A modern mechanical stem-winding wristwatch doeswell to keep accuracy around a second a week. Quartzcrystals, vibrating at 100,000 oscillations a second, haveimproved that precision by orders of magnitude.

In a sense, nature did it first.

From microbe to human, every dividing cell in the bodyrecalls the face, or dial, of human-made timepieces. Onthat notional cellular "dial," the DNA being replicated forsharing by the parent cell's two offspring can becompared to midnight. Across that "clock-face," noonsymbolizes mitosis _ the actual creation of two nucleicontaining the two new sets of chromosomes.

Mammalian cells, including malignant ones, divide oncein 24 hours or so; yeast cells at three-hour intervals;single-cell bacteria, such as Escheria coli, every 20minutes.

The mechanism driving this sequence of cell-cyclesignaling events consists essentially of an array ofenzymes, turned on and off by a panel of regulatoryproteins. Expressing each of these cell-division-activatingcomponents is a gene.

If something goes wrong with these cell-cycling controls,for example, some signals of division get stuck in the"on" position, or an oncogene gets into the act, the cell _now malignant _ keeps dividing out of control.

Cleaning The Cell-Cycle's Clock

Among the cell-cycle proteins that drive division is onefamily of enzymes, CDC25 A and B. Molecular geneticistDavid Beach discovered their genes in 1991. Beach is asenior staff scientist of the Howard Hughes MedicalInstitute at Cold Spring Harbor Laboratory, N.Y.

"CDC25 stands for `cell division cycle,'" Beach toldBioWorld Today. "They are phosphatases; each oneregulates a different step in that cycle."

Unless, that is, it gets into bad company. When a CDC25gene loses its grip, and starts over-expressing its proteinproduct, it teams up with another oncogene, specifically,ras or Rb. "We are not, at this stage anyway," Beachexplained, "in any way looking at mutations in the gene.We're looking at simple, gross over-expression."

He added: "In humans, CDC25 over-expression is one ofthe driving factors behind neoplasia [tumors]."

Beach and his colleagues undertook studies to seewhether CDC25 might be a tumor-triggering oncogene."We were encouraged to do these experiments," he said,"because we noted that both the A and B forms of theseenzymes act before the onset of DNA replication in thecell cycle, which is the critical point at which celldivision is regulated in human cells."

Today's Science reports the results of their experimentsso far, under the title: "CDC25 phosphatases as potentialhuman oncogenes."

First in tissue culture, then cloned into nude mice, Beach(the paper's senior author) and his co-authors observedoncogenic transformation of cells by the enzymes. Thosegenes made normal cells malignant in vitro. "We putthem into mice," Beach said, "to see if they woulddevelop tumors, which they did, extremely rapidly."

Then they turned to "real human tumors," takenretrospectively from 124 patients with invasivemammary-cancers. "It turns out," Beach said, "thatextreme over-expression of this CDC25 gene showed upin about one-third of the breast tumors, but not in normaltissues. And over 37 percent of the former had died oftheir disease within 10 years, but less than 20 percent ofthe non-expressors."

He observed, "We don't know yet what precipitates theirover-expression. But our absolutely next project is to findout. We're fully engaged in it now, and preliminaryresults look very interesting."

Having pinpointed this key player in cell-division fouryears ago, Beach's logical goal became developing a drugthat would clean the oncogenic enzyme's cell-cycle clock.So he promptly co-founded Mitotix Inc. of Cambridge,Mass. in 1992, and licensed his CDC25 genes to it, "asone of the founding events." Beach chairs the company'sscientific board.

Cell biologist Giulio Draetta, another co-founder, and aco-author of the Science paper, is Mitotix's vice presidentof research; biology.

"We have had an ongoing program on CDC25phosphatases for two years now," Draetta told BioWorldToday. "It focuses on identification of small-molecular-weight inhibitors of the enzymes in human cells."

He observed that, "there is more than one CDC25-likeprotein. One of them really acts to precipitate mitosis,which is the separation of the two newly formed nuclei.The CDC25 A and B instead act to allow entry into cell-cycle S-phase, that is, DNA synthesis.

"Since we know how these molecules operate at theenzymatic level," he explained, "we could guess whatkinds of inhibitors we should make and test. So based onthis approach," Draetta continued, "as well as massscreening, we are in a position to identify inhibitors ofthis enzyme that presently show activity in cell lines."

He added: "And which in all likelihood, at some point,will get into animal testing."

In Search Of A Corporate Partner

That likelihood, Draetta indicated, "will become morelikely when Mitotix finds a pharmaceutical partner able tobring this project forward."

If all goes well, at some future date uncertain, Mitotix andits prospective partner will be ready to test their orallyavailable, systemic, anti-cancer CDC25-inhibitor inhuman patients.

"Of course," Draetta observed, "anybody who has to gothrough the FDA approval process won't have any chanceto pre-select patients for clinical trials, based on themolecular alteration of their tumors by CDC25 over-expression. So most likely we will do retrospectivestudies."

He pictures these as "treating a large number of patients,if possible, and looking at efficacy. Once you get yourresults," he continued, "you will have also done yourbiopsies, and then determine if this effect correlates withthe fact that CDC25 is expressed." n

-- David N. Leff Science Editor

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