Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, University Hospital, Uppsala University, 751 85, Uppsala, Sweden.
Cancer Chemother Pharmacol. 2010 May;65(6):1165-72. doi: 10.1007/s00280-009-1125-3. Epub 2009 Sep 30.
Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.
A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.
Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.
Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.
通过抑制其合成来消耗细胞烟酰胺腺嘌呤二核苷酸（NAD）是目前处于临床开发早期阶段的癌症治疗的新药理学原则。我们根据早期临床试验提供了这些药物的安全性和疗效的新的和以前发表的数据。
对晚期实体瘤患者进行 CHS 828 的 I 期临床试验。对用于癌症治疗的 NAD 耗竭药物的已发表临床试验进行了安全性和疗效总结。
7 名先前接受过治疗的实体瘤患者接受了口服 CHS 828 的治疗，剂量范围为 20-80mg，每周一次，每 4 周为一个周期，连续 3 周。毒性主要为胃肠道症状，包括恶心、呕吐、腹泻、便秘、小肠梗阻和胃溃疡。1 例患者出现血小板减少症 2 级。分别有 2 例患者出现 3-4 级高尿酸血症和低钾血症。已从四项 I 期临床试验报告了 NAD 耗竭药物 CHS 828 和 FK866 的安全性和疗效，包括总共 97 名先前接受过治疗的实体瘤患者。报告的突出毒性是血小板减少症和各种胃肠道症状。在上述早期试验中治疗的总共 104 名患者中未观察到客观肿瘤缓解。
在未来的试验中，似乎需要考虑 NAD 耗竭癌症药物的严重毒性是血小板减少症和各种胃肠道症状。单独使用 NAD 耗竭药物的疗效预计较低。
