Lee M V, Fong E M, Singer F R, Guenette R S
Gonda Research Laboratories, John Wayne Cacer Institute, Santa Monica, California 90404, USA.
Cancer Res. 2001 Mar 15;61(6):2602-8.
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 microM) was shown to induce significant amounts of cell death in all three cell lines studied. In contrast, treatment with zoledronate (100 microM) 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 microM 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.
癌症患者出现骨转移会导致多种临床并发症。双膦酸盐是一类具有强大骨吸收抑制活性的药物，在治疗和管理转移性骨病患者方面的应用越来越广泛。多项临床试验表明，双膦酸盐在治疗和管理晚期前列腺癌所致骨转移方面具有临床价值。目前，双膦酸盐发挥其活性的机制才刚刚开始被了解。我们研究了双膦酸盐治疗对前列腺癌细胞系体外生长的影响。用帕米膦酸盐或唑来膦酸盐处理PC3、DU145和LNCaP细胞，显著降低了这三种细胞系的生长。使用流式细胞术，结果显示帕米膦酸盐处理（100微摩尔）可诱导所研究的所有三种细胞系发生大量细胞死亡。相比之下，唑来膦酸盐处理（100微摩尔）并未诱导细胞死亡，而是对细胞增殖产生显著影响，表现为G0 - G1期和S期细胞大量增加。尽管两种药物在有血清存在的情况下均能降低前列腺癌细胞的生长，但唑来膦酸盐在这些条件下更有效，在5%胎牛血清存在时，低至25微摩尔的剂量就能干扰细胞生长。这些结果引发了一个有趣的可能性，即双膦酸盐在管理骨转移方面观察到的临床效用可能部分源于对骨微环境中前列腺癌细胞生长的直接抑制。
