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 --
"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."