A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions

The Fight Against Advanced Cancer:
New and Better Drugs


Experimental Treatments show promise in attacking Hormone-resistant prostate cancer. Mario Eisenberger and colleagues are working to develop, test and refine several new drugs, each of which works in a slightly different way

The most frustrating, agonizing aspect of treating prostate cancer is the fact that, when it had advanced past the prostate, invading the lymph nodes or bone, it can no longer be cured; it can only be controlled. The main way to do this is by hormone therapy -- shutting down the hormones that feed the prostate and nourish the cancer. But hormone therapy isn't a long-term solution. Over time, its effectiveness fades (see related story). To wage a full-scale ware on advanced cancer, hormone therapy must be combined with something else -- chemotherapy, drugs targeted specifically at these malignant cells.

Unfortunately, this is where the picture gets fuzzy: So far, standard chemotherapy hasn't worked in prostate cancer. Not only does it fail to cure cancer, it doesn't prolong survival to any significant degree, and it sometimes harsh side effects can make an unpleasant situation even worse.

But: Experimental treatments show promise in attacking hormone-resistant prostate cancer, says oncologist Mario Eisenberger, M.D.. He and colleagues are working to develop, test and refine several new drugs, each of which works in a slightly different way. These include:

Suramin Originally used more than 50 years ago as a drug to kill parasites, suramin has a unique ability to invade cells and rearrange the furniture -- disrupting a cell's most basic business by hooking itself up to substances called growth factors, chemical switches that help promote cell division (some of which are believed to spur prostate cancer's progress). Suramin is known to inhibit growth in certain prostate cancer cells; as a bonus, it also seems to lower the level of adrenal androgens (weak male hormones made by the adrenal gland, which make up a tiny fraction of the total hormone stimulation to the prostate).

Eisenberger and colleagues at Hopkins and Parke-Davis, the company that makes suramin, have just finished a national, randomized clinical trial, in which 455 men with hormone-resistant prostate cancer received either hydrocortisone plus suramin, or hydrocortisone and a placebo. (Hydrocortisone is known to ease bone pain, and also to cause a short-term drop in PSA; it also offsets suramin's temporary disruption of the adrenal gland.) Says Eisenberger: "We should know the results within the next few months. If it's a positive trial, then the FDA will likely approve suramin for prostate cancer."

In another clinical study (currently open for patients -- see below), Eisenberger is giving suramin along with a drug called topotecan. Early research suggests that giving topotecan after suramin causes both drugs to be more effective.

Just how effective is suramin? No one would say it cures prostate cancer, but suramin can chase it into remission from months to -- in a few cases -- even years. "The remission rate worldwide ranges between 20 percent to 65 percent," says Eisenberger. His patients fall in the highest, the 65-percent category. He attributes these good results to when his patients get suramin: At the earliest signs that cancer is worsening (including a rise in PSA in a man who's been on hormone therapy). "That's the ideal time to get started right away -- even though the patient might be feeling very well," he says. "If you wait too long," and miss the window of opportunity, "treatment is unlikely to work."

And how long is remission? Still too short: The average lifespan of men with hormone-resistant cancer (in other words, the point where the PSA starts to rise while the patient is taking hormones, signaling that cancer has defied hormone therapy) is around 11 months. "In our experience with suramin, it was 21 months, so it's almost twice that," says Eisenberger. "We also found that about 30 percent of our patients had been in remission for two years. So it is possible that there's a subset of patients who got helped quite a bit. In fact, I have one patient, a man in his late sixties, who's now been in remission off treatment for six and a half years -- and that's something I had never seen in my previous experience with chemotherapy in prostate cancer."

Differentiating agents This new class of drugs, also being tested in other forms of cancer, "seems to be particularly active" in prostate cancer, Eisenberger says. Differentiating agents work by slowing down the growth, or proliferation, of cancer.

"Every cancer has cells that are dividing, what we call a cell proliferation subset, and cells that are dying," Eisenberger explains. "If the cells are proliferating very actively -- much more than the rate of dying -- then the cancer's growing." Differentiating agents keep cancer in check by slowing down the booming birth rate, giving the death rate a chance to catch up. "This is not conventional chemotherapy," he adds. "It's not one of those drugs that you give and then you destroy everything, and hope that the healthy things come back very quickly and the cancer cells will not recover. This is more selective." Hopkins oncologist Michael Carducci, M.D., is leading studies of differentiating agents including phenylbutyrate and another drug called targretin.

Retinoids This class of drugs (one of them is the drug Retin-A, derived from vitamin A) has a similar mechanism of action; it slows down cancer growth. The particular drug being tested here is called Targretin, which seems able to hone in selectively on prostate cancer receptors.

Dolostatins Another new class of drugs, dolostatins are also being studied in other forms of cancer. The mode of action is similar to that of taxol, currently being used to treat ovarian cancer. Eisenberger and colleagues will soon begin enrolling patients in a study of the drug cemadotin.

With so many drugs being studied, how do the researchers decide who gets what? "In general, we try to focus on what we call 'Phase II' agents first," says Eisenberger. "That is, we're treating patients with new regiments using safe doses and schedules. So if a man tries suramin and topotecan, for instance, and these things are not working well, then the next drug we would offer would be phenylbutyrate. If that isn't helping, then the next step would be targretin." (Because much is already known about cemadotin's dosage and side effects, it will probably be given to patients as a first-line treatment when that study begins.)

There is, says Eisenberger, a frustrating phenomenon called drug resistance: "The cancer cells activate a number of molecular and genetic mechanisms by which they become resistant to chemotherapy." If one drug fails, and then another, "by that time, cancer cells are even smarter than they were before, and it becomes even more complicated," plus the drugs each take a toll on the patient. So the ultimate hope, obviously, is to be able to control cancer with the first course of chemotherapy.

Also on the horizon, although not yet near the patient-testing stage, are:

Angiogenesis inhibitors Yet another group of drugs. "Cancer cells make certain things that make blood vessels," says Eisenberger. "And that's how they spread -- they sort of pave their way through the body. Now, well over 100 drugs are able to inhibit the formation of blood vessels, and we think that prostate cancer's a very good candidate for that." (For more on this, seerelated story.)

Immunotherapy In about 70 percent of patients, as prostate cancer gets worse, there is a substantial drop in lymphocytes -- blood cells that make antibodies, which help the body's immune system fight off disease. "They decrease substantially over time," says Eisenberger, who discovered this during his studies with suramin. "That's something we're studying, and maybe it will be a good rationale for using immunotherapy" -- special drugs and vaccines designed to jump-start the body's flagging immune system. (For more on this, see related story.)

With so many good prospects in the works, the future of chemotherapy looks brighter than ever before, says Eisenberger: "What I see in cancer, in general, is that we are getting much better in selecting and directing our therapy; and prostate cancer is following that. We understand a lot more about cancer biology -- about the genes, about mechanisms of tumor growth. And we think we understand, in certain circumstances, what's important in making cancer cells grow. And as we begin to understand these steps, we're better able to design treatments that interfere with some of them."

Men interested in participating in any of these studies should call Dr. Eisenberger at (410) 614-3511.

Further Reading

"How Much Can We Rely On The Level Of PSA As An Endpoint for Clinical Trials? A Word of Caution,"Journal of the National Cancer Institute. Vol. 12, June 19, 1996. Mario Eisenberger and William G. Nelson.


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