长春花
紫杉醇
长春碱
长春花生物碱
微管
生物
药理学
DNA损伤
微管聚合
微管蛋白
阿霉素
化学
DNA
生物化学
癌症
细胞生物学
化疗
遗传学
长春新碱
环磷酰胺
作者
Christine C. Zhang,Jinn-Moon Yang,Judy Bash-Babula,Eileen White,Maureen E. Murphy,Arnold J. Levine,William N. Hait
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:1999-08-01
卷期号:59 (15): 3663-70
被引量:39
摘要
Taxanes and Vinca alkaloids are among the most active classes of drugs in the treatment of cancer. Yet, fewer than 50% of previously untreated patients respond, and clinicians have few ways of predicting who will benefit from treatment and who will not. Mutations in p53 occur in more than half of human malignancies and may alter the sensitivity to a variety of anticancer therapies. We have shown that the transcriptional status of p53 determines the sensitivity to antimicrotubule drugs and that this is mediated through the regulation of microtubule-associated protein 4 (MAP4). Expression of MAP4 is transcriptionally repressed by wild-type p53. Increased expression of MAP4, which occurs when p53 is transcriptionally inactive, increases microtubule polymerization, paclitaxel binding, and sensitivity to paclitaxel, a drug that stabilizes polymerized microtubules. In contrast, overexpression of MAP4 decreases microtubule binding and sensitivity to Vinca alkaloids, which promotes microtubule depolymerization. To determine whether induction of endogenous wild-type p53 by DNA-damaging agents alters the expression of MAP4 and changes the sensitivity to antimicrotubule drugs, we assayed cell lines with wild-type or mutant p53 for the expression of MAP4 and drug sensitivity before and after DNA damage. UV irradiation, bleomycin, and doxorubicin increased wild-type p53 expression and decreased MAP4 expression. These changes were associated with decreased sensitivity to paclitaxel and increased sensitivity to vinblastine. These changes in drug sensitivity were no longer observed when p53 and MAP4 returned to baseline levels. Changes in drug sensitivity following DNA-damaging agents were associated with decreased binding of paclitaxel and increased binding of Vinca alkaloids. In contrast, DNA damage did not alter the sensitivity to non-microtubule-active drugs, such as 1-beta-D-arabinofuranosylcytosine and doxorubicin. Changes in drug sensitivity following DNA-damaging drugs were not observed in cells with mutant p53. These studies demonstrate that induction of wild-type p53 by DNA-damaging agents can affect the sensitivity to antimicrotubule drugs through the regulation of MAP4 expression and may have implications for the design of clinical anticancer therapies.
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