Advani Ranjana, Peethambaram Prema, Lum Bert L, Fisher George A, Hartmann Lynn, Long Harry J, Halsey Joanne, Holmlund Jon T, Dorr Andrew, Sikic Branimir I
Oncology Division, Stanford University Medical Center, 269 Campus Drive, Stanford, CA 94305-5151, USA.
Cancer. 2004 Jan 15;100(2):321-6. doi: 10.1002/cncr.11909.
It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense oligonucleotide, has shown ability to inhibit PKC-alpha protein expression and inhibit tumor growth in human xenograft models. In a previous Phase I trial, the authors demonstrated the safety and some evidence of activity in ovarian carcinoma of aprinocarsen administered as a 21-day, continuous, intravenous infusion.
In this Phase II trial, 36 patients with advanced ovarian carcinoma were treated with aprinocarsen at a dose of 2 mg/kg per day delivered as a 21-day, continuous, intravenous infusion. The primary objective was to determine the antitumor response, and the secondary objectives were to evaluate toxicity and to evaluate effects on quality of life (QOL).
Between September 1997 and December 1999, 36 patients (median age, 58 years) were enrolled in this trial. Patients were stratified into 2 groups: a platinum-sensitive group (n = 12 patients) and a platinum-resistant group (n = 24 patients). All 36 patients were evaluable for toxicity, and 27 patients were fully assessable for antitumor response after 2 cycles of therapy. All patients had received prior treatments. No objective responses were noted in the platinum-sensitive group. In the platinum-resistant group, 1 patient had some evidence of antitumor activity indicated by a decrease in serum CA 125 and stable disease on imaging studies for 8 months. No changes were noted in overall patient ratings for any of the five QOL domains.
When it was administered as a single agent, aprinocarsen did not have significant clinical activity in patients with advanced ovarian carcinoma. Further study may be warranted in combination with platinum-based regimens.
据推测，蛋白激酶Cα（PKC-α）在肿瘤癌细胞的信号转导中起关键作用。阿普瑞卡森是一种20个碱基的反义寡核苷酸，在人异种移植模型中已显示出抑制PKC-α蛋白表达和抑制肿瘤生长的能力。在先前的I期试验中，作者证明了阿普瑞卡森以21天连续静脉输注给药时在卵巢癌中的安全性和一些活性证据。
在这项II期试验中，36例晚期卵巢癌患者接受阿普瑞卡森治疗，剂量为每天2mg/kg，以21天连续静脉输注给药。主要目标是确定抗肿瘤反应，次要目标是评估毒性和评估对生活质量（QOL）的影响。
1997年9月至1999年12月期间，36例患者（中位年龄58岁）参加了该试验。患者被分为2组：铂敏感组（n = 12例患者）和铂耐药组（n = 24例患者）。所有36例患者均可评估毒性，27例患者在2个周期治疗后可全面评估抗肿瘤反应。所有患者均接受过先前的治疗。铂敏感组未观察到客观反应。在铂耐药组中，1例患者有一些抗肿瘤活性的证据，表现为血清CA 125降低且影像学检查显示疾病稳定8个月。五个QOL领域中任何一个领域的患者总体评分均未发现变化。
当作为单一药物给药时，阿普瑞卡森在晚期卵巢癌患者中没有显著的临床活性。与铂类方案联合使用可能值得进一步研究。
