长春瑞滨
长春花生物碱
阿霉素
微管聚合
乳腺癌
长春花
医学
化疗
癌症研究
药理学
癌症
紫杉醇
肿瘤科
内科学
微管
生物
微管蛋白
环磷酰胺
细胞生物学
顺铂
长春新碱
作者
Judy Bash-Babula,Deborah Toppmeyer,Marie Labassi,Janice Reidy,Michelle Orlick,Rachelle Senzon,Elizabeth Alli,Thomas Kearney,David A. August,Weichung J. Shih,Jin Ming Yang,William N. Hait
出处
期刊:PubMed
日期:2002-05-01
卷期号:8 (5): 1057-64
被引量:5
摘要
Few molecular determinants of sensitivity to cancer chemotherapy exist. In experimental systems, p53 regulates the sensitivity to antimicrotubule drugs through its effect on microtubule-associated protein 4 (MAP4). MAP4 is the major microtubule-associated protein in nonneuronal tissues and promotes microtubule polymerization. We reported that wild-type p53 induction by doxorubicin in C127 breast cancer cells repressed MAP4, decreased microtubule polymerization, and increased Vinca alkaloid sensitivity. The goals of this Phase I/pilot clinical trial were to determine: (a) the safety of delivering a DNA-damaging agent (doxorubicin) followed in sequence by treatment with an antimicrotubule drug (vinorelbine); and (b) the feasibility of detecting activation of p53 and repression of MAP4 in patients' tissues.Peripheral blood mononuclear cells (PBMNCs) and tumor were obtained from 16 women with locally advanced (stage IIIb) or metastatic (stage IV) breast cancer before doxorubicin treatment and immediately before treatment with vinorelbine 24 or 48 h later.After doxorubicin treatment, p53 increased in 12 of 14 PBMNC and 4 of 10 tumor samples. Changes in MAP4 were variable; however, in samples in which p53 was induced, MAP4 decreased in 7 of 12 PBMNC and 3 of 4 breast cancer specimens. Immunohistochemistry confirmed lower MAP4 expression in tumor cells after doxorubicin treatment. Seven of 16 patients had a partial response, and treatment was well tolerated.These data demonstrate the ability to detect the activation of p53 and the repression of MAP4 in normal and malignant tissues in patients treated with a DNA-damaging agent, and that an antimicrotubule drug can be administered safely at a time when cells may be more sensitive to treatment.
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