Zheng Xi, Chang Richard L, Cui Xiao-Xing, Avila Gina E, Hebbar Vidya, Garzotto Mark, Shih Weichung Joe, Lin Yong, Lu Shou-En, Rabson Arnold B, Kong Ah Ng Tony, Conney Allan H
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USA.
Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3444-51. doi: 10.1158/1078-0432.CCR-05-2823.
To investigate the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate cancer cells cultured in vitro or grown as tumors in immunodeficient mice.
Human prostate cancer LNCaP cells in culture were treated with TPA alone or in combination with paclitaxel. NCr immunodeficient mice with well-established LNCaP tumors received i.p. injections with vehicle or with TPA, paclitaxel, or TPA in combination with paclitaxel. The animals either received daily treatment for 5 consecutive days followed by a 2-day intermission, which was repeated for a total of 28 days (experiment 1), or continuous daily treatment for 28 days (experiment 2).
Treatment of LNCaP cells with a combination of TPA and paclitaxel synergistically inhibited the growth and induced apoptosis in cultured LNCaP cells, and this treatment also induced a marked increase in phosphorylated c-Jun-NH2-kinase (JNK). In animal experiments, tumor growth occurred in all mice treated with vehicle. When treated with TPA alone, the percentage of animals with some tumor regression was 33% in experiment 1 and 100% in experiment 2. Treatment of animals with paclitaxel alone caused some tumor regression in 17% and 57% of the animals in experiments 1 and 2, respectively. All animals treated with TPA + paclitaxel in both experiments had some tumor regression.
TPA and paclitaxel in combination had a stronger inhibitory effect on the growth of LNCaP cells in culture or as xenograft tumors in immunodeficient mice than either agent alone. Clinical trials with TPA alone or in combination with paclitaxel in patients with prostate cancer may be warranted.
研究12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）与紫杉醇联合应用对体外培养或在免疫缺陷小鼠体内形成肿瘤的前列腺癌细胞的影响。
体外培养的人前列腺癌LNCaP细胞分别用TPA单独处理或与紫杉醇联合处理。已建立LNCaP肿瘤的NCr免疫缺陷小鼠腹腔注射溶媒、TPA、紫杉醇或TPA与紫杉醇的组合。动物要么连续5天每日接受治疗，随后间歇2天，如此重复共28天（实验1），要么连续28天每日接受治疗（实验2）。
TPA与紫杉醇联合处理LNCaP细胞可协同抑制其生长并诱导培养的LNCaP细胞凋亡，且该处理还导致磷酸化c - Jun氨基末端激酶（JNK）显著增加。在动物实验中，所有接受溶媒处理的小鼠肿瘤均生长。单独用TPA处理时，实验1中出现部分肿瘤消退的动物百分比为33%，实验2中为100%。单独用紫杉醇处理动物时，实验1和实验2中分别有17%和57%的动物出现部分肿瘤消退。两个实验中所有接受TPA + 紫杉醇处理的动物均出现部分肿瘤消退。
TPA与紫杉醇联合应用对体外培养的LNCaP细胞或免疫缺陷小鼠体内异种移植肿瘤生长的抑制作用比单独使用任何一种药物都更强。或许有必要对前列腺癌患者单独使用TPA或TPA与紫杉醇联合进行临床试验。
