Development of Drug Resistance in Cultured Clonogenic Leukemic Blast Cells during the Clinical Course of Myeloblastic Leukemia

Asano, Yoshizo; Okamura, S; Shibuya, Takashi; Morioka, Eiji; Hirota, Yasuzou; Niho, Y

doi:10.1159/000226744

Cited by 5 publications

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“…There seem to be three main reasons, apart from our efficient use of anionexchange chromatography, for the relative ease with which we could purify native G-CSF compared with earlier reports from other sources [18,20]. The first reason was that the HTB9 cell line, which had been proved to produce prominent leukemic blast growth activity [1,2,8], was able to produce high day-7 CSF activity (7000-12 000 U/ml) at a very low serum concentration even in our micro-carrier culture system. This meant that the starting material already had a high specific activity.…”

Section: Discussionmentioning

confidence: 99%

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Purification of a granulocyte colony-stimulating factor from the conditioned medium of a subclone of human bladder carcinoma cell line 5637, HTB9

et al. 1990

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A colony-stimulating factor (CSF) has been purified to homogeneity from the conditioned medium (CM) of a subclone, designated HTB9, of human bladder carcinoma cell line 5637. HTB9 cells were successfully cultured on micro-carrier beads at low-serum concentration, and the resulting CM (HTB9-CM) was concentrated by ultrafiltration. Purification procedures consisted of anion-exchange column chromatography, gel-filtration column chromatography, and reverse-phase column chromatography. The finally purified protein possessed a specific activity more than 10(8) U/mg protein for day-7 CFU-GM colony formation and exhibited a single band representing a molecular weight of 17,000 upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biological activity was apparently specific for a neutrophilic granulocyte lineage of human non-phagocytic bone-marrow cells in vitro, and antiserum raised against this purified protein completely inhibited the activity of recombinant granulocyte colony-stimulating factor.

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Section: Discussionmentioning

confidence: 99%

“…A subclone of human bladder cell line 5637 designated HTB9 was previously reported to secrete very powerful leukemic blast growth-promoting activity [1,2,8]. Our previous study revealed that this activity also stimulated the growth of normal bone-marrow progenitor cells in vitro [23].…”

Section: Introductionmentioning

confidence: 99%

Purification of a granulocyte colony-stimulating factor from the conditioned medium of a subclone of human bladder carcinoma cell line 5637, HTB9

et al. 1990

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New synergistic combinations of differentiation inducing agents in the treatment of acute myeloid leukaemia

Hassan

Zyada

Ragab

et al. 1991

Eur J Clin Pharmacol

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Differentiation inducing agents in double and triple combinations can induce differentiation in primary culture of more than 80% of blast cells from some AML patients. In the present study, the interactions between these differentiating agents have been analysed using Berenbaum's general algebraic solution and three new, potentially clinically useful synergistic combinations: have been identified all trans retinoic acid (RA) + hexamethylene bisacetamide (HMBA), cytosine arabinoside (Ara-C) + HMBA and RA + Ara-C + HMBA. A measure of the effectiveness of these combinations was that the doses of Ara-C and HMBA required to induce 50% differentiation were decreased about 10-fold and 5-fold, respectively, in combination with 1 microM RA. The new synergistic combinations are important not only to limit toxicity but also because multiple drug combinations may better overcome the inherent molecular heterogeneity of the differentiation defect in AML patients. They warrant clinical trial in AML patients who are either unsuitable for or are unresponsive to conventional cytotoxic chemotherapy.

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Synergistic interactions between differentiation-inducing agents in inhibiting the proliferation of HL-60 human myeloid leukaemia cells in clonogenic micro assays

Hassan

Veit

Maurer

1991

J Cancer Res Clin Oncol

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All-trans-retinoic acid, hexamethylene bisacetamide and 5-azacytidine are inducers of granulocytic differentiation of HL-60 human myeloid leukaemic cells, which eventually leads to inhibition of cell proliferation. The effect of graded concentrations of all-trans-retinoic acid (RA) (1 nM-1 microM), hexamethylene bisacetamide (HMBA) (0.5-4 mM) and/or 5-azacytidine (5azaC) (1 nM-1 mM), alone and in combination with each other on colony formation and growth of HL-60 cells was studied in agar capillary clonogenic micro assays in order to identify new potential therapeutic regimens for elderly patients with acute myeloid leukaemia. ED90 concentrations, inducing 90% inhibition of colony formation for RA, HMBA and 5azaC, were 128 nM, 2.7 mM and 40 microM, respectively. The drug interactions between these differentiating agents were analysed by Berenbaum's general algebraic solution. The combinations: RA + HMBA, 5azaC + HMBA and RA + 5azaC were significantly synergistic in inhibiting HL-60 colony formation. Their interaction indices were 0.62, 0.83, and 0.97, respectively, at a specific effect level of 15%. The addition of 1 mM HMBA to 100 nM 5azaC- and 1 nM RA-treated cultures significantly increased the colony-formation inhibition from only 2.6% and 7.0% to 46.4%, and 43.1%, respectively. Also, HMBA showed marked synergism with RA and 5azaC in inhibiting colony growth. The interaction indices (I) of HMBA + RA and HMBA + 5azaC were 0.013 and 0.009, respectively, at the same specific level of 15%. Moreover, the triple combination of RA + HMBA + 5azaC showed synergism in inhibiting both the colony formation (I = 0.7) and colony growth (I = 0.4) at the same specific level of 15%. Since RA, HMBA and 5azaC were effective when administered alone in phase I clinical trials of myeloid leukaemic patients, their synergistic combinations could provide shorter and less toxic courses of treatment in elderly myeloid leukaemic patients. I is less than 1, = 1 or greater than 1 in synergistic, additive or antagonistic interactions, respectively.

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Development of Drug Resistance in Cultured Clonogenic Leukemic Blast Cells during the Clinical Course of Myeloblastic Leukemia

Cited by 5 publications

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Purification of a granulocyte colony-stimulating factor from the conditioned medium of a subclone of human bladder carcinoma cell line 5637, HTB9

Purification of a granulocyte colony-stimulating factor from the conditioned medium of a subclone of human bladder carcinoma cell line 5637, HTB9

New synergistic combinations of differentiation inducing agents in the treatment of acute myeloid leukaemia

Synergistic interactions between differentiation-inducing agents in inhibiting the proliferation of HL-60 human myeloid leukaemia cells in clonogenic micro assays

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