Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling.
Valerie I. Brown,Junjie Fang,Keith Alcorn,Rosalind Barr,Jenny M. Kim,Robert Wasserman,Stephan A. Grupp +6 more
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It is found that rapamycin inhibited growth of B-precursor acute lymphoblastic leukemia lines in vitro, with evidence of apoptotic cell death, and that one of the growth signals inhibited by this class of drugs in precursor B leukemic cells may be IL-7-mediated.Abstract:
A balance between survival and apoptotic signals regulates B cell development. These signals are tightly regulated by a host of molecules, including IL-7. Abnormal signaling events may lead to neoplastic transformation of progenitor B cells. Signal transduction inhibitors potentially may modulate these abnormal signals. Inhibitors of the mammalian target of rapamycin (mTOR) such as rapamycin have been used as immunosuppressive agents. We hypothesized that rapamycin might demonstrate activity against B-precursor acute lymphoblastic leukemia. We have found that rapamycin inhibited growth of B-precursor acute lymphoblastic leukemia lines in vitro, with evidence of apoptotic cell death. This growth inhibition was reversible by IL-7. One candidate as a signaling intermediate cross-regulated by rapamycin and IL-7 was p70 S6 kinase. Rapamycin also demonstrated in vivo activity in Eμ-ret transgenic mice, which develop pre-B leukemia/lymphoma: Eμ-ret transgenic mice with advanced disease treated daily with rapamycin as a single agent showed a >2-fold increase in length of survival as compared with symptomatic littermates who received vehicle alone. These results suggest that mammalian target of rapamycin inhibitors may be effective agents against leukemia and that one of the growth signals inhibited by this class of drugs in precursor B leukemic cells may be IL-7-mediated.read more
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References
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Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays
TL;DR: A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation and is used to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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Schalm's Veterinary Hematology
TL;DR: Section I - Essential Hematologic Concepts Section II - Hemopoiesis Section III - The Erythrocytes Section IV -Leukocytes - Lymphocytes Section V - Leukocyte - Nonlymphoid Leukocytes Section VI - Hemostasis: Platelets - Platelet Structure and Function.
Journal ArticleDOI
Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease
Marina Cavazzana-Calvo,Hacein-Bey S,Geneviève de Saint Basile,Fabian Gross,Eric Yvon,Patrick Nusbaum,Françoise Selz,Christophe Hue,Stéphanie Certain,Jean-Laurent Casanova,Philippe Bousso,Françoise Le Deist,Alain Fischer +12 more
TL;DR: A gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells, which provided full correction of disease phenotype and clinical benefit.
Journal ArticleDOI
A mammalian protein targeted by G1-arresting rapamycin–receptor complex
Eric J. Brown,Mark W. Albers,Tae Bum Shin,Kazuo ichikawa,Curtis Keith,William S. Lane,Stuart L. Schreiber +6 more
TL;DR: A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.
Journal ArticleDOI
A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency
Salima Hacein-Bey-Abina,Christof von Kalle,Manfred Schmidt,Françoise Le Deist,NM Wulffraat,Elisabeth McIntyre,Isabelle Radford,Jean-Luc Villeval,Christopher Fraser,Marina Cavazzana-Calvo,Alain Fischer +10 more
TL;DR: The sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease has been reported.
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