Around the third month of pregnancy, the steroid androgen hormonetestosterone kicks in to form the genitalia of a future boy baby. Adozen years or so later, the same testosterone changes the boy into aman, enlarging those sexual organs, growing under-arm and pubichair _ not to mention adolescent acne _ deepening the voice,awakening the libido.
A little later in life, that same male sex hormone perpetrates male-pattern baldness, a loss of scalp hair peculiar to men.
Then in a man's advancing years, that androgen turns ugly by causingand fueling cancer of the prostate _ a small gland that secretes a partof the seminal fluid, which carries sperm into the female of thespecies.
Of all the malignancies diagnosed today in American men, prostatecancer is the commonest. This year, an estimated 317,100 new caseswill arise, and 41,400 may die of the disease. (See BioWorld Today,Sept. 28, 1995, p. 1.)
Fifty-five years ago, urologist Charles Huggins showed that thedriving force behind prostate tumor growth and spread istestosterone, which the testicles' Leydig cells pump out in largeamounts. Huggins, at the University of Chicago, proposed castrationas a way to stop the hormone-dependent prostate cancer by cuttingoff its fuel supply at the source. For this discovery he won a Nobelprize in 1966.
To this day, testicular ablation remains the only effective treatment,once the tumor has metastasized beyond its prostate margins. Butalthough such surgery has a recovery rate of 80 percent, its benefit topatients is not permanent. A new discovery suggests that in somecases, a dose of the androgen can be beneficial.
University of Chicago biochemist and molecular biologist ShutsungLiao, who trained under Huggins, told BioWorld Today: "In one tothree years after castration, the cancer comes back, this timeindependent of androgen [i.e., testosterone]. They are able to thriveand proliferate without the androgen, and there is now no way to treatthat tumor. Which is why we are focusing our studies on how to treatthe androgen-independent cancers."
Liao's studies have reaped a startling dividend: For certain types ofprostate tumors, the hair of the dog that bit them _ i.e., doses oftestosterone, can reverse the renewed growth and metastasis of thepost-ablation tumor.
His article in today's Proceedings of the National Academy ofSciences (PNAS), dated Oct. 15, 1996, reports: "Human prostatetumor growth in athymic mice: Inhibition by androgens andstimulation by finasteride."
Liao observed: "We do not really know the mechanism by whichtestosterone is converted from a bad-guy tumor promoter to a good-guy tumor suppressor. However," he explained, "what we did wastake androgen-dependent cancer cells and grew them for over 100passages during two or three years in androgen-depleted culturemedium. These cells became androgen-independent; in other words,they don't need androgen but can still grow."
However, he pointed out, "although independent of the hormone,they remain sensitive to androgen, which will promote either cellgrowth or cell killing. And we found in our experimental mice thatwe could really kill some of those cells by putting in small amountsof testosterone."
He and his co-authors determined _ in mice bearing human tumorsweaned off testosterone _ that the reason for this counter-intuitiveeffect was that "some of the androgen-independent cancer cells havea large amount of androgen receptors. These for some reason madeproteins in the original androgen-dependent cells that were useful formalignant proliferation. But after going through passages in culture,those receptors now make proteins that can help the cancer cells dieby apoptosis."
This phenomenon, Liao added, "is what we see in prostate cancerpatients. Those we can probably cure by androgens. But insensitivetumors that have progressed to androgen independence cannot becured by testosterone."
He and his team have more experiments in progress, showing that"these cells can grow back to androgen-dependent tumors, thusreversing the course of cancer progression. That is, they again needtestosterone to grow."
Cure It's Not, But Aims To Prolong Life
Thus, he observed, "one can now repeat what Huggins did by a newround of androgen-ablation therapy." He noted that the adrenalglands also produce androgens, which may support the newly re-dependent tumor cells. You probably can now use anti-testosteronecompounds, such as finasteride _ Proscar _ to treat these post-castration patients again. We think one can go back and forth manytimes in a cycle of treatment, and prolong the life of the patient."
But Liao emphasized: "It's a very important point that this is not acure for cancer. It is more or less manipulation, so we can keep thetumor, and its metastases, always at a small size, so the patient willnot die."
He also made the point that "Prostate cancer is a very complexmixture of cell types. The cells we are talking about may be only onetype."
Liao counseled that a large-scale, National Institutes of Health-sponsored clinical trial of Proscar in prostate cancer patients shouldproceed with caution. "In some of the patients, those who havecancer cells that are androgen-independent but sensitive totestosterone killing, it will actually stimulate the growth of theirtumors." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.