EORTC-NCI-AACR: Compound Slows Prostate Cancer In Mice

PRAGUE, Nov. 8 - A key biochemical pathway that leads to prostate cancer has been uncovered in mice and blocked by a previously known compound, a U.S, group reported here.

Results are promising enough that the researchers are planning a clinical trial to test the compound - dubbed MDL - as an adjuvant therapy after surgery for prostate cancer, according to Hirak Basu, Ph.D., of the University of Wisconsin's Paul P. Carbone Comprehensive Cancer Center in Madison.

The research builds on the established fact that oxygen-free radical production in the prostate drives the growth and in many cases the occurrence of cancer, Dr. Basu told a symposium here on molecular targets and cancer therapeutics, organized by the European Organisation for Research and Treatment of Cancer, the National Cancer Institute, and the American Association for Cancer Research.

But until now it has not been clear how such molecules were created in the organ, he said. Dr. Basu and colleagues, using genetically engineered mice that are prone to develop spontaneous prostate cancers, showed that the process begins with increased androgen.

"This androgen signaling causes many things, among which is an increase in production of oxygen free radicals in the prostate," Dr. Basu said.

In vitro, Dr. Basu and colleagues showed that androgen increased the expression of the enzyme spermidine/spermine acetyl transferase by a factor of 50. The enzyme acetylates the polyamines spermidine and spermine, which leads to the production of acetyl polyamine oxidase, which in turn leads to the production of reactive oxygen species such as hydrogen peroxide.

"These results demonstrate that polyamine oxidation is one of the major causes of androgen-induced oxidative stress in prostate cancer cells," Dr Basu said. "The discovery of this pathway is a major step forward in understanding the role of androgen in prostate cancer development."

The acetyl polyamine oxidase, he said, is the target of the compound MDL, known formally as N1,N4-bis(2,3-butadienyl)-1,4-butanediamine, developed more than 20 years ago as a possible cancer therapy.

In mice prone to develop prostate cancer -TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice - the compound was safe and effective in slowing the progression of tumors, Dr. Basu reported here.

Specifically:

• At a dose of 25 mg/kg, injected intra-peritoneally every two weeks, MDL "completely inhibits" acetyl polyamine oxidase.
• Control mice began to develop tumors at 13 weeks of age and the proportion with a palpable tumor reached 100% at 20 weeks.
• MDL-treated mice also began to develop cancer at 13 weeks, but the proportion of mice with a palpable tumor climbed more slowly, and reached a plateau of about 55% at 20 weeks.
• The MDL-treated animals also lived longer than the controls.
• At that dose there was no evidence of toxicity.

The compound is known to have toxicity in humans at a daily dose of 100 mg/kg, Dr. Basu said, but that is 40 times the dose used in the mice. He noted that MDL is a "very organ-specific molecule" because acetyl polyamine oxidase is mainly found in prostate cells.

"To the best of our knowledge," Dr. Basu said, "this is the first report of a specific enzyme inhibitor that blocks androgen-induced oxidative stress in the prostate and prevents spontaneous prostate tumor development."