Albert-Ludwigs-University Medical Center Department
of Hematology/Oncology Hugstetter Str 55, 7800 Freiburg, Germany
Since the late 1940s systemic cancer therapy has focussed on the
development of cytotoxic agents. In recent years, endogenous defense
mechanisms regulated by a group of peptide hormones termed cytokines
and capable of directly or indirectly suppressing and eliminating
cancer cells, are attracting increasing numbers of investigators.
Improved understanding of host biology, immunology, and tumor pathophysiology
raises the possibility of introducing new treatment modalities for
cancer patients: stimulation of host defense mechanisms, including
specific and nonspecific immunological approaches, as well as strategies
aimed directly at altering tumor growth and differentiation by therapeutically
influencing pathophysiological mechanisms. In addition, amelioration
of cancer and cancer treatment-associated morbidity offers new possibilities
of improving the quality of life for many patients, as well as options
for increased dose-intensity regimens, with the potential of achieving
higher remission and cure rates in some patient groups. In this
article I will focus on insights gained into the in vivo biology
of human cytokines, the possible role of cytokines in the pathophysiology
of leukemia and on the experience gained with the use of hematopoietins
in cancer therapy. Hematopoietins belong to the family of cytokines
which are polypeptide hormones secreted by activated cells. Soluble
factors regulating immunity have been postulated and investigated
for many years ( e.g. I, 2). With the advent of modern biochemical
and molecular techniques a much clearer picture has emerged. In
most instances, cytokines provide short range communications between
cells by influencing their survival, selfrenewal, proliferation,
differentiation, and state of activation. These hormone-like agents
are produced by multiple cell types, bind to specific receptors,
and have pleiotropic, overlapping and frequently synergistic or
additive activities. The majority of cytokines have the capacity
of inducing the release of other cytokines in responsive cells making
a dissection of in vivo activities of individual cytokines increasingly
complex. The communication between cells by cytokines could be compared
to a language where cytokines represent the letters of the alphabet
and where individual letters are mostly meaningless while "words",
i.e. multiple cytokines in correct sequence and concentration, provide
the desired information. The cytokine family of genes is not only
involved in regulating cellular interactions in the mature organism
but also play an important role during embryogenesis . Conversely,
another set of developmental genes, the homeobox genes appear to
be important for normal cellular development from progenitor cells
in the adult organism . Upon ligand stimulation of cytokine receptors,
activities of a series of downstream stimulatory and inhibitory
molecules are influenced which, in combination, determine the nature
of the response. Apart from the potential use in cancer therapy,
there is a number of nonneoplastic disorders associated with defects
in hematopoiesis and immunity in which the use of cytokines may
prove to be beneficial. Clinical application of cytokines has to
take into account the physiological mode of action of these agents,
i.e. endocrine, paracrine or autocrine. While in vivo augmentation
of hematopoiesis is easily achieved by systemic administration,
i.e. by endocrine mechanisms, stimulation of specific immunity appears
to require paracrine secretion in most instances. Augmentation of
specific immunity against cancer in man has remained elusive with
cytokines were administered systemically. Remarkable progress, however,
has been achieved in the enhancement of myelopoiesis by cytokines
in clinical syndromes of myelosuppression.
The hematopoietic growth factors are a family of glycoprotein hormones
which regulate survival, self-renewal, proliferation, and differentiation
of hematopoietic progenitor cells as well as the functional activities
of mature cells. Although direct actions of these factors upregulate
cell function, they may also induce the production of molecules
which exert inhibitory effects on hematopoiesis. As an example CSF
for granulocytes and macrophages (GM-CSF), which promotes growth
and differentiation of myeloid cells, has been shown to induce production
of tumor necrosis factor-alpha (TN F -alpha) by monocytes and granulocytes,
which is known for its inhibitory action on several hematopoietic
lineages [4,5,6]. Moreover, transforming growth factor-beta (TGF-beta),
leukemia inhibiting factor (LIF), and possibly IL-l 0 may playa
role in downmodulation of hematopoiesis [7,8,9]. On the other hand
TNF-alpha which has been primarily recognized as a potent inhibitor
, is also known to induce the production of growth promoting
factors by hematopoietic cells [10,11]. Whereas accessory cells,
present in the bone marrow micro-environment, including endothelial
cells and fibroblasts, produce a broad spectrum of factors with
hematopoietic activity under steady state conditions , the potential
of mature hematopoietic cells including monocytes, granulocytes,
T -lymphocytes and B-Iymphocytes to synthesize such factors is linked
to cellular activation. Lectine stimulation results in growth factor
expression by monocytes, granulocytes and T -lymphocytes. This unspecific
induction can be replaced by more physiological stimuli. I L-I for
example triggers granulocytes, monocytes and preactivated T -cells
to synthesize and release hematopoietins. However, with a variety
of stimulating agents that we used to induce growth factor production
we found a restricted production pattern of colony stimulating factors
by hematopoietic cells: i.e. monocytes and granulocytes share the
capacity to produce CSF for granulocytes (G-CSF and M-CCSF) but
fail to produce GM-CSF and IL-3, whereas T-cells exhibit the opposite
behaviour [5, 13]. Hematopoietic growth factors and cytokines interact
with their target cells via specific receptor structures. In general
the numbers of growth factor receptors do not exceed a few hundred
per cell. M-CSF receptors are exclusively present on cells derived
from the monocyte macrophage lineage and possibly in very low number
on neutrophils . G-CSF receptors are present on cells derived
from the neutrophil granulocyte lineage and with a much lower number
on monocytes/macrophages . The distribution of receptors for
GM-CSF and IL-3 appears to be broader, including neutrophil and
eosinophil granulocytes as well as monocytes/macrophages . IL-l,
IL-6 and TNF-alpha are molecules with pleiotropic activity with
receptors on hematopoietic, non-hematopoietic and accessory cells.
