scholarly journals A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1413-1419 ◽  
Author(s):  
ZX Chen ◽  
YQ Xue ◽  
R Zhang ◽  
RF Tao ◽  
XM Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Bone Marrow Cells ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Therapeutic Effects ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

scholarly journals A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1413-1419 ◽  
Author(s):  
ZX Chen ◽  
YQ Xue ◽  
R Zhang ◽  
RF Tao ◽  
XM Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Bone Marrow Cells ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Therapeutic Effects ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

scholarly journals Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells [see comments]

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2175-2181 ◽  
Author(s):  
L Delva ◽  
M Cornic ◽  
N Balitrand ◽  
F Guidez ◽  
JM Miclea ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Induction Therapy ◽  
Binding Protein ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Differentiation Induction ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with “virgin”-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.

scholarly journals Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 567-572 ◽  
Author(s):  
ME Huang ◽  
YC Ye ◽  
SR Chen ◽  
JR Chai ◽  
JX Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Nitroblue Tetrazolium Reduction ◽  
Morphological Maturation

Twenty-four patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (45 to 100 mg/m2/day). Of these, eight cases had been either nonresponsive or resistant to previous chemotherapy; the other 16 cases were previously untreated. All patients attained complete remission without developing bone marrow hypoplasia. Bone marrow suspension cultures were studied in 15 of the 24 patients. Fourteen of these patients had morphological maturation in response to the retinoic acid (1 mumol/L). Chloroacetate esterase and alpha-naphthyl acetate esterase staining as well as electronmicroscopic examination confirmed that retinoic acid-induced cells differentiated to granulocytes with increased functional maturation (as measured by nitroblue tetrazolium reduction, NBT). The single nonresponder to retinoic acid in vitro was resistant to treatment with retinoic acid but attained complete remission after addition of low-dose cytosine arabinoside (ara-C). During the course of therapy, none of the patients showed any abnormalities in the coagulation parameters we measured, suggesting an absence of any subclinical disseminated intravascular coagulation. The only side effects consisted of mild dryness of the lips and skin, with occasional headaches and digestive symptoms. Eight patients have relapsed after 2 to 5 months of complete remission. The others remain in complete remission at 1+ to 11+ months and are still being followed up. We conclude that all-trans retinoic acid is an effective inducer for attaining complete remission in APL.

All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biologic response relationship.

1995 ◽  
Vol 13 (10) ◽  
pp. 2517-2523 ◽  
Author(s):  
A Agadir ◽  
M Cornic ◽  
P Lefebvre ◽  
B Gourmel ◽  
M Jérôme ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Group A ◽  
In Vitro Response

PURPOSE This study investigated the in vitro pharmacologic behavior and disposition kinetics of all-trans retinoic acid (ATRA) in acute myeloid leukemic (AML) cells, their sensitivity to its differentiating effect, and the in vivo response of acute promyelocytic leukemia (APL) patients after therapy. PATIENTS AND METHODS Fresh leukemic cells from 14 AML patients (nine APL and five non-APL), were incubated in suspension culture in the absence or presence of 10(-6) mol/L ATRA. Intracellular ATRA concentration and ATRA metabolism was determined by high-performance liquid chromatography (HPLC). RESULTS Immediate uptake is observed with maximal intracellular levels (Cmax) achieved after 24 hours of incubation. At this time, ATRA levels were variable, ranging from 20 to 230 pmol/10(6) cells (median, 100 pmol/10(6) cells). Comparison of ATRA intracellular levels with the in vitro response of patients' cell samples as measured by the percentage of nitro blue tetrazolium (NBT)-positive cells after a 3-day incubation period allowed us to discriminate a group of APL patients (n = 6) with high Cmax (group A; median, 200 pmol/10(6) cells) and maximal differentiation at day 3 (median, 80%), and a group of patients (n = 8, three APL and five non-APL) with low Cmax (group B; median, 35 pmol/10(6) cells) and poor in vitro response (median, 40%; APL cases only). Interestingly, all APL patients, except one included in group A (rapid in vitro ATRA uptakers), achieved a complete remission. CONCLUSION These findings suggest that intracellular ATRA concentrations are determinant for ATRA response and should be taken into account when monitoring the efficacy of ATRA differentiation therapeutic trials in malignant disorders.

scholarly journals Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells [see comments]

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2175-2181 ◽  
Author(s):  
L Delva ◽  
M Cornic ◽  
N Balitrand ◽  
F Guidez ◽  
JM Miclea ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Induction Therapy ◽  
Binding Protein ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Differentiation Induction ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with “virgin”-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.

Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 567-572 ◽  
Author(s):  
ME Huang ◽  
YC Ye ◽  
SR Chen ◽  
JR Chai ◽  
JX Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Nitroblue Tetrazolium Reduction ◽  
Morphological Maturation

Abstract Twenty-four patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (45 to 100 mg/m2/day). Of these, eight cases had been either nonresponsive or resistant to previous chemotherapy; the other 16 cases were previously untreated. All patients attained complete remission without developing bone marrow hypoplasia. Bone marrow suspension cultures were studied in 15 of the 24 patients. Fourteen of these patients had morphological maturation in response to the retinoic acid (1 mumol/L). Chloroacetate esterase and alpha-naphthyl acetate esterase staining as well as electronmicroscopic examination confirmed that retinoic acid-induced cells differentiated to granulocytes with increased functional maturation (as measured by nitroblue tetrazolium reduction, NBT). The single nonresponder to retinoic acid in vitro was resistant to treatment with retinoic acid but attained complete remission after addition of low-dose cytosine arabinoside (ara-C). During the course of therapy, none of the patients showed any abnormalities in the coagulation parameters we measured, suggesting an absence of any subclinical disseminated intravascular coagulation. The only side effects consisted of mild dryness of the lips and skin, with occasional headaches and digestive symptoms. Eight patients have relapsed after 2 to 5 months of complete remission. The others remain in complete remission at 1+ to 11+ months and are still being followed up. We conclude that all-trans retinoic acid is an effective inducer for attaining complete remission in APL.

In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2862-2864 ◽  
Author(s):  
Bruno Cassinat ◽  
Sylvie Chevret ◽  
Fabien Zassadowski ◽  
Nicole Balitrand ◽  
Isabelle Guillemot ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Event Free Survival ◽  
Free Survival ◽  
Acid Sensitivity ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Acute promyelocytic leukemia (APL) blasts possess a unique sensitivity to the differentiating effects of all-transretinoic acid (ATRA). Multicenter trials confirm that the combination of differentiation and cytotoxic therapy prolongs survival in APL patients. However relapses still occur, and exquisite adaptation of therapy to prognostic factors is essential to aim at a possible cure of the disease. A heterogeneity was previously reported in the differentiation rate of patients' APL blasts, and it was postulated that this may reflect the in vivo heterogeneous outcome. In this study, it is demonstrated that patients of the APL93 trial whose leukemic cells achieved optimal differentiation with ATRA in vitro at diagnosis had a significantly improved event-free survival (P = .01) and lower relapse rate (P = .04). This analysis highlights the importance of the differentiation step in APL therapy and justifies ongoing studies aimed at identifying novel RA-differentiation enhancers.

scholarly journals Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (29) ◽  
pp. 46028-46041 ◽  
Author(s):  
Farzaneh Atashrazm ◽  
Ray M. Lowenthal ◽  
Joanne L. Dickinson ◽  
Adele F. Holloway ◽  
Gregory M. Woods
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Therapeutic Potential ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid

Blood ◽  
1995 ◽  
Vol 86 (4) ◽  
pp. 1540-1547 ◽  
Author(s):  
RE Gallagher ◽  
YP Li ◽  
S Rao ◽  
E Paietta ◽  
J Andersen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
High Sensitivity ◽  
Promyelocytic Leukemia ◽  
Reaction Products ◽  
Reading Frame ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Fusion Site

Of 113 acute promyelocytic leukemia cases documented to have diagnostic PML-RAR alpha hybrid mRNA, 10 cases (8.8%) had fusion sites in PML gene exon 6 (V-forms) rather than in the two common hybrid mRNA configurations resulting from breaksites in either PML gene intron 6 (L- forms) or intron 3 (S-forms). In 4 V-form cases, a common break/fusion site was discovered at PML gene nucleotide (nt) 1685, abutting a 3′ cryptic splice donor sequence. The fusion site was proximal to the common site in 1 case and more distal in 5 cases. The open reading frame encoding a PML-RAR alpha gene was consistently preserved, either by an in-frame fusion site or by the insertion of 3 to 127 unidentified nts. In 2 V-form cases, hybridization analysis of the reverse transcriptase-polymerase chain reaction products with a PML-RAR alpha juction probe was required for discrimination from L-form cases. Two V- form subgroups were defined by in vitro sensitivity to all-trans retinoic acid (tRA)-induced differentiation: 4 of 4 cases tested with fusion sites at or 5′ to nt 1685 (subgroup E6S) had reduced sensitivity (EC50 &gt; or = 10(-7) mol/L), whereas 4 of 4 cases with fusion sites at or 3′ to nt 1709 (subgroup E6L) had high sensitivity (EC50 &lt; 10(-8) mol/L) indistinguishable from that of L-form and S-form cases. These results provide the first link between PML-RAR alpha configuration and tRA sensitivity in vitro and support the importance of subclassifying APL cases according to PML-RAR alpha transcript type.

Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5512-5521 ◽  
Author(s):  
Maaike Luesink ◽  
Jeroen L. A. Pennings ◽  
Willemijn M. Wissink ◽  
Peter C. M. Linssen ◽  
Petra Muus ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Differentiation Therapy ◽  
Chemokine Production ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Pulmonary Infiltration

Abstract In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

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