Macaulay V M, O'Byrne K J, Saunders M P, Braybrooke J P, Long L, Gleeson F, Mason C S, Harris A L, Brown P, Talbot D C
Imperial Cancer Research Fund, Medical Oncology Unit, Churchill Hospital, Oxford, United Kingdom.
Clin Cancer Res. 1999 Mar;5(3):513-20.
Tumor cells and associated stromal cells secrete matrix metalloproteinases (MMPs), contributing to invasion, angiogenesis, and metastasis. Batimastat (BB-94) is a broad-spectrum MMP inhibitor that causes resolution of ascites and/or tumor growth delay in animal models of breast, ovarian, and colorectal cancer. We recruited 18 patients with cytologically positive malignant pleural effusions into a Phase I study of intrapleural BB-94. Three patients received single doses of BB-94 at each dose level: 15, 30, 60, 105, 135, and 300 mg/m2. Two patients were retreated with a second course at 60 and 105 mg/m2. BB-94 was detectable in plasma 1 h after intrapleural administration, and peak levels of 20-200 ng/ml occurred after 4 h to 1 week. BB-94 persisted in the plasma for up to 12 weeks, at levels exceeding the IC50s for target MMPs. Peak values were higher, and persistence in the plasma was longer after higher doses of BB-94. The treatment was well tolerated. Toxic effects included low-grade fever for 24-48 h (6 of 18 patients, 33%) and reversible asymptomatic elevation of liver enzymes (8 patients, 44%). Toxicity seemed unrelated to BB-94 dose or plasma levels. Sixteen patients evaluable for response required significantly fewer pleural aspirations in the 3 months after BB-94 compared with the 3 months before. Seven patients (44%) required no further pleural aspiration until death/last follow-up. After 1 month, patients treated with 60-300 mg/m2 BB-94 had significantly better dyspnea scores, indicating improved exercise tolerance, compared with baseline scores the day after BB-94. The maximum tolerated intrapleural dose remains to be defined, but it is clear that intrapleural BB-94 is well tolerated, with evidence of local activity.
肿瘤细胞和相关基质细胞分泌基质金属蛋白酶（MMPs），促进肿瘤侵袭、血管生成和转移。batimastat（BB - 94）是一种广谱MMP抑制剂，在乳腺癌、卵巢癌和结直肠癌动物模型中可使腹水消退和/或肿瘤生长延迟。我们招募了18例细胞学检查确诊的恶性胸腔积液患者，进行胸腔内注射BB - 94的I期研究。每个剂量水平有3例患者接受单剂量的BB - 94：15、30、60、105、135和300mg/m²。2例患者在60和105mg/m²剂量水平接受了第二个疗程的治疗。胸腔内给药1小时后，血浆中可检测到BB - 94，4小时至1周后达到20 - 200ng/ml的峰值水平。BB - 94在血浆中持续存在长达12周，其水平超过靶标MMPs的IC50。较高剂量的BB - 94峰值更高，在血浆中的持续时间更长。该治疗耐受性良好。毒性作用包括24 - 48小时的低热（18例患者中有6例，33%）和肝酶可逆性无症状升高（8例患者，44%）。毒性似乎与BB - 94剂量或血浆水平无关。16例可评估反应的患者在接受BB - 94治疗后的3个月内，胸腔穿刺次数明显少于治疗前的3个月。7例患者（44%）直至死亡/最后一次随访都无需进一步胸腔穿刺。1个月后，与BB - 94给药后第二天的基线评分相比，接受60 - 300mg/m² BB - 94治疗的患者呼吸困难评分明显改善，表明运动耐量提高。最大耐受胸腔内剂量仍有待确定，但很明显胸腔内注射BB - 94耐受性良好，有局部活性的证据。
