By David N. Leff

Editor's note: Science Scan is a round-up of recently published biotechnology-related research.

CAG is a three-letter word that spells bad news in a number of inherited maladies, notably Huntington's disease, fragile-X syndrome and muscular dystrophy.

Those three letters stand for a triplet of nucleic-acid bases — cytosine-adenine-guanine — which occur over and over again in the mutant genes implicated in these afflictions.

Now there's evidence that this same stretch of junk DNA has something sinister to do with prostate cancer (PC) — but with a twist.

In Huntington's disease, the greater the number of CAG repeats, the more severe the symptoms and the earlier the onset. (See BioWorld Today, Aug. 28, 1995, p. 1.) But in cancer of the prostate, the shorter that iteration of junk, the more likely the cancer is to spread and metastasize.

A paper in the current Proceedings of the National Academy of Sciences (PNAS), dated April 1, 1997, reports this counterintuitive finding. Its title: "The CAG repeat within the androgen receptor gene and its relation to prostate cancer."

Its principal author, Philip Kantoff, of Harvard Medical School's Dana-Farber Cancer Institute, compared 587 newly diagnosed cases of the disease with 588 controls * men who did not have PC.

He and his co-authors counted the CAG repeats in a gene closely related to the prostate gland, namely, the DNA sequence that encodes the androgen receptor. Its interaction with testosterone controls cell division in the prostate. (See BioWorld Today, Oct. 15, 1996, p. 1.) In PC patients, they averaged 18 iterations; in controls, 26.

"Men with shorter repeats," PNAS reported, "were at particularly high risk for distant metastases and fatal prostate cancer."

In support of this finding, it pointed out that "African Americans, who have generally shorter CAG repeat lengths in the androgen receptor, have a higher incidence and mortality rate from prostate cancer."

Insulin Given By Mouth Lowered Glucose Levels;
Plasmid DNA Taken Orally Showed Gene Activity

Three current mantras in the drug discovery game are: "small molecule," "bioavailable" and "orally active." All three add up to the simple truth that the spoon beats the needle as a way to take your medicine.

Equally true is the fact that stomach acids chew up most therapeutic proteins before they get a chance to reach the bloodstream via the intestine. Hence, millions of diabetics are tormented by having to self-inject insulin one or more a times a day.

In the age-old quest for drugs that can be gulped down instead of shot up, the latest entry is a polymeric microcarrier developed by molecular pharmacologists at Brown University.

They report success in delivering oral insulin to its metabolic target, as well as plasmid DNA for gene therapy, also administered by mouth.

Their paper, in Nature, dated March 17, 1997, bears the title: "Biologically erodable microspheres as potential oral drug delivery systems."

Rather than using conventional hydrophilic polymers to make their carriers, the Brown group employed the opposite — fast-degrading hydrophobic polymer microspheres." These were co-polymers of fumaric and sebacic acids, which "stayed in the stomach longer than microspheres made of other polymers [36 hours against 18 hours]."

They encapsulated insulin in carriers averaging 96.7 nanometers in particle size and fed them to six glucose-loaded fasted rats. Their blood glucose levels never exceeded fasting levels, and were lower than control groups of animals.

This suggested, the paper said, "that the insulin crossed the intestinal barrier and was released from the microspheres in a biologically active form."

The group attained "perhaps the most surprising results" in orally ingested plasmids for in vivo gene transfer.

Five days after swallowing a single dose of microspheres loaded with cytomegalovirus/beta-galactosidase genes, rats "showed greater levels of beta-gal activity in both the small intestine and the liver than either those receiving unencapsulated material or unfed animals." *