On the world precious-metals markets, platinum is worth about 4percent more than gold. To a patient with metastatic ovarian, testicularor lung cancer, the price of platinum is far above rubies.Administered in the form of cisplatin _ one atom of platinumsurrounded by two of chloride and two ammonia molecules _ theheavy metal crosses up DNA, producing cross-links especially in targettumors.As Robert Jackson, vice president of research and development atAgouron Pharmaceuticals, Inc., told BioWorld, cisplatin cancer therapyoften causes advanced tumors to recede, but after a couple of yearsthey tend to recur, and to resist further cisplatin treatment. One waythat tumors acquire this drug resistance is, he said, "by producingelevated levels of the enzyme DNA polymerase b (pol b). Its job is torepair damaged DNA."Last Friday's issue of Cell carries a report by a team of Agouron X-raycrystallographers announcing they had elucidated the three-dimensional atomic structure of pol b's business end. This is the 31-kilodalton catalytic portion of the enzyme's 39kd structure _ thesmallest known DNA polymerase."The discovery," said Peter Johnson, Agouron's president and chiefexecutive officer, "sets the stage for the design of drugs that canenhance the anti-tumor activity of platinum-containingchemotherapeutic agents."An earlier discovery, that platinum inhibits microorganisms, wasserendipitous: In 1965, microbiologists observed that bacteria in anelectrical field with platinum electrodes clumped, and failed toreproduce. Platinum's use in cancer chemotherapy spread quickly. Sodid the tumor cells' ability to trump cisplatin's ace. They step up theirsynthesis of pol b , which can efficiently repair the drug-damagedDNA. The feat of X-ray diffraction reported in Cell exposes theenzyme's innermost crystal-structure secrets.Starting some 18 months ago, the Agouron team overexpressed rat polb in E. coli from a construct containing a PCR-amplified clone from arat brain cDNA library. They grew crystals of the resulting protein,which within a week measured an average 0.35 x 0.4 x 0.3 millimeters.Under X-ray diffraction _ the same process Crick and Watson reliedon to conceive their double helix 40 years ago _ they dissected theenzyme's 31-kd catalytic domain's three sub-domains, and mapped themolecule's unique folding topology."The high-resolution structure," stated their Cell report, "represents themost detailed characterization of a DNA polymerase thus fardetermined."Agouron's vice president of clinical affairs, Neil Clendeninn, observed,"There previously has been no basis for the rational design of inhibitorsof pol b, "so this portion of the field is uncluttered by competition."The company will not patent its 3D crystallographic construct, Johnsontold BioWorld, "because its patentability is uncertain, and we mightimprudently disclose data to the world." The world market forcisplatin, and its analogue, carboplatin, is estimated at $450 million ayear.Jackson told BioWorld, "Knowing the architecture of the pol bcatalytic domain in atomic detail, we are now positioned to designsmall, synthetic molecules that bind tightly in the active site of theenzyme, and inactivate it."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.