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Experimental Therapeutics |
Gonda Research Laboratories, John Wayne Cancer Institute, Santa Monica, California 90404
The presence of skeletal metastases in patients suffering from cancer leads to a variety of clinical complications. Bisphosphonates are a class of drugs with a potent bone resorption inhibition activity that have found increasing utility in treating and managing patients with metastatic bone disease. Several clinical trials have demonstrated that bisphosphonates have clinical value in the treatment and management of skeletal metastases derived from advanced prostate cancer. Currently, the mechanism(s) through which bisphosphonates exert their activity is only beginning to be understood. We have studied the effects of bisphosphonate treatment on the growth of prostate cancer cell lines in vitro. Treatment of PC3, DU145, and LNCaP cells with pamidronate or zoledronate significantly reduced the growth of all three cell lines. Using flow cytometry, pamidronate treatment (100 µM) was shown to induce significant amounts of cell death in all three cell lines studied. In contrast, treatment with zoledronate (100 µM) did not induce cell death, instead exerting dramatic effects on cell proliferation, as evidenced by a major increase in cells present in the G0-G1 and S phase. Although both drugs reduced prostate cancer cell growth in the presence of serum, zoledronate was more potent under these conditions, disrupting growth at doses as low as 25 µM in the presence of 5% fetal bovine serum. These results raise the intriguing possibility that the observed clinical utility of bisphosphonates in managing skeletal metastases may in part derive from direct inhibition of prostate cancer cell growth in the bone microenvironment.
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