and 552,200 Americans will die of malignancy.
Just as the military is rethinking its cold-war reliance on nuclear missiles, heavy artillery and super-sophisticated bombers - while casting about for novel defenses against terrorism - oncologists are turning to the human body's secret weapon system against cancer - its own immune defenses.
Last week, a medium-size biotech company, Viragen Inc., based in Plantation, Fla., announced a multipronged, multinational assault on cancer, by mustering weapons in the immune system's arsenal. Its allies in this new-style war on cancer include the U.S. National Institutes of Health (NIH) in Bethesda, Md., Memorial Sloan-Kettering Cancer Center in New York, Britain's Cancer Research Campaign Technology (CRCT) and the company's own production facility in Edinburgh, Scotland.
This industry-academic consortium's all-out anticancer crusade mobilizes key immune-defense strategies, to detect, pin down and slaughter tumor cells, while preventing friendly fire from harming innocent, healthy cells. To wit:
Interferon deployment: White blood cells launch alpha-interferon, a natural cytokine, in response to infection-caused inflammation. Interferon molecules act as the immune system's "mission control," and like night-vision goggles, may make tumors more visible as targets for destruction. Viragen's proprietary interferon analogue, Omniferon, already in Phase II clinical trials against hepatitis C virus infection, will be deployed against cancers. Viragen has preferential access to white blood cells collected by the German Red Cross and the American Red Cross.
Complement deactivation: Cell-killing proteins of the complement system destroy material not recognized as normal parts of the body. A molecule called CD55 acts as a signal flag, protecting normal cells from friendly fire. Some tumor cells camouflage themselves to look like normal cells, rather than alien invaders. And these treacherous malignant cells pave their surfaces with CD55 to ward off destruction by complement. The UK's CRCT has granted Viragen a worldwide exclusive commercial license for a vaccine to strip tumors of their CD55 protection. It is earmarked to treat colorectal, breast, ovarian and certain bone cancers.
Antibody therapy: Like smart-guided missiles, monoclonal antibodies mark diseased cells for destruction by the complement system - among their other missions. One such antibody blocks a protein called "Notch-1," which normally acts in the body to get rid of redundant tissues by apoptosis - programmed cell death. Clever tumor cells overexpress Notch-1, thus blocking the suicide signal, and leaving them a free hand to grow and metastasize. Specially trained monoclonal antibodies prevent Notch-1 from reaching the malignant cells, so they die. The NIH has licensed to Viragen a monoclonal antibody primed against tumors that overexpress Notch-1. Targets in the company's cross hairs include cervical, breast and lung cancer.
Do Mutations In Tumor Suppressor Gene Cause Lung Cancer In Smokers? Dogma Challenged
Now, even tobacco company CEOs concede that smoking causes lung cancer. And oncologists posit that the major carcinogenic risk of tobacco smoke is in its direct mutagenic action on the DNA of cancer-related genes - notably the tumor-suppressor gene p53. In other words, mutation causes the suppressor to change its spots and become a tumor-promoting oncogene instead.
That received wisdom is challenged in the Proceedings of the National Academy of Sciences (PNAS), dated Oct. 24, 2000, by an article titled: "Human lung cancer and p53: The interplay between mutagenesis and selection." Its authors "point to a different causative link." They propose that DNA repair of primary lesions on the p53 DNA strands and selection of the resulting mutations "determine the lung-cancer-specific hot spots of [base-pair swaps] along the p53 gene." To which they add the wisdom-rebutting observation, "Our tests revealed no significant difference between smokers and nonsmokers, either in the frequency of different types of mutations or in the frequency of their occurrence along the p53 gene."
How then to account for the unquestioned preponderance of lung cancer in smokers over nonsmokers? "We conclude," the co-authors state, "that physiological stresses . . . are the leading risk factor in the p53-associated etiology of lung cancer. We propose," they added, "that smoking aggravates these stresses and, thus, intensifies the processes of strand-asymmetric repair and selection of tumorigenic stem cells carrying mutations in stress-responsive genes such as p53."
Teratogenic Plant Compound From Wild Lily Has Potential For Treating Commonest Cancer In U.S.
A skunk cabbage called the corn lily, or false hellebore (Veratrum californicum), grows wild in the Western U.S. If a pregnant ewe nibbles this lily, her lamb is liable to be born with a single eye in the middle of its forehead. This birth defect is cyclopia, named after the one-eyed giant of Greek mythology.
Geneticists at The Johns Hopkins University in Baltimore, who investigated an epizootic outbreak of cyclopia in a herd of sheep, discovered a causative compound, which they named cyclopamine. Tracing its devious genetic pathway, they determined that cyclopamine had attributes that might make it useful for treating basal cell carcinoma and related cancers. Their report, in Nature dated Aug. 31, 2000, bears the title: "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine."