The PSA-Making Phenomenon

A strange thing happens as prostate cancer becomes very aggressive: Some cells start making less PSA, and some cells stop making it altogether. This probably has a lot to do with cell differentiation: How well-defined and close to "normal-looking" cancer cells are. (On the Gleason scale, the lowest, best grade goes to cancer cells with distinct, clearly defined borders. The highest, worst score is fore poorly differentiated, aggressive cells that seem to melt together into solid, malignant blobs.)

Over time, scientists believe, there's a genetic mutation that uncouples the control of cell growth and PSA; the two are no longer linked. The cell loses its higher-order functions -- in other words, it loses its ability to do prostate-specific things, and oozes down the evolutionary scale, regressing into a primordial dividing machine. All the other things it used to do -- which now get in the way of growth -- become superfluous.

"It's interesting," comments oncologist Mario Eisenberger, M.D. "If you take a drug like phenylbutyrate, which slows the cancer cell: As it slows down, the cancer cell also makes more PSA." Hopkins oncologist Michael Carducci, M.D., decided to study phenylbutyrate because of work done at the National Institutes of Health on phenylacetate, a pharmacological "cousin" of the drug -- and, particularly, because of its spectacular results on one patient. "The man was in a lot of pain, he was not working, almost bedridden," says Eisenberger. "He got phenylacetate, and all of a sudden, his pain went away, his strength came back, he went back to work and he was exercising. And his PSA -- it went from 30 to about 3,000! So you look at the PSA and say, 'He's not going to be around here anymore,' but the gentleman was there."

What happened? It may be that, as the cancer cells slowed down with phenylbutyrate -- which, in effect, took away their main activity -- they also began making more PSA: "Cancer cells that are not growing very much have less to do with their energy and they make PSA," says Eisenberger. "That's a very crude analogy, but it gives you an idea that the cancer cells that don't grow very rapidly tend to make more PSA than those that do."

Much is understood about the relationship between PSA and growth in prostate cancer's earliest stages. "But later on, if your cancer disseminates, that relationship between PSA and tumor burden becomes less well-defined," and much more study is needed. As a consequence, Eisenberger hesitates to over-rely on PSA to monitor his patients with advanced disease: "We need to examine the patient frequently, listen to him carefully, and we probably need to do radiographs and scans a little more often."