Watson S A, Morris T M, Collins H M, Bawden L J, Hawkins K, Bone E A
Department of Surgery, Queen's Medical Centre, Nottingham, UK.
Br J Cancer. 1999 Sep;81(1):19-23. doi: 10.1038/sj.bjc.6690645.
Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orally administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour antigens was used for evaluating biological activity and defining optimum dosage in the early clinical trials of marimastat. Although tumour antigen levels have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to investigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumour, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a significant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In addition, carcinoembryonic antigen (CEA) levels were measured in serum samples from animals sacrificed at regular intervals, and correlated with excised tumour weight. It was shown that the natural log of the CEA concentration was linearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did reflect tumour size. These results support the use of cancer antigens as markers of biological activity in early phase trials of non-cytotoxic anticancer agents.
抑制基质金属蛋白酶（MMPs）是癌症辅助治疗中一种有吸引力的方法。马立马司他是首个作为口服合成MMP抑制剂在临床上进行这种能力评估的药物。在马立马司他的早期临床试验中，通过测量循环肿瘤抗原的变化率来评估其生物活性并确定最佳剂量。尽管肿瘤抗原水平多年来一直用于癌症的临床管理，但它们尚未被确认为疾病进展的标志物。为了研究马立马司他对肿瘤生长的影响与循环肿瘤抗原水平之间的关系，对携带人胃肿瘤MGLVA1的小鼠进行了马立马司他治疗。MMP抑制剂发挥了显著的治疗效果，将肿瘤生长速率降低了48%（P = 0.0005），并将中位生存期从19天延长至30天（P = 0.0001）。此外，定期处死动物，采集血清样本测量癌胚抗原（CEA）水平，并将其与切除的肿瘤重量相关联。结果显示，CEA浓度的自然对数与肿瘤重量的自然对数呈线性关系，且治疗在这种关系中不是一个显著因素（P = 0.7）。总之，循环CEA水平不受马立马司他直接影响，但确实反映了肿瘤大小。这些结果支持在非细胞毒性抗癌药物的早期试验中使用癌症抗原作为生物活性标志物。
