Ignite Creation Date:
2024-05-06 @ 5:29 PM
Last Modification Date:
2024-10-26 @ 2:30 PM
Study NCT ID:
NCT05326984
Status:
UNKNOWN
Last Update Posted:
2022-04-14
First Post:
2022-02-15
Brief Title:
Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia
Sponsor:
Hospital General de Mexico
Organization:
Hospital General de Mexico
Study Overview
Official Title:
Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia
Status:
UNKNOWN
Status Verified Date:
2022-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
Detailed Description:
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 ABCB1MDR1 multidrug resistance 1 expression and high AMPK expression
The investigators propose if the metformin has any effect on ABCB1MDR1 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
This study pretends to evaluate the effect of the addition of metformin to a standard chemotherapy regimen in the modification of the expression of the ABCB1 and AMPK genes during the remission induction of newly diagnosed adolescents with acute lymphoblastic leukemia
Also to describe the expression levels of ABCB1 and AMPK of healthy adolescents and those diagnosed with acute lymphoblastic leukemia Compare the expression level of those genes at diagnosis and at the end of remission induction and to compare the global and event free survival based on the initial expression of those genes and the use of metformin
The investigators proposed an randomized open clinical trial to compare the modification of the expression of the ABCB1 and AMPK genes in adolescents with newly diagnosed acute lymphoblastic leukemia in patients receiving conventional chemotherapy versus conventional chemotherapy plus metformin 1000 mgm2SC per day during the remission induction phase of the treatment
All patients with new acute lymphoblastic leukemia between 10 and 21 years old are invited to participate with informed consent authorized The exclusion criteria includes patients with previous use of steroids or other chemotherapy and patients with Down syndrome
The investigators pretend to enroll 10 patients for each group After the morphological and cytometry diagnosis confirmation of acute lymphoblastic leukemia the adolescents are invited to participate with informed consent signed by the patients and legally authorized representative
The samples are obtain from mononuclear cells from peripheral blood the total RNA Ribonuceid acid are obtain by TRIzol InvitrogenR Life Technologies The integrity and purity of the nucleic acid are determined by spectrophotometry The RNA is frozen at -80ºC until needed The DNAc complementary desoxyribonucelic acid synthesis is made from 2micrograms of RNA oligonucleotides dNTPs buffer MgCl2 KCl potassium chloride and DTT dithiothreitol are added to obtain a final volume of 20micrograms The mix is incubated at 37ºC for 2 minutes and 1microliter of inverse transcriptase and incubated for 50 minutes at 37ºC The qRT-PCR quantitative Real time-plymerase chain reaction of the genes is made using the genic expression assay TaqMan The expression levels are calculated using the 2-delta-delta-Ct method
The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60 mgm2SCD The proper remission induction phase consist in prednisone 60 mgm2 daily from day 0 to 28 Vincristine 15mgm2 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 After the remission induction scheme bone marrow aspiration is performed to evaluate morphology if less of 5 of lymphoid blast are reported the patients continue with consolidation phase with high dose methotrexate and 6 mercaptopurine and after that the maintenance phase until the end of the protocol
The intermediate variables are the peripheral blast count on day 0 morphology examination of bone marrow on days 14 and at the end of induction and end of induction MRD minimal residual disease
Metformin will be administered to the experimental group by randomization at a dose of 1000mgm2 per day with maximum dose of 850mg three times a day from day -7 to the end of the remission induction period The procurement of the peripheral blood samples for determination of the expression od the genes ABCB1 and AMPK will be made on day -7 and at the end of the remission induction Follow up of the patient will be done to calculate the global and event free survival
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 ABCB1MDR1 multidrug resistance 1 expression and high AMPK expression
The investigators propose if the metformin has any effect on ABCB1MDR1 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
This study pretends to evaluate the effect of the addition of metformin to a standard chemotherapy regimen in the modification of the expression of the ABCB1 and AMPK genes during the remission induction of newly diagnosed adolescents with acute lymphoblastic leukemia
Also to describe the expression levels of ABCB1 and AMPK of healthy adolescents and those diagnosed with acute lymphoblastic leukemia Compare the expression level of those genes at diagnosis and at the end of remission induction and to compare the global and event free survival based on the initial expression of those genes and the use of metformin
The investigators proposed an randomized open clinical trial to compare the modification of the expression of the ABCB1 and AMPK genes in adolescents with newly diagnosed acute lymphoblastic leukemia in patients receiving conventional chemotherapy versus conventional chemotherapy plus metformin 1000 mgm2SC per day during the remission induction phase of the treatment
All patients with new acute lymphoblastic leukemia between 10 and 21 years old are invited to participate with informed consent authorized The exclusion criteria includes patients with previous use of steroids or other chemotherapy and patients with Down syndrome
The investigators pretend to enroll 10 patients for each group After the morphological and cytometry diagnosis confirmation of acute lymphoblastic leukemia the adolescents are invited to participate with informed consent signed by the patients and legally authorized representative
The samples are obtain from mononuclear cells from peripheral blood the total RNA Ribonuceid acid are obtain by TRIzol InvitrogenR Life Technologies The integrity and purity of the nucleic acid are determined by spectrophotometry The RNA is frozen at -80ºC until needed The DNAc complementary desoxyribonucelic acid synthesis is made from 2micrograms of RNA oligonucleotides dNTPs buffer MgCl2 KCl potassium chloride and DTT dithiothreitol are added to obtain a final volume of 20micrograms The mix is incubated at 37ºC for 2 minutes and 1microliter of inverse transcriptase and incubated for 50 minutes at 37ºC The qRT-PCR quantitative Real time-plymerase chain reaction of the genes is made using the genic expression assay TaqMan The expression levels are calculated using the 2-delta-delta-Ct method
The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60 mgm2SCD The proper remission induction phase consist in prednisone 60 mgm2 daily from day 0 to 28 Vincristine 15mgm2 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 After the remission induction scheme bone marrow aspiration is performed to evaluate morphology if less of 5 of lymphoid blast are reported the patients continue with consolidation phase with high dose methotrexate and 6 mercaptopurine and after that the maintenance phase until the end of the protocol
The intermediate variables are the peripheral blast count on day 0 morphology examination of bone marrow on days 14 and at the end of induction and end of induction MRD minimal residual disease
Metformin will be administered to the experimental group by randomization at a dose of 1000mgm2 per day with maximum dose of 850mg three times a day from day -7 to the end of the remission induction period The procurement of the peripheral blood samples for determination of the expression od the genes ABCB1 and AMPK will be made on day -7 and at the end of the remission induction Follow up of the patient will be done to calculate the global and event free survival
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None