There will never be "a cure for cancer," conventional wisdom tells us,because there are over 100 kinds of malignancy, all different as tocause, character and treatment.Yet, over half of the known types of cancer have one thing in common:a mutated p53 tumor-suppresser gene. And 100 percent of all tumorsshare a single syndrome: their thirst for blood, their need to build asteadily expanding network of venules, arteriolae and capillaries. (SeeBioWorld Today, May 17, 1994, p. 1.) Without this burgeoning bloodsupply, a tumor would never grow bigger than a pinhead.These two cancer commonalties come together in this week's Science,out today. A paper titled "Control of angiogenesis in Fibroblasts by p53regulation of thrombospondin-1" tells the tale. Its principal author ismicrobiologist Nol Bouck of Northwestern University MedicalSchool, Chicago.Named for its 53-kilodalton mass, the normal 393-amino-acid p53protein keeps healthy cells from over-replicating. But mutant p53apparently aids and abets the transformation of cancer-stricken cellsinto growing and metastasizing tumors. Of some 6.5 million cancersdiagnosed each year in the world, half have p53 mutations in theirtumors.One step in this cellular flip-flop from normal to malignant involvesswitching off the genes that inhibit angiogenesis, the tumor's growingblood-vessel system. Another is loss of the normal p53 gene.Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis. WhenBouck and her colleagues cultured fibroblast cells from three cancerpatients, they found that the switch from normal quiescence to hecticgrowth of blood vessels involved lowering thrombospondin-1 levels.The three patients whose fibroblasts they tested all had Li-Fraumenisyndrome, a form of cancer in which they had inherited one wild-type(normal) p53 gene, and one mutant allele, different in each of the threeindividuals. This genomic bequest enhanced their risk of developingother malignancies, in which the remaining healthy p53 gene becomesinactivated. This loss occurs after extended passages of fibroblasts inculture.In the mammalian eyeball, the cornea has no blood supply of its own.When Bouck implanted cell-free culture media from late-passagefibroblasts into the corneas of anesthetized rats, "they all dramaticallyinduced vascularization." Early-passage cell extracts did not.Verifying the angiogenic-switch hypothesis, which they had first testedin vitro with hamster fibroblasts, they found that cells from their threehuman patients secreted high amounts of TSP-1 during early passage,when they still retained an unmutated p53 gene allele. At late passage,now minus that normal gene, TSP-1 amounts fell off, and could nolonger damp down angiogenesis in vitro or in vivo.In today's Science, Bouck "raises the possibility that TSP-1, or anti-angiogenic peptides derived from it, might be developed into effectiveprophylactic agents for delaying or preventing tumors in individualswho carry only one wild-type p53 allele."She has since done just that. "I want to develop thrombospondin as ananti-angiogenic drug," she told BioWorld Today, which can delaymetastases in patients after primary surgery." She noted thatthrombospondin "is a huge molecule; each of its three monomers hasover 1,000 amino acids.""So what we've done," she continued, "is get it down to very smallpeptides that carry anti-angiogenic activity. We have one at sevenamino acids and one at 12."In these analogs, Bouck and her team at Northwestern have repeatedtheir in vivo corneal tests in rats. "Each one works," she said, adding, "Iknow what amino acids are important in these peptides, and now Ithink it needs to be made into a stable peptide mimetic that can actuallybe used in animal trials."For this, Bouck is actively looking for a biotechnology company tohelp develop it. "I've gone as far as I can as a basic science lab in auniversity setting," she explained. "It really needs some commercialcollaboration."One thing the university brings to the table is an issued U.S. patent, No.5,192,744, dated March 9, 1993, titled "Method of InhibitingAngiogenesis in Tumors." n
-- David N. Leff Science Editor
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