When a man tells his doctor that he's having to wake up most nightsto urinate, the first thought that crosses both their minds is an up-sizing prostate gland.
Normally about the size, and shape, of a chestnut, the prostate wrapsaround the pipeline bringing urine from bladder to penis. As thegland grows, it squeezes this conduit, the urethra, thus causing thenocturnal awakenings that presage prostate problems.
This trouble can take one of two forms, benign or malignant: As mostmen pass the age of 60, their prostate begins to swell with advancingage. By age 90, benign prostatic hyperplagia (BPH), unless alleviatedby surgery that pares the gland's encroaching bulk, besets virtually100 percent of the male population.
Prostate carcinoma is something else again. This fast-growing,viciously metastasizing cancer kills some 40,000 victims a year in theU.S. alone; another 220,000 will get the diagnostic message: prostatecancer. (See BioWorld Today, April 21, 1995, p. 1.)
By the time that verdict is in, there's often little the physician can doother than excising the entire gland, and hoping it hasn'tmetastasized.
Hence, early and accurate diagnosis is a matter of life and death.Manual palpation of the gland is the doctor's first recourse, but hisfinger can't distinguish a benign from a malignant tumor. A needlebiopsy helps some, but in recent years the mainstay of differentialdiagnosis is PSA _ prostate-specific antigen.
This simple blood test measures the amount of PSA at time A andcompares it with time B, months or more in the future, reflecting thecancer's growth, if any. But PSA is a feeble quantitative indicator;urologists crave a qualitative test that truly signals the presence ofmalignancy.
A paper in the current Proceedings of the National Academy ofSciences (PNAS), dated July 9, 1996, offers the prospect of such adifferential diagnostic, with the potential for a therapeutic kicker aswell. Its title tells it all: "Surface-epitope masking and expressioncloning identifies the human prostate carcinoma tumor antigen genePCTA-1 a member of the galectin family."
What this boils down to is development and testing of twoimmunogenetic strategies, creating a gene and an antibody thatbetween them make a prostate tumor cell _ but no other tissue in thebody _ visible and defenseless to its patient's immune system.
The PNAS paper's senior author is molecular biologist Paul Fisher,who directs the neuro/oncology program at Columbia University'sCollege of Physicians & Surgeons in New York.
Fisher also is principal inventor, he told BioWorld Today, of "apending patent that the university medical school has filed on theepitope-masking approach, and CIPs [continuations-in-part] onapplications of the approach in genes discovered by this strategy."
Columbia has licensed these inventions to Fisher's new company,GenQuest Inc. "We're incubating this venture," Fisher added, "at theFred Hutchinson Cancer Center in Seattle, where we've developed arelationship with the Corixa Corp."
The molecule encoded by the gene that Fisher has just cloned,PCTA-1, "appears to be an antigen involved in cell-to-cell adhesionand metastatic spread," he said. "To test whether it is expressed oncancerous but not on normal cells," he continued, "we looked athistologic sections from normal and benign-hyperplagia prostatetissue, as well as the first stages of cancer, and advanced prostatecarcinoma. We found that the antibody interacted with the latter two,but not the first two.
"The gene itself," he observed, "is first of all a diagnostic marker fordetecting various cancers _ tumors that may have metastatic andaggressive potential. One of the biggest thrusts now in looking atprostate carcinoma is to see if malignant cells have escaped from thegland's capsule, and are found in the bloodstream."
Fisher explained, "Since this gene is expressed only in cancer, not innormal or BPH, it allows one to rule out that it will be expressed innormal cells. So if you find it in the blood, it would be a pre-indicatorof cancerous or metastatic potential."
Similarly, he pointed out, "the antibody to the gene-expressed antigenis shed from cancer cells, also into the bloodstream. So this too," headded, "may be the basis for a simple serum test that would be muchmore sensitive than PSA, because it will pick up cancer only fromtumors that have shed this protein.
"PSA," he went on, "is quantitative. This would be a qualitative yes-or-no answer, though theoretically it also could be used as aquantitative monitor of tumor burden."
As for testing these potential blood tests preclinically, Fisher said,"We're right in the initial phases of doing that, as we speak. Our firstmodel is to blindly look at human blood samples that have been PCR-isolated for the current PSA test. This now is in progress in ourlaboratory."
Beyond prognosis and diagnosis, he foresees therapeutic potentials:"The other aspect," he explained, "is to determine if interfering withthis gene can block the ability of cells that normally express it to formcancer or to metastasize."
For that purpose, his lab is "already initiating antisense strategy andribozyme approaches."
Fisher's paper reports setting up nude mice with xenografted humanprostate carcinoma, then injecting them with the antibody. "We foundthat in a number of the animals we could suppress the growth of thecancer, and actually get remission of the carcinoma." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.