By David N. Leff
Criminals condemned to death often spend an inordinate amount of time on death row - from guilty verdict to sentencing to multiple appeals and retrials, until the climax of execution.
Men diagnosed with prostate cancer also face a long, drawn-out future - from cancer in situ (confined to the gland's capsule, causing no trouble) to invasive breakout to metastasis and eventual death. Like so many trial attorneys, their urologists attempt to forestall these developments with surgery, radiation and chemotherapy.
A telltale molecule called PSA - prostate-specific antigen - is a witness for the prosecution. Its testimony determines the degree of guilt or innocence; it signals the presence of malignancy. Since its emergence in urological practice a decade or so ago, PSA has served as a convenient blood test to indicate the extent and progress of the cancer, and its response to treatment.
But PSA also has a day job. "Prostate-specific antigen is a protein-cleaving enzyme - a protease of about 30,000 molecular weight," explained molecular and cell biologist Raymond Jones. "PSA is exclusively a human enzyme; no other species has it. Its normal function in the body is to hydrolyze - to cleave - the gel component of semen. In seminal fluid," he continued, "there are several gelatinous proteins called semenogelins. And the physiological function of the PSA enzyme is to hydrolyze that gel so the sperm can escape and go out for their fertilization purpose."
Driving the prostate cancer prosecution is a male hormone called androgen, or testosterone. Just as estrogen in hormone-sensitive women can cause recurrence of breast cancer following surgical mastectomy, so testosterone in androgen-susceptible men can trigger invasive and metastatic flare-ups following excision of a cancerous prostate.
Testosterone, of course, is secreted from the testes, so at this late stage of disease, the only remaining therapy is castration - cutting the testosterone attack off at its source. But then comes a time, with all appeals exhausted, when the prostate malignancy throws off its hormonal dependence and goes on its final rampage - with death in a year or so.
The crowning Catch-22 is that doxorubicin (a.k.a. adriamycin) is a chemotherapeutic for treating prostate tumors. It's so efficacious that it's too good for its own good. That is, doxorubicin in a dosage capable of halting or abolishing the malignancy is so toxic that it threatens the patient's life, and has to be stopped.
Beating Cancer At Its Own Unfair Game
A paper in the November 2000 issue of Nature Medicine reports a proposed way around this pitiless verdict. Its title: "A peptide-doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen in vivo." The article's senior and lead authors are, respectively, molecular and cell biologists Raymond Jones and Deborah Feo-Jones. Both are senior investigators in the Cancer Research Department of the Merck Research Laboratories in West Point, Pa.
"What we did," Jones told BioWorld Today, "was to identify in the semenogelin protein the amino acid residues that are cleaved by PSA. Then through our medicinal chemistry efforts, we modified that sequence, reduced it down to 7 amino acids, and covalently linked them to the doxorubicin molecule.
"When that 7-amino-acid peptide is on doxorubicin," Jones continued, "it has little or no cytotoxic activity. But in the presence of PSA, that enzyme cleaves the peptide, releasing leucine covalently attached to doxorubicin, and subsequently doxorubicin itself. Both agents proved to be cytotoxic - capable of killing prostate tumors."
Feo-Jones described how she and her co-authors tested their candidate cytotoxic peptide (code-named L-377202) in nude mice: "On day one," she recounted, "we inoculated human prostate cancer cells that secrete PSA into the flanks of our experimental mice. Then, the next day, or within four or five days of implanting the tumors, we started the animals on the drug. Usually, we dosed them once a day for five days, or once a week for five weeks, using doxorubicin alone as a control.
"At the end of 5.5 weeks," she went on, "the animals were euthanized, and their tumors taken, as well as plasma. We examined the plasma for circulating PSA and weighed the tumors, to determine the percent efficacy of the drug. Our studies were invariably set up to compare the L-377202 leucine-doxorubicin prodrug with doxorubicin alone."
To which Jones added, "With doxorubicin alone, we got not even a onefold reduction in tumor weight - about 10 percent efficacy. Whereas with the L-377202 prodrug compound, we got a 15-fold reduction in tumor weight - the equivalent of about 90 percent-plus efficacy. So," he summed up, "our compound proved less toxic than doxorubicin, and more efficacious."
Late-stage prostate cancer is infamous for its serial killer-like metastatic spread to bone and other bodily tissues. "It is known," Jones observed, "that where clinicians have looked at individuals with bone metastatic deposits of prostate cancer, they found that at least a fraction of those tumor cells secreted PSA. So this L-377202 therapy should be effective against metastases, as well as with the malignant prostate gland itself."
Safety Testing Goes To The Dogs
Besides disfiguring loss of body hair and insufferable nausea caused by doxorubicin, the chemotherapeutic packs far more life-threatening side effects, directed mainly at the heart. This menace can lie silently in wait for many years after treatment has stopped, before delivering a cardiovascular death sentence.
"The long-term cardiotoxicity studies for these compounds," Feo-Jones recalled, "were done with dogs. We were able to give them a lot more L-377202. In fact, the studies really didn't show any cardiotoxicity. But with doxorubicin alone, cardiac lesions were seen. So we think we have a pretty good cardiotoxicity profile."
Those canine experiments, Jones said, "were part of our safety assessment analysis, which included a number of animal models - rats, mice and dogs. They supported the IND [investigational new drug] application that Merck filed with the FDA. The only thing we can say now is that the compound is in Phase I human clinical trials at multiple cancer centers in patients with advanced prostate disease. Early results," he concluded, "were presented in a poster at the American Society of Clinical Oncology meeting in New Orleans last May."