Differentiation induction in myelodysplasia and acute myeloid leukaemia: Use of synergistic drug combinations

Francis, G. E.; Mufti, Ghulam J.; Knowles, Sue; Berney, J. J.; Guimarães, José E.; Secker-Walker, LM; Hamblin, Terry J.

doi:10.1016/0145-2126(87)90115-9

Cited by 26 publications

(9 citation statements)

References 18 publications

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“…Retinoic acid showed a striking advantage over aggressive cytotoxic chemotherapy for those APL patients; instead of destroying leukemic cells and causing the release of procoagulant factors from the azurophilic granules into the circulation which usually results in disseminated intravascular coagulopathy (DIC), retinoic acid induced leukemic cell differentiation in APL patients and thus avoided any release of such coagulant factors during therapy (Meng-er et al, 1988). Recently, Francis et al reported AML and MDS patients, who failed to respond to single agent differentiation therapy, showed clinical response after treatment with retinoic acid in combination with 6-thioguanine (Francis et al, 1987) suggesting that such combination may be superior to single agent differentiation therapy. The highly effective results of the present study justify a clinical trial of the triple combination of retinoic acid + low dose cytosine arabinoside + hexamethylene bisacetamide for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.…”

Section: %mentioning

confidence: 97%

Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human aml blasts in primary culture

Hassan¹,

Rees²

1989

Hematological Oncology

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Differentiation induction therapy provides an alternative therapeutic approach for patients with acute myeloid leukemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + low concentration of cytosine arabinoside (Ara-C) + hexamethylene bisacetamide (HMBA) on differentiation of blasts from 24 AML patients was studied. Non-adherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells per ml in 24-well tissue culture plates containing RPMI 1640 culture medium with 20 per cent fetal calf serum and 10 per cent 5637-conditioned medium and incubated with 10(-6) M retinoic acid, 10(-6) M cytosine arabinoside and/or 2 mM hexamethylene bisacetamide for six days at 37 degrees C in a humidified incubator under 5 per cent CO2. Morphological, cytochemical and functional differentiation into mature cells were induced in blasts from 22 out of the 24 AML patients following exposure to the triple combination of 10(-6) M RA + 10(-6)M Ara-C + 2 mM HMBA in primary culture. These effective results justify a clinical trial of such triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

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Section: %mentioning

confidence: 97%

Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human aml blasts in primary culture

Hassan¹,

Rees²

1989

Hematological Oncology

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“…While early events anteceding precommit ment regulate growth arrest, late events subsequent to precommitment regulate the choice of a specific differentiation lineage [20], The results of several preliminary re ports showed an excellent response to RA retinoic acid when given alone, only in APL patients [21]. Recently, Francis et al [22] reported that 7 AML and MDS pa tients, who failed to respond to single agent differentiation therapy, showed clinical response after treatment with RA + DNA synthesis inhibitor, suggesting that such combination may be superior to single-agent differentiation therapy. The highly effective results of the present study justify a clinical trial of the triple combination: RA + low-dose Ara-C + DMF for AML patients who are either unsuitable for or unresponsive to conven tional cytotoxic chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Triple Combination of Retinoic Acid, Low Concentration of Cytarabine and Dimethylformamide Induces Differentiation of Human Acute Myeloid Leukaemic Blasts

Hassan¹,

Rees²

1990

Chemotherapy

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Differentiation induction therapy provides an alternative for treatment of patients with acute myeloid leukaemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + low concentration of cytarabine (Ara-C) + dimethylformamide (DMF) on the differentiation of blasts from 24 AML patients was studied. Nonadherent mononuclear cells were cultured at a concentration of 5 x 105 cells/ml in 24-well tissue culture plates containing RPMI 1640 culture medium with 20% fetal calf serum, 10% autologous serum and 10% 5637-conditioned medium and incubated with 10^––⁶M RA, 10^––6M Ara-C and/or 100 mM DMF alone and in combination with each other for 6 days in primary culture at 37°C in a humidified incubator under 5% CO₂. The triple combination of 10^––6 M RA+ 10^––6M Ara-C + 100 mMDMF induced 90% of blasts from 22 out of 24 AML patients to differentiate. These highly effective results justify a clinical trial of this triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

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“…Since some leukemic cells cannot be induced to terminal di¡erentiation or apoptosis, combined therapy with di¡erentiation inducer and cytotoxic antileukemic drugs has been proposed in experimental and clinical studies [39][40][41]. In several studies, successful results have been described since the early 1990s in patients with APL by using retinoic acid as a di¡erentiation inducer and intensive chemotherapy [41].…”

Section: Effec T Of C Om B Ined H D M P and C Ytotoxic C H Em Oth Er mentioning

confidence: 99%

A Novel Approach to Treatment With High-Dose Steroid as a Differentiation Inducer in Children With Acute Myeloblastic Leukemia

Hiçsönmez¹

2000

Pediatric Pathology & Molecular Medicine

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H icÓ so È nmez, M D Hacettepe IÇ hsan Children's Hospital, Ankara, T urkey experimental studies have demonstrated that certain steroid hormones can induce di¡erentia-Several tion of mouse myeloid leukemic cells to macrophages and granulocytes. We have shown that high-dose methylprednisolone treatment ( HD M P, 20-30 mg/kg/day ) can induce di¡erentiation of leukemic cells to mature granulocytes in children with di¡erent morpholog ical subtypes of acute myeloblastic leukemia ( FAB AM L M 1, M 2, M 3, M ). In addition, apoptosis can also be induced in vivo and in vitro in A M L blast by HD M P treatment. Short-course ( 3 to 5 days ) HD M P treatment increases the hematopoietic CD34-positive progenitor cells in both bone marrow and peripheral blood in children with AM L. A cceleration of leukocyte and neutrophil recovery has been obtained by the administration of short-course HD M P in chemotherapy-induced neutropenic children with AM L. T he addition of HD M P to antileukemic chemotherapy increased the complete remission rate and prolonged the duration of remission in children with AM L and signi cantly improved the outcome of A M L children who presented with extramedullary in ltration.We sugg est that the possibility of HD M P-induced di¡erentiation and apoptosis should be evaluated in patients with other malignant diseases.

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Differentiation induction in myelodysplasia and acute myeloid leukaemia: Use of synergistic drug combinations

Cited by 26 publications

References 18 publications

Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human aml blasts in primary culture

Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human aml blasts in primary culture

Triple Combination of Retinoic Acid, Low Concentration of Cytarabine and Dimethylformamide Induces Differentiation of Human Acute Myeloid Leukaemic Blasts

A Novel Approach to Treatment With High-Dose Steroid as a Differentiation Inducer in Children With Acute Myeloblastic Leukemia

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