Festuccia Claudio, Gravina Giovanni Luca, Muzi Paola, Pomante Roberto, Angelucci Adriano, Vicentini Carlo, Bologna Mauro
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
J Urol. 2008 Jul;180(1):367-72. doi: 10.1016/j.juro.2008.02.036. Epub 2008 May 22.
The profound decrease in serum dihydrotestosterone observed with the dual 5alpha-reductase inhibitor dutasteride makes it an attractive agent for prostate cancer therapy. To our knowledge we compared for the first time the antitumor effect of dutasteride with that of the specific 5alpha-reductase-1 inhibitor MK386 and the specific 5alpha-reductase-2 inhibitor finasteride in human prostate primary cultures.
Biochemical markers of the cellular response to 5alpha-reductase inhibitors were evaluated in primary cultures of prostate epithelial cancer cells from 54 patients with prostate carcinoma.
In our cohort of 54 patients prostate cancer cell growth decreased with dutasteride in 42 (about 78%), whereas in 21 (39%) it decreased with finasteride or MK386 alone. We observed a relationship between the levels of 5alpha-reductase enzymes in cell culture extracts and those revealed by immunohistochemistry in sections of samples from which we established primary cultures. Finasteride effects depended on 5alpha-reductase-2 levels and they were higher when the 5alpha-reductase-1:2 ratio was low. However, dutasteride effects were related to 5alpha-reductase-1 and 2 levels, and were not influenced by the 5alpha-reductase-1:2 ratio. Conversely the effects of MK386 were related to 5alpha-reductase-1 levels and they were higher when the 5alpha-reductase-1:2 ratio was high.
Our data may provide a rationale for the use of a dual 5alpha-reductase inhibitor rather than a mono specific inhibitor for the prevention or treatment of early prostate cancer. This finding appears to confirm some preliminary clinical results and it could be due to the simultaneous presence of each 5alpha-reductase isoenzyme in prostate tumor cells.
双重5α-还原酶抑制剂度他雄胺可使血清二氢睾酮显著降低，这使其成为前列腺癌治疗的理想药物。据我们所知，我们首次比较了度他雄胺与特异性5α-还原酶-1抑制剂MK386和特异性5α-还原酶-2抑制剂非那雄胺在人前列腺原代培养物中的抗肿瘤作用。
在54例前列腺癌患者的前列腺上皮癌细胞原代培养物中，评估细胞对5α-还原酶抑制剂反应的生化标志物。
在我们的54例患者队列中，42例（约78%）的前列腺癌细胞生长随度他雄胺降低，而单独使用非那雄胺或MK386时，21例（39%）的癌细胞生长降低。我们观察到细胞培养提取物中5α-还原酶的水平与我们建立原代培养物的样本切片中免疫组化显示的水平之间存在关联。非那雄胺的作用取决于5α-还原酶-2的水平，当5α-还原酶-1:2比例较低时作用更强。然而，度他雄胺的作用与5α-还原酶-1和2的水平相关，且不受5α-还原酶-1:2比例的影响。相反，MK386的作用与5α-还原酶-1的水平相关，当5α-还原酶-1:2比例较高时作用更强。
我们的数据可为使用双重5α-还原酶抑制剂而非单一特异性抑制剂预防或治疗早期前列腺癌提供理论依据。这一发现似乎证实了一些初步临床结果，可能是由于前列腺肿瘤细胞中同时存在每种5α-还原酶同工酶。
