In the late 1960s and 1970s, many researchers were searching for tumor-specific antigens that might be useful as biomarkers or targets for immunotherapy of cancer and other diseases.
I am frequently asked about the “true” history of prostate-specific antigen (PSA). As PSA has become more important, a controversy about its discovery has increased. I lived through much of this history and have known many of the “players.” Here are the relevant facts, as I believe them to be true.
Before PSA, prostatic acid phosphatase was the most important blood test for prostate cancer, but it was useless for early detection of prostate cancer because it was elevated largely in men who already had bone metastases.
In the late 1960s and 1970s, many researchers were searching for tumor-specific antigens that might be useful as biomarkers or targets for immunotherapy of cancer and other diseases. Typical experiments involved searching for “antigens” by injecting extracts of human tissues and body fluids into rabbits and testing the rabbit serum for antibodies against the antigens contained in the extracts. The earliest report on the properties of antigens in the prostate was by urologist Rubin Flocks in 1960.1
In 1966, a Japanese forensic scientist, Mitsuwo Hara, partially characterized and reported on a protein similar to what might have been PSA. He called it “gamma-seminoprotein” and suggested its possible value as forensic evidence in rape cases in the Japanese Journal of Legal Medicine.
In 1970 and 1972, Richard Ablin reported finding two antigens that were specific to the human prostate, one of which was separate from acid phosphatase. I do not believe Dr. Ablin knew what the antigens were or contemplated their potential uses. In any case, he didn’t characterize the antigens further, but rather, moved on to studies of the possible induction of an antitumor immune response in the prostate gland by freezing the prostate.
In 1970, Tien Shun Li and Carl Beling, conducting research in male infertility reported there were antigens in human semen, some of which might have been PSA. In 1978, forensic scientist George Sensabaugh identified a protein in semen that was similar to one of Li’s that later was also shown to be similar to PSA.
The debate about who really deserves credit for discovering PSA has focused on whether the reported early “antigens” were actually PSA. Many did not exhibit all the properties that would be expected of PSA. The molecular weight and amino acid composition of gamma-seminoprotein as initially reported were different from those of PSA. Both Li and Beling and Sensabaugh reported their antigens were not of prostatic origin. Ablin could not detect his antigen in semen or prostatic fluid where PSA should be easily detected. Ultimately, Chu received the patent for the discovery of “purified human prostate antigen” in 1984, and has been honored on many occasions as the discoverer of PSA.
In my opinion, the real credit for the “discovery” of PSA as a marker for prostate disease and for beginning to introduce it into clinical use belongs to T. Ming Chu and his research laboratory staff, notably Ming C Wang, at Roswell Park Memorial Institute (as it was known from 1946 to 1992) in New York. In 1979, they purified and characterized PSA, demonstrated its presence in normal, benign, and malignant prostate tissue, and showed that it was virtually prostate specific. Later they developed an immunoassay that could be used for blood testing and performed early studies exploring its potential clinical uses in prostatic diseases.
Monitoring and Screening
What emerged from the early clinical studies by Chu’s group and by other researchers and was further demonstrated in 1987 by Thomas A. Stamey of Stanford University was that PSA is quite useful for monitoring the course of patients already known to have prostate cancer. However, it was not really appreciated that it could be used as a first-line screening test for prostate cancer, because PSA could be elevated in patients with benign prostate conditions and “normal” or low in patients with prostate cancer.
In 1991, I published the first results of a study showing that the PSA test was the most accurate method of detecting prostate cancer.2 Using a PSA cutoff of 4 ng/mL, about 25% of men were found to have cancer. Moreover, PSA could detect many cancers that were missed by both the rectal exam and ultrasonography. Thus, I was the first to suggest that PSA could be used as a first-line screening test for prostate cancer.
I still believe that PSA is the best cancer blood test in medicine, and certainly the best we currently have for early prostate cancer detection. I believe that if it were used intelligently and were combined with high-quality, effective treatment, it could reduce the prostate cancer death rate by more than half. ■
—William J. Catalona, MD
Professor in Urology
Feinberg School of Medicine
1. Rao AR, Motiwala HG, Karim OM, et al: The discovery of prostate-specific antigen. BJU Int 101:5-10, 2008.
2. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324:1156-1161, 1991.