By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-related research.

Napoleon ¿ no slouch of a military commander ¿ is said to have said: ¿An army marches on its stomach.¿

So, one way to win battles is to target the field kitchens and prepackaged meals that feed fighting men and women. That tactic finds a counterpart of sorts in an unconventional way to fight cancer. It¿s documented in a report just published by the National Cancer Institute (NCI) in its twice-monthly journal, Cancer Research, dated May 15, 1999.

The article, ¿Proteasome inhibitors: A novel class of potent and effective anti-tumor agents,¿ is co-authored by a congeries of scientists from industry, academia and the NCI.

Just as most military strategists attack the enemy¿s formations head-on with land, sea and air weapons of deadly force, most anticancer strategies assail their enemy with the blunt-instrument, tumor-destroying weapons of surgery, radiation and chemotherapy. Anti-proteasome tactics sneak around the actual tumor target, at the level of cell division, to prevent it from forming in the first place.

This approach is based on the proposition that the ubiquitin-proteasome pathway masterminds the orderly degradation of key proteins involved in control of the cell cycle, and hence of tumor growth. It was pioneered by ProScript Inc., of Cambridge, Mass. Half of the journal¿s 10 co-authors are ProScript scientists.

Proteasomes, nature¿s sanitation system, are enzyme complexes that chop up proteins in cells ¿ for instance, cytokines such as interferon ¿ after they have done their job, and recycle them into amino acids. If not for this feedback mechanism, such surplus molecules would keep right on doing their thing, with chaotic cellular consequences. (See BioWorld Today, Dec. 23, 1998, p. 1.)

Other key molecules that proteasomes routinely get rid of are proteins that regulate cell-cycle progression. Unless kept on that leash, they keep on instigating cells to continue dividing ¿ that is, they go to the tumorigenesis route of growth, invasion and metastasis.

Inhibiting the proteasome pathway is ProScript¿s proprietary way of combating cancers. Its chosen instrument is a patented cytotoxic compound called PS341. Concretely, this is a synthetic dipeptide analog of boronic acid. It works by blocking the proteasome¿s enzymatic activity against cell-cycle proteins.

To gauge PS341¿s cytotoxic effect, the company screened it against the NCI¿s historical file of 60,000 compounds. As the paper noted, ¿It was found to be unique, with little correlation to other standard¿ or investigational agents.¿

Moreover, NCI¿s database showed that ¿the prostate tumor PC-3 cell line was sensitive to PS341¿s anti-proliferative effects.¿ So, as a proof-of-principle model, the company chose to sic its PS341 compound on prostate cancer.

The co-authors implanted this malignancy in a cohort of nude mice by injecting them subcutaneously with PC-3 cells. When the resulting tumors had grown to a palpable size of at least 300 cubic millimeters, the animals began receiving weekly intravenous injections of PS341. By the fourth week of this treatment, tumor volume had shrunk ¿significantly.¿

In a second experiment, the investigators injected the PS341 directly into the tumor mass for four consecutive days. As the paper reported, ¿Results clearly showed a dramatic decrease [of 70 percent] in tumor burden. In addition, two out of five mice (40 percent) had no detectable tumors at the end of the study.¿ It added, ¿No adverse effects of drug treatment were noted.¿

Phase I safety and dose-escalation studies of PS341 are now ongoing at the M.D. Anderson Cancer Center in Houston and at the Memorial Sloan-Kettering Cancer Center in New York.

Genomically Neglected Rat Gets First High-Resolution Whole-Genome Map; Complete Sequencing Some Day?

When biotechnology got started 20 years ago, its main research activity was cloning genes into host microorganisms. Whence one working definition of the field: ¿Biotechnology means how to make bugs make bucks.¿ Nowadays, what with the proliferation of preclinical testing, biotechnology seems to be more about: ¿How to make mice make money.¿

Where do rats fit in? For one thing, the genus Rattus has a bad rap. Its name is a synonym for sneaky snitches, deserters of sinking ships and purveyors of bubonic plague, not to mention hantavirus.

But, pejorative name-calling aside, rats and humans have a lot in common, genetically and physiologically. Which is why laboratory rats do duty as models for several classes of disease where mice do less well. We have Rattus to thank for research in genetically complex maladies such as hypertension, Type 2 diabetes mellitus, renal disease, autoimmune disorders, and behavioral studies like schizophrenia and drug addiction, plus the central nervous system in general.

However, when it comes to genomics, rats scarcely seem to rate. The Big Seven model organisms include viruses, bacteria, fungi, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster and Mus musculus. Now, the rat seems about to come on board.

A paper in the May 1999 issue of Nature Genetics reports ¿A radiation hybrid [RH] map of the rat genome containing 5,255 markers.¿ Its 34 co-authors come from six laboratories in three countries ¿ the U.S., U. K. and Japan.

Their paper presents the first high-resolution whole-genome map of the rat. It includes 3,019 new microsatellite dinucleotide (CA) DNA repeats, a resource for building both genetic and physical maps and sequences as signposts for guiding eventual total-genome sequencing.

Sequencing Complete Fruit-Fly Genome Gets Under Way At Celera, Berkeley Consortium

In a related development, Celera Genomics, of Rock ville, Md., has begun to sequence the genome of Drosophila melanogaster, the fruit fly.

The company, a business unit of Perkin-Elmer Corp., of Norwalk, Conn., made the announcement earlier this month. Its press statement pointed out that ¿completion of the sequencing of Drosophila, anticipated later this year, will represent the largest genome sequenced to date. In addition, it will be the first insect genome sequenced, and will serve as a model for other insect genomes in medical and agricultural research.¿

This undertaking results from a scientific collaboration set up in January 1999 between Celera¿s president, J. Craig Venter, and Gerald Rubin, leader of the Berkeley Drosophila Genome Project (BDGP). Under the new agreement, BDGP will modify its strategy to sequence the fruit-fly genome by producing a larger number of Bacterial Artificial Chromosome (BAC) end sequences. These will provide a necessary component of the whole-genome shotgun sequencing Celera will carry out. n