Wall L, Talbot D C, Bradbury P, Jodrell D I
Cancer Research UK Oncology Unit, Western General Hospital, Edinburgh EH4 2XR, Scotland, UK.
Br J Cancer. 2004 Feb 23;90(4):800-4. doi: 10.1038/sj.bjc.6601594.
BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended.
BB - 3644是一种口服的广谱基质金属蛋白酶抑制剂（MMPI），其结构与marimastat和BB - 94相关。它在抑制细胞结合型肿瘤坏死因子-α（TNF-α）的加工过程中，活性也比marimastat高10倍以上。临床前研究表明，与marimastat相比，其毒性特征良好，因此被选用于临床评估。符合条件的患者为患有晚期实体瘤，现有治疗方法已失败，或没有令人满意的治疗方法且身体状况良好的患者。治疗方案为每天口服BB - 3644两次（bid），持续84天。初始剂量为5mg bid，随后的队列分别接受10、20和30mg bid的治疗。总共招募了22名患者。剂量限制毒性（DLT）为肌肉骨骼疼痛。在用BB - 3644治疗28天时，20mg bid是最大耐受剂量（MTD），因为在30mg bid时，9名患者中有6名在第28天出现了明显的肌肉骨骼毒性。在长期口服BB - 3644（>28天）后，接受10mg bid治疗的5名患者中有3名在第84天出现了肌肉骨骼DLT，将MTD定义为5mg bid。由于在BB - 3644的剂量下出现了剂量限制的肌肉骨骼毒性，而这些剂量不太可能比现有的MMPIs具有优势，因此不建议进一步评估。
