As a city spreads outward toward its suburbs, homes, stores, officebuildings and industrial plants sprout up and multiply. Along with thesteel, concrete, brick and glass that go into their construction comes amultiple network of utilities.

From reservoirs and treatment plants to faucets and shower-heads,water distribution demands an ever-branching proliferation of piping,from very large diameter to very small. So do sewage systems.

On a micro-scale, so do solid tumors in the body of a cancer patient.

In order to grow and spread, a tumor needs an escalating network ofblood vessels, large, small and tiny, to feed its mass, and fuel itsmetastasis.

This process, angiogenesis, "is a pretty hot field right now," observedmolecular and cell biologist Laurie Strawn, a scientist in the in vitropharmacology group at Sugen Inc., of Redwood City, Calif.

Strawn is first author of a paper in the journal Cancer Research, datedAug. 1, 1996. Its title: "Flk-1 as a target for tumor inhibition."

Flk-1, Strawn explained to BioWorld Today, is a crucial player intumor angiogenesis. As a malignancy grows, it secretes a substance,vascular endothelial growth factor (VEGF). This molecule binds toFlk-1 TK receptors, which signal the endothelial cells that linearteries, veins and capillaries to lay down blood vessels aimed at thetumor mass.

Flk-1 has tyrosine kinase receptors for VEGF, by which it triggers thesprouting of new capillaries from the endothelial cells to endow thetumor with its own oxygen and nutrient pipeline. Blocking those Flk-1 receptors could cut off a cancer's meal ticket at the pass.

In pursuit of that tumor-starving strategy, Strawn said, Sugen istesting a collection of five proprietary small-molecule compoundsthat inhibit both Flk-1, which is a mouse molecule, and its humancounterpart, KDR.

Initial leads to four of the five drug candidates profiled in the articlecame to Sugen from collaborators in Hungary and Israel; thecompany itself synthesized the fifth in house, Strawn said.

After preliminary testing found that a compound did indeed inhibitFlk-1 tyrosine kinase, she said, "we compared them to other kinases,looking for things specific to Flk-1, because we don't want to havetoxicity problems by inhibiting other TKs."

Then the proto-drugs underwent screening to measure DNA synthesisin endothelial cells from human umbilical-cord veins.

"That's an indication of growth," Strawn observed, "and we foundthat all the compounds prevented that in these cells. Then," shecontinued, "we put them into the chorioallantoic membrane assay,CAM for short, just to see if they actually inhibited the growth ofblood vessels, not just of endothelial cells. They did."

That CAM membrane lines the inside of a bird's egg shell, and shetested the compounds by placing pellets of them on those membranes.The yolks of fertilized eggs, Strawn mentioned in passing, display theveins and arteries of angiogenesis on their surface.

VEGF foments angiogenesis by making the usually hermetic walls ofendothelial cells permeable. Via these newly opened pores, the cellsrelease enzymes that migrate across their outer basement membranelining, and form a sprout that proliferates to extend the vessel.

To verify in vivo that the Sugen compounds can abrogate thisprocess, Strawn and her co-authors deposited pellets of them underthe upper abdominal skin of nude mice. The absence of redness andswelling seen on control mice within 24 hours confirmed theblockage of vascular permeability.

Since submitting their paper to Cancer Research in March, Strawnsaid, "we have screened thousands and thousands of compounds invitro and many in vivo, and found others that seem to show potential.We are now testing drug candidates' anti-angiogenesis efficacy onhuman solid tumors implanted in nude mice.

"Only when we have selected an IND candidate," she added, "will weconsider in vivo preclinicals in primates."

Right now, Sugen scientists are debating such questions as to whetherthe compound finally developed for human use will be oral orinjectable, systemic or topical.

"I think," Strawn observed, "that this approach to angiogenesisinhibition looks very promising as a new mode of treatment forcancer, metastases in particular."

And in general, her paper concluded that angiogenesis inhibitors"may be useful therapeutics for a variety of disease states, such aspsoriasis and diabetic retinopathy." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

No Comments