Bioavailability of Azacitidine Subcutaneous Versus Intravenous in Patients With the Myelodysplastic Syndromes

Marcucci, Guido; Silverman, Lewis R.; Eller, Mark G.; Lintz, Linda; Beach, C. L.

doi:10.1177/0091270004271947

Cited by 140 publications

(119 citation statements)

References 7 publications

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“…Inhibitory activity was seen within 24 hours of treatment in all human myeloma cell lines tested and was achieved at AZA concentrations well below those safely achievable in vivo with either intravenous or subcutaneous administration schedules. 37 These in vitro observations were consistent with the anti-MM activity that AZA demonstrated in vivo despite only modest inhibition of the 5T33 cell line in vitro. The 5T33 model that we utilized is a systemic model of aggressive MM with the unambiguous end-point of hind limb paralysis.…”

Section: Discussionsupporting

confidence: 78%

The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

Khong

Sharkey²,

Spencer³

2008

Haematologica

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Section: Discussionsupporting

confidence: 78%

The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

Khong

Sharkey²,

Spencer³

2008

Haematologica

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“…This 28-d cycle is repeated for as long as patients show benefit and often continues for many years. The dose of AZA (10 μM) that was required in conjunction with PDGF-AB to generate iMS cells was selected after testing concentrations within the peak plasma concentrations measured in patients (38,39). AZA is incorporated into DNA and RNA (38), and PDGF-AB is both a mitogen and cell survival factor (40)(41)(42).…”

Section: Pdgf-ab/aza-treated Osteocytes Reexpress Pluripotency Factormentioning

confidence: 99%

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

Chandrakanthan

Yeola

Kwan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor–AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

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“…All four patients had measurable plasma concentrations, allowing for comparison with historical s.c. azacitidine PK data. The 80-mg oral azacitidine dose had mean bioavailability of 17% of that of s.c. azacitidine [56,65]. No severe drug-related toxicities were observed, and results from this pilot study led to the development of a phase I study of oral azacitidine.…”

Section: Pilot Study Of Oral Azacitidinementioning

confidence: 92%

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

Cogle

Scott

Boyd³

2015

The Oncologist

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The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by multilineage cytopenias, recurrent cytogenetic abnormalities, and risk of progression to acute myeloid leukemia (AML). AML, which can occur de novo as well as secondary to MDS, is characterized by malignant clones of myeloid lineage in the bone marrow and peripheral blood, with dissemination into tissues. The cytidine nucleoside analog and epigenetic modifier azacitidine is approved in the U.S. for the treatment of all French-American-British subtypes of MDS and in many countries for the treatment of AML with 20%-30% blasts and multilineage dysplasia according to the World Health Organization classification. Benefits of azacitidine treatment of patients with AML with .30% blasts have also been shown in a recent phase III trial. Oral administration of azacitidine may enhance patient convenience, eliminate injection-site reactions, allow for alternative dosing and scheduling, and enable long-term treatment. Phase I studies with oral azacitidine (CC-486) have shown biological activity, clinical responses, and tolerability in patients with MDS and AML. Extended dosing schedules of oral azacitidine (for 14 or 21 days of 28-day cycles) are currently under investigation as frontline therapy in patients with lower risk MDS, as maintenance therapy for patients with AML not eligible for stem cell transplant, and as maintenance therapy for patients with MDS or AML following stem cell transplant. This review presents clinical data supporting the use of injectable azacitidine in MDS and AML and examines the rationale for and results of the clinical development of oral azacitidine.

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Bioavailability of Azacitidine Subcutaneous Versus Intravenous in Patients With the Myelodysplastic Syndromes

Cited by 140 publications

References 7 publications

The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

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