Boland I, Vassal G, Morizet J, Terrier-Lacombe M J, Valteau-Couanet D, Kalifa C, Hartmann O, Gouyette A
Laboratory of Pharmacotoxicology and Pharmacogenetics (CNRS URA147), Villejuif, France.
Br J Cancer. 1999 Feb;79(5-6):787-92. doi: 10.1038/sj.bjc.6690126.
High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.
含大剂量白消安的化疗方案已在复发或难治性神经母细胞瘤、尤因肉瘤和髓母细胞瘤患儿中显示出高缓解率。然而，白消安作为单一药物的抗肿瘤活性仍有待确定，为此在携带晚期皮下小儿实体瘤异种移植物的无胸腺小鼠中进行了评估。由于白消安在水中极难溶解，首先从药代动力学和毒性方面研究了几种用于肠内和肠外给药的载体。腹腔注射二甲基亚砜中的白消安可获得最高生物利用度。当白消安悬浮于羧甲基纤维素中口服或腹腔注射时，生物利用度较差。然后，在治疗实验中，于第0天和第4天腹腔注射二甲基亚砜中的白消安。在最大耐受总剂量（50 mg kg⁻¹）时，白消安可显著延迟肿瘤生长，在所评估的三种神经母细胞瘤以及三种髓母细胞瘤中的一种中，肿瘤生长延迟时间为12至34天。在高于最大耐受剂量的剂量水平时，白消安可诱导肿瘤完全或部分消退。白消安在周围原始神经外胚层肿瘤（PNET）异种移植物中无活性。考虑到小鼠和人类的白消安药代动力学，小鼠治疗活性剂量下的估计全身暴露量（113 μg h ml⁻¹）接近接受大剂量白消安治疗的儿童的平均全身总暴露量（102.4 μg h ml⁻¹）。总之，在接受含大剂量白消安方案治疗的儿童中，血浆药物浓度达到临床可实现水平时，白消安在神经母细胞瘤和髓母细胞瘤异种移植物中显示出显著的抗肿瘤活性。
