New 'Calibrator' Should Improve Prostate Cancer Testing

In recent years, clinicians and researchers have noted that bloodtests made by different companies for the prostate-specific antigen(PSA) yield different results from identical blood samples. Inaddition, physicians often don't know which PSA assay their laboratoryuses. This makes it difficult to track changes in a patient'sPSA level, especially if the lab switches to a different companyor PSA test without notice. These inconsistencies have led todifficulties in assessing patients, Thomas Stamey, MD, Professorof Urology at Stanford says.

Stamey and two coworkers, Dr. Zuxiong Chen and graduate studentAnthony Prestigiacomo, have developed a stable and reproducibleassay calibrator to solve this problem. Earlier this year, theInternational Federation of Clinical Chemistry recommended Stamey'scalibrator for international investigation, and initiated a workinggroup, headed by Stamey, to oversee standardization of the 25different PSA assays in Europe.

Stamey's calibrator is now on the agenda for the December meetingof the National Committee on Clinical Laboratory Standards, whichwill consider standardizing the four PSA assays used in the UnitedStates.

A paper describing the Stanford team's work appears in the September1995 issue of the journal Clinical Chemistry.

The problem with currently available assays, Stamey says, is thattheir calibration is based on the form of PSA in semen, althoughthe assays are used to measure PSA in blood. Early in this decade,researchers discovered that the form of PSA in blood is completelydifferent from its form in semen.

"PSA was meant to be only in the ejaculate, because that'swhere its natural function is," said Stamey, who pioneereddevelopment of the PSA blood test for prostate cancer in the late1980s.

When a man first ejaculates, the ejaculate is a jelly, Stameyexplained. PSA is the enzyme that liquefies the ejaculate andfrees 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 functionof retaining PSA in the ejaculate, the body recognizes the blood-bornePSA as an invader, and releases a protein that binds the PSA toprevent it from breaking down other proteins in the body. So,to properly calibrate assays for PSA in the bloodstream, Stamey'steam set out to mimic this binding process in the laboratory.

Chen, a senior research associate in urology, figured out howto take PSA from ejaculate and bind it under laboratory conditionswith the naturally occurring protein that binds it in the bloodstream.He also purified the resulting protein complex. Then, Prestigiacomofound that a mixture of 10% PSA in its pure form with 90% PSAin its bound form would almost exactly mimic the state of PSAin the blood. He substituted this new calibrator in each of thefour assays approved by the US Food and Drug Administration, andobtained identical blood PSA readings, effectively solving theproblem of disparate test results. The team then devised a measuringsystem for the calibrator that will allow laboratories to useit as a standard with any of the currently approved PSA assays.

This summer, Stamey's lab began packaging enough of the standardizedpreparation to fill 6,000 vials, which Stamey hopes will be usedinternationally to recalibrate all assays.

"I believe this is all good news for men over 40 years ofage, in that prostate cancer detection will now be more accurate,and year-to-year variations caused by switching assays shouldnot occur," Stamey said.