Sweeney Christopher, Liu Glenn, Yiannoutsos Constantin, Kolesar Jill, Horvath Dorothea, Staab Mary Jane, Fife Karen, Armstrong Victoria, Treston Anthony, Sidor Carolyn, Wilding George
Division of Hematology-Oncology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.
Clin Cancer Res. 2005 Sep 15;11(18):6625-33. doi: 10.1158/1078-0432.CCR-05-0440.
To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic.
Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly.
Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and approximately 85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were approximately 4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56.
2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.
确定2-甲氧基雌二醇的临床前抗肿瘤和抗血管生成活性是否能转化至临床。
激素难治性前列腺癌男性患者被纳入这项II期随机双盲试验，给予两种剂量的口服2-甲氧基雌二醇胶囊（400和1200毫克/天），每4周为一个周期。在第1和第2周期的第1天进行药代动力学采样，并每周采集谷值样本。
2001年2月至9月间招募了33名男性患者。与治疗相关的显著毒性为1例2级和2例3级肝转氨酶升高，其中2例患者在继续治疗后症状缓解。有2例深静脉血栓形成。该药物具有非线性药代动力学，迅速转化为2-甲氧基雌酮，约85%发生结合。未结合的2-甲氧基雌二醇和2-甲氧基雌酮谷值血浆水平分别约为4和40纳克/毫升。1200毫克组有7例患者、400毫克组有1例患者的前列腺特异性抗原下降了21%至40%。高剂量组的前列腺特异性抗原速度显著降低（P = 0.037），与400毫克剂量组相比，前列腺特异性抗原进展的中位时间更长（109天对67天；P = 0.094），研究时间也更长（126天对61天；P = 0.024）。在第28天和第56天，400毫克和1200毫克剂量水平的性激素结合球蛋白分别增加了2.5倍和4倍。
2-甲氧基雌二醇耐受性良好，尽管血浆水平不理想且该胶囊制剂的口服生物利用度有限，但在1200毫克/天剂量时仍显示出一定的抗癌活性。
