Download Bringing blood to life Extending the scope of FTIs

Bringing blood to life
Since ancient times, the heart and blood
have been inextricably linked as fundamental elements to the process of life.
William Harvey was the first to provide a
plausible mechanism for blood circulation
when in 1628 he defined the circulatory
system to comprise a cardiac pump, intact
vascular system, and recirculating blood.
Harvey believed that blood was the fountain
of life, the first (tissue) to live, and the last
to die. His thesis has been supported in part
by modern evidence that murine embryos
mutant for genes necessary for blood, endothelial, and/or cardiac development who fail
to establish or maintain circulation perish in
utero. Harvey never articulated when he
believed the blood comes to “life” (circulation commences) during mammalian
development. Emergence of primitive erythroblasts (PEs) and nascent endothelial cells
on embryonic day (E) 7.0 in the murine
yolk sac may herald the beginnings of a
circulatory system. But beating of the developing heart tube and linkage of the yolk sac
and embryonic vascular systems on E8.25 is
identified by some as evidence for the onset
of systemic blood flow. But is blood flow
equivalent to circulation? When does circulation (as defined by Harvey) begin in the
murine embryo?
McGrath and colleagues (page 1669)
provide compelling evidence that circulation
is established in a graded series of maturational steps. Using simple tools and clever
intuition, they examined murine embryos
from E8.0 to E10.5 to determine the steady
state density of PEs in the embryo proper
and the distribution of PEs in the developing embryonic vessels. They report that
the first PEs enter embryonic vessels at the
4 somite pair (sp) stage of development
(E8.25) but that complete equilibration of
PEs in the circulation is not accomplished
until 35 sp (E10.5). What takes so long?
The authors suggest that the process of
cardiac maturation and/or vascular
BLOOD, 1 MARCH 2003 䡠 VOLUME 101, NUMBER 5
remodeling may regulate the dispersal of
PEs throughout the vasculature. William
Harvey would be intrigued.
—Mervin C. Yoder Jr
Indiana University School of Medicine
Extending the scope
of FTIs
Advances in molecular biology and the understanding of signal transduction are allowing us to identify novel targets for the
development of drugs for hematologic malignancies. One such potential target is farnesyl transferase, the enzyme responsible
for the prenylation of proteins. Prenylation,
the addition of a 15-carbon unsaturated
polymer derived from the lipid pathway (a
farnesyl group) appears to be important in
posttranslational modification of several proteins critical to cell signaling, proliferation,
and differentiation. Farnesyl transferase inhibitors (FTIs) have been developed to obstruct this process.
FTIs have demonstrated anticancer activity as single agents and in combination
with standard cytotoxic chemotherapy in
solid tumors. In the first clinical trial of an
FTI in the hematologic malignancies, Karp
et al (Blood. 2001;97:3361-3369) demonstrated both efficacy and tolerability of FTI
R115777 (Zarnestra) in patients with acute
leukemias. In this issue Cortes and colleagues (page 1692) report their encouraging results of a clinical trial of this agent
in patients with a variety of hematologic
malignancies: CML, myelofibrosis, and multiple myeloma.
Patients were treated at a dose of 600
mg orally twice a day for 4 weeks every 6
weeks. Responses were seen in 7 of 22 patients with CML, 4 of 8 patients with myelofibrosis, and only 1 of 10 patients with
myeloma. This dosing schedule required
dose interruptions and/or reductions in 58%
of the patients. Alternate schedules or doses
might further enhance the efficacy, by
allowing prolonged administration if toxicity
is decreased.
The authors also report their correlation
of response with baseline VEGF levels, as
well as with changes in VEGF concentrations with therapy, a finding that they wish
to pursue in further studies. Despite uncertainty about the true target of FTIs, this
agent has promising activity in a variety of
hematologic malignancies, and further
studies are warranted.
—Selina M. Luger
University of Pennsylvania Cancer Center
Closing the gap for
detection of residual
posttransplantation
leukemia?
The detection of minimal residual disease
(MRD) after allogeneic hematopoietic stem
cell transplantation (HSCT) by molecular
methods has become an important diagnostic tool for clinical decision-making with
regard to posttransplantation immunomodulatory measures, such as the withdrawal of
immunosuppression or adoptive infusions of
donor lymphocytes. The high efficacy of
early interventions directed against residual
molecular and cytogenetic disease after allogeneic HSCT is best documented for imminent relapses of chronic myelogenous
leukemia as demonstrated by the induction
of complete and durable cytogenetic, as well
as molecular, responses in patients with residual cells bearing the bcr-abl gene rearrangement and its chimeric transcripts.
Indeed, the success of adoptive cellular
immunotherapy of MRD after allogeneic
HSCT currently represents some of the most
convincing clinical evidence supporting the
concept of cellular immunotherapy of
human cancer.
The Wilms tumor suppressor gene (WT1)
encodes a zinc-finger transcriptional factor
that can modulate the expression of several
genes coding for growth factors and their
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