Schrappe M, Bumol T F, Apelgren L D, Briggs S L, Koppel G A, Markowitz D D, Mueller B M, Reisfeld R A
Department of Pediatric Oncology, Zentrum Kinderheilkunde, Medizinische Hochschule Hannover, Germany.
Cancer Res. 1992 Jul 15;52(14):3838-44.
A conjugate of 4-desacetylvinblastine-3-carboxyhydrazide (DAVLBHY) and the glioma-reactive monoclonal antibody (mAb) 9.2.27 induced long-term suppression of tumor growth in athymic nude mice engrafted with U87MG human glioma cells. In vitro, DAVLBHY had the strongest antiproliferative activity (inhibitory concentration at which incorporation of [3H]thymidine is at 50% of untreated control is 2.0 x 10(-9) M) of seven cytotoxic drugs tested and so was chosen for conjugation to mAb 9.2.27, which reacts specifically with the core protein of chondroitin sulfate proteoglycans found in human glioblastomas. After conjugation of DAVLBHY to the carbohydrate residues of mAb 9.2.27 it retained its full binding capacity. For in vivo studies, DAVLBHY and several conjugate derivatives were evaluated by using two dosages of i.v. injections, each starting 2 days after s.c. tumor inoculation. The control tumors reached a volume of nearly 3000 mm3 within 30 days. Tumor growth was delayed by about 20 days with four i.v. injections of 0.5 mg/kg 9.2.27-DAVLBHY, which was slightly superior to the unconjugated drug. Moreover, 9.2.27-DAVLBHY produced a highly significant suppression of growth so that the average tumor volume was only 3% of that observed in untreated controls after 28 days. Four injections of this conjugate at a larger dose, 2.0 mg/kg, prevented recurrence of the tumors for 130 days in all animals tested, thus demonstrating a significant increase in the therapeutic index, since the unconjugated drug provided limited inhibition of tumor growth for only 40 days. The specificity of the antitumor effect was demonstrated in a comparison with the control conjugate, KS1/4-DAVLBHY, which despite partial tumor suppression had only a transient effect. The specific antitumor effect of 9.2.27-DAVLBHY was unexpected, since the target antigen is expressed at a relatively low density (40,000 sites/cell) on U87MG glioma cells.
4-去乙酰长春碱-3-羧基酰肼（DAVLBHY）与胶质瘤反应性单克隆抗体（mAb）9.2.27的偶联物可长期抑制接种U87MG人胶质瘤细胞的无胸腺裸鼠体内肿瘤生长。在体外，DAVLBHY在七种测试的细胞毒性药物中具有最强的抗增殖活性（[3H]胸腺嘧啶掺入量为未处理对照的50%时的抑制浓度为2.0×10(-9) M），因此被选择与mAb 9.2.27偶联，mAb 9.2.27与人胶质母细胞瘤中发现的硫酸软骨素蛋白聚糖的核心蛋白特异性反应。DAVLBHY与mAb 9.2.27的碳水化合物残基偶联后，仍保留其全部结合能力。在体内研究中，通过静脉注射两种剂量评估DAVLBHY和几种偶联衍生物，每种剂量在皮下接种肿瘤后2天开始。对照肿瘤在30天内体积达到近3000 mm3。静脉注射四次0.5 mg/kg的9.2.27-DAVLBHY可使肿瘤生长延迟约20天，略优于未偶联的药物。此外，9.2.27-DAVLBHY对生长产生了高度显著的抑制作用，以至于28天后平均肿瘤体积仅为未处理对照中观察到的3%。以2.0 mg/kg的较大剂量注射四次这种偶联物，可在所有测试动物中防止肿瘤复发130天，从而证明治疗指数显著提高，因为未偶联的药物仅在40天内对肿瘤生长有有限的抑制作用。与对照偶联物KS1/4-DAVLBHY相比，证明了抗肿瘤作用的特异性，KS1/4-DAVLBHY尽管有部分肿瘤抑制作用，但只有短暂效果。9.2.27-DAVLBHY的特异性抗肿瘤作用出乎意料，因为靶抗原在U87MG胶质瘤细胞上以相对较低的密度（40,000个位点/细胞）表达。
