POLY ICLC AND ALPHA INTERFERON IN REFRACTORY MALIGNANCY

干扰素诱导大量基因产物的合成。这些 产品在抗病毒和抗增殖作用中发挥作用， α干扰素 两种诱导的基因产物，2 '，5'-寡腺苷酸 合成酶和双链抑制剂（DSI）由 但需要双链RNA来激活它们。 的DSI 在抑制蛋白质合成起始中起主要作用， 磷酸化真核起始因子2（eIF-2）， 它的α亚基。 本研究联合使用干扰素α和聚ICLC， 双链RNA的形式，以确定最佳剂量水平 干扰素诱导DSI的最佳剂量和Poly ICLC的最佳剂量 用于激活激酶。 干扰素的三个剂量水平是 与四种剂量水平的聚ICLC组合。 本研究旨在确定该组合的毒性， 最大耐受剂量。 观察到剂量限制性毒性， 干扰素10 μ/m2和聚ICLC 0.03 mg/m2的组合。 毒性 包括长期低血压，需要住院治疗， 静脉输液。允许更高剂量的聚ICLC 以10 μ/m2剂量水平施用干扰素，而不使用此 毒性这些结果表明，聚ICLC可能在较低浓度下毒性更大。 剂量或更高剂量的ICLC可以降低干扰素的毒性。

Interferon induces the synthesis of a large number of gene products. These products play a role in the antiviral and antiproliferative effects of alpha interferon. Two of the induced gene products, 2',5'-oligoadenylate synthetase and the double-stranded inhibitor (DSI) are induced by interferon but require double-stranded RNA to activate them. The DSI plays a major role in inhibiting protein synthesis initiation by phosphorylating the eukaryotic initiation factor 2 (eIF-2) on serine 51 of its alpha subunit. This study combined administration of interferon alpha and Poly ICLC, a form of double-stranded RNA, in order to determine the optimal dose level of interferon for induction of the DSI and the optimal dose of Poly ICLC for activation of the kinase. Three dose levels of interferon were combined with one of four dose levels of Poly ICLC. This study was designed to determine the toxicity of this combination and the maximal tolerated dose. Dose-limiting toxicity was observed with the combination of interferon 10 mu/m2 and Poly ICLC 0.03 mg/m2. Toxicity consisted of prolonged hypotension requiring hospitalization for intravenous fluid administration. Higher doses of Poly ICLC allowed administration of interferon at the 10 mu/m2 dose level without this toxicity. These results suggest that Poly ICLC may be more toxic at lower doses or that higher doses of ICLC may reduce the toxicity of interferon.