A simplified assay for measurement of cytosine arabinoside incorporation into DNA in Ara-C-sensitive and-resistant leukemic cells

1990 ◽  
Vol 27 (2) ◽  
pp. 151-156 ◽  
Author(s):  
Louisa P. Colly ◽  
Dick J. Richel ◽  
Willy Arentsen-Honders ◽  
Ingrid W. J. Starrenburg ◽  
Peter M. Edelbroek ◽  
...  
Keyword(s):  
Cytosine Arabinoside ◽  
Leukemic Cells

scholarly journals Anti-CD33 monoclonal antibody and etoposide/cytosine arabinoside combinations for the ex vivo purification of bone marrow in acute nonlymphocytic leukemia

Blood ◽  
1991 ◽  
Vol 77 (2) ◽  
pp. 355-362 ◽  
Author(s):  
PJ Stiff ◽  
WC Schulz ◽  
M Bishop ◽  
L Marks
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Cytosine Arabinoside ◽  
Ex Vivo ◽  
Leukemic Cells ◽  
Acute Nonlymphocytic Leukemia ◽  
Drug Concentrations ◽  
Pharmacologic Agents

Abstract Pharmacologic and immunologic methods of ex-vivo bone marrow (BM) purging for acute nonlymphocytic leukemia (ANLL) were combined to augment the effect of either method alone. Etoposide (VP16; 20 to 30 micrograms/mL) with or without cytosine arabinoside (Ara C; 10 mg/mL) was used in tandem with the anti-CD33 monoclonal antibody (MoAb), MY9, chosen because CD33 is found on the stem cell pool in the majority of patients with ANLL. The agents were tested singly or sequentially, with a 1-hour incubation of the drugs preceding complement-mediated lysis using MY9. VP16 combined with Ara C killed up to 3.9 +/- 0.3 and 5.11 +/- 0.4 logs of the human ANLL cell lines HL60 and K562 at drug concentrations that killed only 1.2 +/- 0.1 logs of normal committed granulocyte/macrophage stem cells (CFU-GM). Adding a single exposure of the MY9 and complement (C′) to the drug-treated cells, greater than 5.4 logs of HL60 were killed. Similar to other pharmacologic agents, no differential kill for clonagenic leukemic cells (colony-forming unit- leukemia; CFU-L) from patients with ANLL was seen for drug only treated blasts versus normal CFU-granulocyte-macrophage (CFU-GM), with less than 1 log CFU-L kill at drug concentrations that spared 1 log of CFU- GM. Similarly, only 1.1 +/- 0.3 logs of ANLL CFU-L were eliminated using MY9 and C′. However, with the sequential VP16/Ara C----MY9 + C′ treatment, synergy was demonstrated and 2.6 +/- 0.3 logs of CFU-L were eliminated. Because CD33 is also found on the normal CFU-GM pool, two- stage long-term BM cultures were performed to determine pluripotent stem cell elimination by the drug/MoAb purging combination. No difference of CFU-GM or BFU-E production at 4 to 6 weeks of culture for VP16/Ara C, MY9 + C′, or VP16/AraC----My9 + C′ treated cells was seen compared with untreated controls indicating sparing of early progenitor cells. Sequential ex vivo treatment of human ANLL CFU-L with VP16/Ara C followed by complement-mediated lysis using MY9 synergistically kills CFU-L while sparing early normal hematopoietic progenitor cells, and thus may be a more effective way to purge BM than either alone.

Protection of leukemic cells by deoxycytidine: in vitro measures of protection against cytosine arabinoside

1998 ◽  
Vol 22 (5) ◽  
pp. 421-427
Author(s):  
Justin D Cohen ◽  
David J Strock ◽  
Elizabeth A LaGuardia ◽  
Zhi Mao ◽  
Joanne E Teik
Keyword(s):  
Cytosine Arabinoside ◽  
Leukemic Cells

High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study.

1987 ◽  
Vol 5 (1) ◽  
pp. 75-82 ◽  
Author(s):  
H D Preisler ◽  
A Raza ◽  
M Barcos ◽  
N Azarnia ◽  
R Larson ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Cytosine Arabinoside ◽  
Cell Mass ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Poor Performance Status ◽  
High Dose ◽  
Acute Nonlymphocytic Leukemia ◽  
Anthracycline Antibiotic ◽  
Days Of Therapy

Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.

scholarly journals Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 817-825 ◽  
Author(s):  
Shiuan Wey ◽  
Biquan Luo ◽  
Chun-Chih Tseng ◽  
Min Ni ◽  
Hui Zhou ◽  
...  
Keyword(s):  
Cytosine Arabinoside ◽  
Childhood Leukemia ◽  
Leukemia Cell ◽  
Conditional Knockout ◽  
Leukemic Cells ◽  
Stem Cell Population ◽  
Oncogenic Signaling ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Knockout Mouse Model

Abstract Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through regulation of oncogenic PI3K/AKT signaling. In agreement with PI3K/AKT as an effector for cytosine arabinoside resistance in acute myeloid leukemia, overexpression of GRP78 renders human leukemic cells more resistant to cytosine arabinoside-induced apoptosis, whereas knockdown of GRP78 sensitizes them. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia, suggest that GRP78 is a novel therapeutic target for leukemia.

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