MOLECULAR DETERMINANTS OF CHEMOTHERAPY RESISTANCE
MOLECULAR DETERMINANTS OF CHEMOTHERAPY RESISTANCE
批准号:
6237225
负责人:
ALBERT B DEISSEROTH
金额:
$15.12万
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-05-27 至 1998-03-31
中文摘要
虽然诱导联合化疗方案用于急性
骨髓性白血病(AML)与完全
诱导缓解频率为75%,仅占总数的20%左右
每年有许多AML患者治愈了他们的疾病,
常规剂量联合化疗。AML的具有
平衡易位[倒位l 6和t(8;21)]已经被
治愈率超过60% t(15; 17)是
与中间预后相关。预后不良
亚群与5号染色体的单体性有关,
7、t(9;22)和8号三体。这些病人几乎都不能
经常规剂量联合化疗治愈。的基因
在良好预后亚组的易位断点处
包括t(15;17)中的MIL RAR α和CBF的嵌合体,
t(8;21)和逆16子集中的α和β,
分别这些子集,尤其是反转16,属于
所有肿瘤状态中最敏感的疾病。单个
阿糖胞苷(Ara-C)可以治愈这种患者
亚群,而不根除正常的骨髓细胞。这
这表明这些倒位16的AML细胞更容易受到
化疗诱导的细胞死亡比正常细胞,而
预后不良的亚群是所有抗肿瘤药物中最耐药的。
肿瘤,通常甚至在超致命水平的
化疗
该项目旨在确定AML中的分子变化
对化疗反应起主导作用的细胞
和生存,并将这些信息应用于发展
治疗这种疾病的新方法这个项目是
(一)在前几个供资年度的工作情况
赠款揭示了水平和功能状态的变化,
生长因子诱导途径中的蛋白质(Rb、p53和WAF-1),
1)这预示着对治疗的反应降低,
(2)WAF-1被P53激活抑制增殖
在AML细胞中,与化疗耐药性有关
细胞遗传学改变的组合
AML患者细胞中的分子变化定义了一种
一组标志物,不仅可用于预测敏感性,
或对治疗的抵抗,但也要了解的机制,
(4)在突变点的基因的同一性,
大多数平衡易位已被确定;和
(5)基因改造可用于开发治疗
基于逆转这些遗传变化的干预措施,
AML细胞,从而抑制AML的肿瘤表型,
急性髓细胞白血病细胞或增加其对化疗的敏感性。对
基于这些发现,我们建议使用治疗
结果数据和遗传变化的分子分析,
缓解者和非缓解者,以确定AML中的变化
细胞在产生高水平和低水平的
对化疗的敏感性低。我们亦会研究如何利用
分子和遗传学方法修饰AML细胞,
抑制耐药表型作为治疗的主要手段。
这些信息的最终应用是使用这些
替代反应标志物,以将患者分配到
适当的治疗。
英文摘要
Although induction combination chemotherapy regimens for acute
myelogenous leukemia (AML) are associated with a complete
remission induction frequency of 75 %, only about 20% of the total
number of AML patients per year are cured of their disease with
conventional dose combination chemotherapy alone. AML with
balanced translocations [inversion l6 and t(8;21)] have been
associated with cures in excess of 60%. The t(15; 17) has been
associated with an intermediate prognosis. The poor prognosis
subsets have been associated with monosomies of chromosomes 5 and
7, t(9;22), and trisomy 8. Almost none of these patients can be
cured with conventional dose combination chemotherapy. The genes
at the translocation breakpoints in the good prognosis subsets
include the MIL RARalpha in t(15;17), and the chimeras of CBF
alpha and beta in the t(8;21) and the inversion 16 subsets,
respectively. These subsets, especially inversion 16, are among
the most sensitive diseases of all the neoplastic states. A single
drug, cytosine arabinoside (Ara-C), can cure patients with this
subset, while not eradicating the normal myeloid cells. This
suggests that these inversion 16 AML cells are more vulnerable to
chemotherapy-induced cell death than are normal cells, whereas the
poor prognosis subsets are among the most resistant of all of the
neoplasms, often surviving even super lethal levels of
chemotherapy.
This project is designed to identify the molecular changes in AML
cells which exert a dominant effect on response to chemotherapy
and on survival, and to apply that information to the development
of novel approaches to therapy of this disease. This project is
based on the following data: (I) Work in prior funding years of
the grant revealed changes in the levels and functional states of
proteins in the growth factor induction pathway (Rb, p53 and WAF-
1) which are predictive of decreased response to therapy and
survival; (2) WAF-1 is activated by P53 suppresses proliferation
in AML cells, and is associated with resistance to chemotherapy
induced apoptosis; (3) The combination of the cytogenetic changes
and the molecular changes in the cells of AML patients define a
set of markers which can be used to not only predict sensitivity
or resistance to therapy but also to understand the mechanisms of
this resistance; (4) The identity of genes at the breakpoints of
the majority of balanced translocations have been identified; and
(5) Genetic modification can be used to develop therapeutic
interventions based on the reversal of these genetic changes in
the AML cell so as to either suppress the neoplastic phenotype of
the AML cell or to increase their sensitivity to chemotherapy. On
the basis of these findings, we have proposed to use therapy
outcome data and molecular analysis of genetic changes in
responders and nonresponders to identify the changes within AML
cells that are exerting a dominant effect in generating a high and
low sensitivity to chemotherapy. We will also study ways of using
molecular and genetic methods to modify AML cells so as to
suppress the resistance phenotype as a primary means of therapy.
The ultimate application of this information is to use these
surrogate markers of response to allocate patients to the most
appropriate therapy.
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