Phase I/IB study of polyadenylic-polyuridylic acid in patients with advanced malignancies: clinical and biologic effects.
Phase I/IB study of polyadenylic-polyuridylic acid in patients with advanced malignancies: clinical and biologic effects.
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聚腺苷酸-聚尿苷酸治疗晚期恶性肿瘤的 I/IB 期研究：临床和生物学效应。
DOI：
10.1089/jir.1996.16.631
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Borden,EC
中科院分区：
文献类型：
--
作者：
Witt,PL;Zahir,S;Ritch,PS;McAuliffe,TM;Ewel,CH;Borden,EC
合成的多核苷酸聚腺苷酸-聚尿苷酸（polyA：polyU）在小鼠研究和人类乳腺癌中显示出抗肿瘤活性。PolyA：polyU在25名接受3至600 mg/m2每周静脉注射剂量的癌症患者中进行了评价。PolyA：polyU耐受性良好，高达600 mg/m2，无剂量限制毒性（均<3级）。副作用包括轻度体温升高、疲劳和轻度高血糖。未观察到红细胞压积、WBC计数、血小板计数、总胆红素或碱性磷酸酶超出正常范围的变化。在25例患者中，18例完成了至少一个6周周期，5例完成了两个周期（中位数6周）。4名患者在11-13周的治疗中病情稳定，未观察到临床反应。首次治疗后24 h，生物学反应（血清中β2-微球蛋白和新蝶呤或外周血单核细胞中2′，5 ′-寡腺苷酸合成酶）无显著增加。第3周治疗后24 h观察到β2-微球蛋白小幅增加（1.1倍，p< 0.01）。到治疗的第三周，2-5A合成酶水平略微下降（至基线的80%，p< 0.01）。治疗24 h后，血清中细胞因子IL-6、IL-12、肿瘤坏死因子（TNF）或IL-2受体未发生变化。因此，在这些剂量下，polyA：polyU对体内生物学反应没有明显的调节作用，尽管该制剂在体外显著诱导外周血单核细胞2-5A合成酶。PolyA：PolyU耐受性良好。在该每周一次给药方案中，未达到MTD，但大于600 mg/m2。
The synthetic polynucleotide polyadenylic-polyuridylic acid (polyA:polyU) has shown antitumor activity in murine studies and human breast cancer. PolyA:polyU was evaluated in 25 cancer patients receiving weekly intravenous doses between 3 and 600 mg/m2. PolyA:polyU was well tolerated up to 600 mg/m2, with no doselimiting toxicity (all < grade 3). Side effects included mild elevation in temperature, fatigue, and mild hyperglycemie. No changes outside of the normal range in hematocrit, WBC count, platelet count, total bilirubin, or alkaline phosphatase were observed. Of 25 patients, 18 completed at least one cycle of 6 weeks, and 5 completed two cycles (median 6 weeks). Four patients had stable disease over 11–13 weeks of treatment, and no clinical responses were observed. At 24 h after the first treatment, there were no significant increases in biologic response (β2-microglobulin and neopterin in serum, or 2′,5′-oligoadenylate synthetase in peripheral blood mononuclear cells). A small increase in β2-microglobulin was observed 24 h after the week 3 treatment (1.1-fold,p< 0.01). By the third week of treatment, 2-5A synthetase levels decreased slightly (to 80% of baseline,p< 0.01). No changes in cytokines IL-6, IL-12, tumor necrosis factor (TNF), or IL-2 receptor in serum were detected after 24 h of treatment. Thus, at these doses, polyA:polyU had no marked modulation on biologic responsesin vivo, although this preparation significantly induced 2-5A synthetase in peripheral blood mononuclear cellsin vitro. PolyA:polyU was well tolerated. An MTD was not reached but was greater than 600 mg/m2on this weekly schedule.