Docetaxel-Thalidomide Combo Increases Survival Rate in Prostate Cancer Patients

Survival rates increased and prostate-specific antigen (PSA) levels decreased in men with androgen-independent prostate cancer (AIPC) when they were treated with thalidomide in addition to docetaxel, compared with docetaxel alone, according to a study by Dr. William Dahut and his colleagues at NCI's Center for Cancer Research, reported in the July 1 Journal of Clinical Oncology.

In a randomized phase II trial of 75 men with chemotherapy-naive metastatic AIPC, patients received either docetaxel alone or combined with thalidomide. Docetaxel has been shown to decrease PSA levels in AIPC patients. After a 26.4-month follow-up, the combination group had a 53 percent PSA decline compared with a 37 percent decline in the docetaxel-only group. The combination group also had a median progression-free survival of 5.9 months compared with 3.7 months in the monotherapy group. At 18 months, the combination group had an overall survival rate of 68.2 percent compared with 42.9 percent with docetaxel alone.

According to the researchers, the study represents the first randomized trial suggesting that an anti-angiogenesis agent may be helpful in treating prostate cancer. "Combination therapy with a chemotherapeutic agent and an angiogenesis inhibitor represents a promising new area of investigation for metastatic AIPC," said Dr. Dahut, "But the small numbers of patients in this study means that statistical significance has not been reached, and larger randomized trials are needed."

Nitric Oxide Amount and Duration Affect Key Tumor-Related Proteins

Certain key proteins involved in tumor development have been found to respond to the concentration and duration of nitric oxide (NO). According to a study in the June 15 issue of the Proceedings of the National Academy of Sciences, Dr. Douglas Thomas of the Radiation Biology Branch in NCI's Center for Cancer Research and his colleagues found that the dose and duration of NO exposure had a significant effect on the regulation of three proteins - hypoxic inducible factor 1α (HIF-1α), extracellular signal-regulated kinase (ERK), and p53 in MCF7 breast cancer cells.

Of almost 20 proteins surveyed, only ERK, HIF-1α, and p53 responded differentially to NO levels - ERK to low NO concentrations, HIF-1α to medium, and p53 to the highest concentrations. They also noted that the duration of NO exposure affected these signal transduction responses. ERK was rapidly phosphorylated, but the effect was transient. HIF-1α accumulation continued only when there was an adequate, sustained NO flux. The response of p53 was detected during NO exposure and persisted for 12 hours afterwards.

While many studies have shown that NO is involved in a variety of physiological functions important to tumor survival, this is the first study to quantify the effects of NO dose and concentration on proteins critical to tumor development in a breast cancer cell line. In solid tumors, cell density and oxygen gradients will also regulate the response of proteins to NO.

"The role of NO as either growth-promoting or cytotoxic in tumors may be explained by differences in both the concentration and exposure time of cells to NO," Dr. Thomas reported.