In recent years, clinicians and researchers have noted that blood tests made by different companies for the prostate-specific antigen (PSA) yield different results from identical blood samples. In addition, physicians often don't know which PSA assay their laboratory uses. This makes it difficult to track changes in a patient's PSA level, especially if the lab switches to a different company or PSA test without notice. These inconsistencies have led to difficulties in assessing patients, Thomas Stamey, MD, Professor of Urology at Stanford says.
Stamey and two coworkers, Dr. Zuxiong Chen and graduate student Anthony Prestigiacomo, have developed a stable and reproducible assay calibrator to solve this problem. Earlier this year, the International Federation of Clinical Chemistry recommended Stamey's calibrator for international investigation, and initiated a working group, headed by Stamey, to oversee standardization of the 25 different PSA assays in Europe.
Stamey's calibrator is now on the agenda for the December meeting of the National Committee on Clinical Laboratory Standards, which will consider standardizing the four PSA assays used in the United States.
A paper describing the Stanford team's work appears in the September 1995 issue of the journal Clinical Chemistry.
The problem with currently available assays, Stamey says, is that their calibration is based on the form of PSA in semen, although the assays are used to measure PSA in blood. Early in this decade, researchers discovered that the form of PSA in blood is completely different from its form in semen.
"PSA was meant to be only in the ejaculate, because that's where its natural function is," said Stamey, who pioneered development of the PSA blood test for prostate cancer in the late 1980s.
When a man first ejaculates, the ejaculate is a jelly, Stamey explained. PSA is the enzyme that liquefies the ejaculate and frees the sperm. Its function is to break down proteins.
When small amounts of PSA leak naturally into the bloodstream, or when a cancerous cell totally abandons its normal function of retaining PSA in the ejaculate, the body recognizes the blood-borne PSA as an invader, and releases a protein that binds the PSA to prevent it from breaking down other proteins in the body. So, to properly calibrate assays for PSA in the bloodstream, Stamey's team set out to mimic this binding process in the laboratory.
Chen, a senior research associate in urology, figured out how to take PSA from ejaculate and bind it under laboratory conditions with the naturally occurring protein that binds it in the bloodstream. He also purified the resulting protein complex. Then, Prestigiacomo found that a mixture of 10% PSA in its pure form with 90% PSA in its bound form would almost exactly mimic the state of PSA in the blood. He substituted this new calibrator in each of the four assays approved by the US Food and Drug Administration, and obtained identical blood PSA readings, effectively solving the problem of disparate test results. The team then devised a measuring system for the calibrator that will allow laboratories to use it as a standard with any of the currently approved PSA assays.
This summer, Stamey's lab began packaging enough of the standardized preparation to fill 6,000 vials, which Stamey hopes will be used internationally to recalibrate all assays.
"I believe this is all good news for men over 40 years of age, in that prostate cancer detection will now be more accurate, and year-to-year variations caused by switching assays should not occur," Stamey said.