By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
Mark your calendar for September. It's National Prostate Cancer Awareness Month, as proclaimed by the American Cancer Society - although a recent feature article in a Boston newspaper inadvertently spread the word that the month in question was June.
Last Thursday, Boston-based SafeScience Inc. disclosed completion of a Phase I/II clinical trial against prostate cancer (PC) of its anti-metastasis drug, GBC-590. The firm's chief medical officer, molecular biologist Clark Springgate, told BioWorld Today, "It's quite serendipitous that these results became available during this month of June."
The dose-escalating, open-label study took place at the M.D. Anderson Cancer Institute, in Houston, directed by genitourinary oncologist Christopher Logothetis. "The Phase I study for relapsing prostate cancer," he said "has indicated that GBC-590 is well-tolerated at the administered doses. We observed interesting qualitative changes in the kinetics of PSA [prostate-specific antigen] subsequent to administration of [the drug], which included stabilization of the PSA level, as well as increasing PSA levels after its administration was terminated."
Springgate noted the trial "enrolled 22 patients with end-stage prostate cancer, who had relapsed from radical prostatectomy or radiation, and were refractory to all standard treatments. They had to have rising PSA levels as well."
PSA counts are a widely-used indicator of a patient's PC status. Drastic increases in PSA numbers suggest that the tumor has broken out of its capsule and may well be metastasizing to brain, bone and/or lung. In 1997, a typical year, 209,000 new PC cases were diagnosed in the U.S. About 40,000 die of the disease annually.
"Patients entering the M.C. Anderson trial," Springgate said, "first received a test dose of GBC-590, administered as an intravenous infusion over three hours. It can be done on an outpatient basis, and the company is now developing an oral version that can be taken twice a week as a pill. All enrollees tolerated the test dose, so were eligible to receive two escalating therapeutic doses a week for four weeks. Dosing started at 1.9 milligrams per square meter of body surface, and ranged up to 20 mg."
Of the 22 enrollees, PSA numbers dropped or stabilized in 18.
SafeScience's chairman and CEO, David Platt, explained that GBC-590 "is a new class of drugs called 'lectin inhibitors,' which competitively bind to unique lectins - protein-based receptors on cancer cells - and disrupt the metastatic process."
The acronym GBC, Springgate said, "stands for 'galactin-binding carbohydrate.' This is a carbohydrate-based drug," he explained, "that has several proprietary carbohydrate moieties in it. Galactin is a cell-surface receptor. What our carbohydrate does is bind to those galactin receptors in metastatic tumor cells." Animal data, he observed, "showed reduction in the primary tumor as well."
In August, SafeScience will launch a Phase II double-blind, placebo-controlled clinical trial of GBC-590 for prostate cancer. It will enroll 192 patients at six centers, Springgate said, and will be completed within 12 months.
"This trial too," he said, "will be for patients who have relapsed from radical prostatectomy, and have rising levels of PSA. Given the anti-metastatic mechanism of action of this drug, we will first treat all participants for two months with androgen hormone ablation only. That should bring their PSA levels down to less than one. Then, in a double-blind manner, they will receive either GBC-590 or placebo for six months.
Milk Thistle, Ancient Herbal Remedy, Harbors Protein That Inhibits Prostate Cancer Cells
Meanwhile, back at the lab, an ancient herbal folk remedy scored in vitro points against prostate cancer. A research article in the current Proceedings of the National Academy of Sciences (PNAS), dated June 22, 1999, tells how, It bears the title: "Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: Implications for prostate cancer intervention." Its senior author is cancer-prevention scientist Rajesh Agarwal, at the AMC Cancer Research Center, a not-for-profit organization, in Denver.
Silibinin is the active ingredient of a widespread weed, the milk thistle (Silybum marianum). "It's a wild plant, but very useful," Agaral told BioWorld Today. "Silibinin is a very ancient compound, which originally was used in Europe to treat various liver disorders, especially alcohol-generated cirrhosis. Now, it's widely sold in American health food stores."
How silibinin works in PC is not entirely clear, Agarwal said, "but my bias is that it acts as a strong flavonoid antioxidant, much stronger than vitamins C or E."
In laboratory experiments pitting silibinin against the standard LNCaP prostate cancer cell line, he found it "inhibits PSA expression within the tumor cell, including androgen-receptor-mediated PSA." Agarwal is now gearing up to commence in vivo experiments in mice. As for human trials, he said, "I would say a year at the most."
OD-ing On Maternal Coffee During Pregnancy, Can Be hazardous To Health Of Unborn Child
A cup of java never hurt anyone, right? Most research suggests that caffeine, in the doses coffee-lovers ingest it, is by and large harmless. Carl Sandburg remarked that "there is no such thing as strong coffee, only weak people."
Now, French neuroscientists find that the weakest people of all - prenatal fetuses - are in danger of epilepsy if their mothers imbibe too much of the brew. To be sure, the fetuses they investigated were rats, but in the light of their results they're beginning to look into the potential adverse effects of caffeine in certain human perinatal situations.
Their report appears in the July 1999 issue of the Annals of Neurology, under the title: "Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus." Its co-authors are in the Epilepsy and Cerebral Ischemia unit of INSERM - the French National Institute of Scientific and Medical Research, in Marseilles.
This discovery, they point out, "strengthens the current FDA recommendations that pregnant women should not drink large amounts of coffee, especially toward the end of pregnancy."
In their animal model, the researchers simulated two factors that work together in the human fetal brain: Caffeine binds specifically to neuronal adenosine receptors, and during the contractions that accompany labor, the neonate may be temporarily starved of oxygen. Together, they point out, these conditions can trigger seizures. (See BioWorld Today, Aug. 14, 1997, p. 1.)