Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 不适用
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Increase of AMPK gene expression
研究概览
简要总结
Acute lymphoblastic leukemia, is the most frequent cancer in children and adolescents. Some genes have been described to produce drug resistance, as ABCB1 probably by lack of activation of AMPK. Some manuscripts have shown that metformin has antitumoral activity, mainly by activation of AMPK.
This is an experimental one center trial, that pretend analyze the effect of metformin at a dose of 1000mgm2 per day, on the expression of the ABCB1 and AMPK genes, when is added to conventional induction remission chemotherapy in newly diagnosed adolescents with acute lymphoblastic leukemia.
详细描述
Acute lymphoblastic leukemia, is the most frequent cancer in children and adolescents. By now, chemotherapy agent combination achieves remission in more than 90% of patients. But, adolescents have an adverse prognosis compared with children.
The multiple drug resistant genes are well known the cause resistance in different cancers, most important of these genes are the ABCB gene family, specially ABCB1. This resistance is also reported in acute lymphoblastic leukemia. Also changes in AMPK (adenosine triphosphate) gene expression is related to antitumor effects within the cell.
Metformin, a biguanide, has demonstrated that decrease the intracellular ATP levels by AMPK activation, and the blockade of the glycoprotein P, product of the ABCB1 gene. Many reports had described the effect of metformin on different cancer types. In adults, the use of metformin has demonstrated to be useful improving the overall and event free survival, related to low ABCB1/MDR1 (multidrug resistance 1) expression and high AMPK expression.
The investigators propose if the metformin has any effect on ABCB1/MDR1 and AMPK during remission induction phase in adolescents with newly diagnosed Acute Lymphoblastic Leukemia.
Hypothesis: If metformin is added to standard chemotherapy during the remission induction in Mexican adolescents with newly diagnosed acute lymphoblastic leukemia, so the mRNA (messenger ribonucleid acid) expression levels of the ABCB1 gene will decrease and the AMPK gene expression will increase at the end of remission induction.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 10 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed adolescents with acute lymphoblastic leukemia by morphology analysis in bine marrow
- •Adolescents between 10 and 21 years old
- •Participants with the informed consent signed by themselves and the parents or legally authorized representative.
排除标准
- •Participants with previous use of any antineoplastic drug
- •Down syndrome patients
研究组 & 干预措施
Interventional group
This group will receive conventional chemotherapy plus metformin 1000mgm2 per day, with maximum dose of 850mg three times a day, from day -7 to the end of the remission induction period.
The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60mgm2SCD. The proper remission induction phase consist in prednisone 60mgm2 daily from day 0 to 28; Vincristine 1.5mgm2 on days 0, 7, 14 and 21; Doxorubicin 25mgm2 on days 0, 7, 21; L-asparaginase 10, 000 Um2 on days 2, 4, 6, 8, 10 and 12. Etoposide 300mgm2 and cytarabine 300mgm2 on days 22, 25 and 29. Intrathecal chemotherapy is administered on days 0, 7, 14 and 21.
干预措施: Metformin (Drug)
结局指标
主要结局
Increase of AMPK gene expression
时间窗: The assessment of AMPK gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33
During the trial AMPK gene expression is measure by rt-PCR in mononuclear cells in peripheral blood, at athe beginning and end of the remission induction.
Decrease of ABCB1 gene expression
时间窗: The assessment of ABCB1 gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33
During the trial ABCB1 gene expression is measure by rt-PCR in mononuclear cells in peripheral blood, at at the beginning of treatment and end of the remission induction
次要结局
- Overall survival(From randomization and initiation of the treatment until the date of death from any cause, assessed up to 2 years)
- Event free survival(From randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed upt to 2 years)
研究者
Daniel Ortiz Morales
Head of pediatric hematology & oncology
Hospital General de Mexico