LoRusso P, Wozniak A J, Polin L, Capps D, Leopold W R, Werbel L M, Biernat L, Dan M E, Corbett T H
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48202-0188.
Cancer Res. 1990 Aug 15;50(16):4900-5.
PD115934 (NSC 366140) is a soluble pyrazoloacridine derivative presently undergoing preclinical toxicology evaluation with the anticipation of Phase I human investigation. The agent displayed both human and murine solid tumor selectivity in vitro in a soft agar disk diffusion assay, relative to its activity against murine L1210 leukemia. In vivo it was highly active against solid tumors colon adenocarcinoma 38 and pancreas ductal carcinoma 03, which was consistent with the cellular cytotoxicity seen in the disk diffusion assay. A log cell kill of greater than 4.0 was demonstrated in vivo against both models. PD115934 was administered by both bolus and infusional therapy. After completion of these trials, it was determined that this compound was a schedule category III agent, i.e., a schedule-independent agent with peak plasma level toxicity. The main toxicity encountered with infusional therapy was myelosuppression. With bolus therapy, central nervous system toxicities were dose limiting. On the basis of our preclinical infusion studies, we recommend a 2-h infusion twice weekly in humans in order to obtain a total dose of 360 mg/m2 over 8 weeks.
PD115934（NSC 366140）是一种可溶性吡唑并吖啶衍生物，目前正在进行临床前毒理学评估，预计将开展I期人体研究。在软琼脂平板扩散试验中，相对于其对小鼠L1210白血病的活性，该药物在体外对人和小鼠实体瘤均表现出选择性。在体内，它对实体瘤结肠腺癌38和胰腺导管癌03具有高度活性，这与平板扩散试验中观察到的细胞毒性一致。在体内对这两种模型均显示出大于4.0的对数细胞杀灭率。PD115934通过推注和输注疗法给药。在这些试验完成后，确定该化合物为III类药物，即一种血浆峰值水平毒性与给药方案无关的药物。输注疗法遇到的主要毒性是骨髓抑制。推注疗法中，中枢神经系统毒性是剂量限制性的。基于我们的临床前输注研究，我们建议在人体中每周两次进行2小时输注，以便在8周内获得360 mg/m²的总剂量。
