Novobiocin in combination with high-dose chemotherapy for the treatment of advanced breast cancer: A phase 2 study
Novobiocin in combination with high-dose chemotherapy for the treatment of advanced breast cancer: A phase 2 study
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DOI：
10.1016/s1083-8791(00)70059-0
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发表时间：
2000-01-01
影响因子：
4.3
通讯作者：
Kennedy, MJ
中科院分区：
文献类型：
--
作者：
Hahm, HA;Armstrong, DK;Kennedy, MJ
我们进行了第一项II期和药理学研究，以评估新生霉素（一种在实验模型中已被证明可增加烷化剂细胞毒性的香豆霉素抗生素）与高剂量环磷酰胺和塞替派联合使用，然后在对化疗敏感的晚期乳腺癌患者中进行自体骨髓支持。其目的是（1）确定无进展生存期（PFS）和总生存期（OS），（2）评价环磷酰胺和塞替派的药代动力学，（3）测量新生霉素逆转体外烷化剂耐药性的能力。41例化疗敏感的晚期乳腺癌患者接受环磷酰胺（4 g/m2）进行外周血干细胞动员（治疗1），随后接受高剂量环磷酰胺（1.5 g/m2/天，持续4天）、塞替派（200 mg/m2/天，持续4天）和新生霉素（4 g/天，口服7天）（治疗2）和自体骨髓支持。中位PFS为10个月（范围：0.2-70.6个月），OS为21.5个月（范围：0.2-70.6个月）。PFS或OS与环磷酰胺、塞替派或4-羟基环磷酰胺的曲线下面积值之间无统计学显著性关系。新生霉素治疗期间获得的患者血浆样品（n = 12）能够在体外集落形成测定中逆转烷化剂耐药性。体外模型系统中的相关实验室研究表明，新生霉素治疗后的患者血浆导致先前临床前实验预测的耐药性逆转幅度。然而，在临床上，新生霉素的这种活性与仅用高剂量烷化剂治疗的历史对照相比并没有转化为PFS或OS的实质性增加。
We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m(2)) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m(2) per day for 4 days), thiotepa (200 mg/m(2) per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.