Mechanisms involved for signal transduction of CSFs after ligand
binding to the receptor include tyrosine kinase activity of the
receptor molecule as well as a link to GTP-binding proteins which
results in an increase of intracellular calcium via activation of
the phosphatidylinositol-specific phospholipase C [17-20]. Moreover,
various CSFs have been shown to modulate the function of other enzyme
systems, thereby regulating the intracellular A TP levels, glucose
transport and Na + K +-dependent A TPase-systems [21-23]. The factors
currently under active clinical investigation include multipotential
colony-stimulating factor (multi-CSF or interleukin-3), granulocyte-macrophage
CSF (GM-CSF), granulocyte CSF (G-CSF) and erythro poietin (EPO)
which will be the focus of this discussion. More recently, also
macrophage CSF (M-CSF), Interleukin-l, Interleukin-6 and others
are being investigated clinically. Erythropoietin (EPO) is a glycoprotein
hormone produced predominantly in the kidney and to a small extent
in the liver. It regulates the proliferation and differentiation
of erythroid progenitor cells to mature erythrocytes . The mechanism
by which a hypoxic stimulus triggers the production and release
of EPO is still unknown. Evidence has been presented that the oxygen
sensor is a heme protein . EPO is a heavily glycosylated, 166
amino acid protein with a molecular mass of 34-39 kD. While glycosylation
is a prerequisite for in vivo activity, in vitro activity is also
provided by the non-glycosylated form. The EPO gene has been localized
to chromosome 7q 11-q22 . Like those of its natural counterpart,
the major target cells of recombinant EPO have been identified as
colonyforming progenitor cells committed to the erythroid lineage
(CFU-E, colony-forming unit-erythroid) and to a minor extent as
more immature erythroid progenitor cells, the BFU-E (burst-forming
unit-erythroid). Recent in vitro data also indicate that EPO induces
expansion of very early progenitor cells . Granulocyte Colony-Stimulating
factor (G-CSF) was molecular defined in 1985  and cloned in
1986 [29,30]. Due to alternative splicing, two cDNAs representing
a 177 amino acid protein form and a 174 amino acid protein form
of human G-CSF have been isolated . The shorter version of
the molecule seems to be more active in vivo. The gene which encodes
G-CSF is located on chromosome 17 q11-q22. G-CSF is a rather lineage-specific
hematopoietic growth factor, in that it acts on cells capable of
forming one differentiated cell type: the neutrophil granulocyte.
In combination with other hematopoietic growth factors it acts synergistically
to stimulate a broader spectrum of colony-forming cells . As
an example for the extremely rapid clinical development of these
new agents, G-CSF entered clinical trials in 1987 and was approved
world-wide in 1991-1992. The human gene encoding Granulocyte-Macrophage
Colony-Stimulating Factor (GM-CSF) is located on chromosome 5q21-5q32
. Due to variable glycosylation, the molecular mass of the mature
protein which comprises 127 amino acids, ranges from 14 to 35 kD
. A variety of cells producing GM-CSF have been identified,
among them monocytes, fibroblasts, endothelial cells, epithelial
cells, and T -lymphocytes . GM-CSF stimulates granulocyte/macrophage
and eosinophil colony formation in vitro and acts in combination
with erythropoietin as erythroid burst-promoting activity .
In addition to its effect on progenitor cell differentiation, GM-CSF
also induces a variety of functional changes in mature cells. It
increases neutrophil phagocytic activity, inhibits the random migration
of neutrophil granulocytes , and induces the production of other
cytokines (e.g. tumor necrosis factor, interleukin-l) by these same
cells [36, 37]. It also induces macrophage tumor cytotoxicity ,
activates macrophages to synthesize MHC class II molecules, to augment
antigen presentation , and to release oxygen radicals .
As for GM- and G-CSF, the gene for interleukin-3 (IL-3) has been
located on chromosome 5 q23-q31 . The protein is produced by
activated T -lymphocytes and has a molecular mass of 14-28 kD. 1L-3
is a multilineage hematopoietin which promotes the growth and differentiation
of various myeloid and lymphoid progenitor cells including early
multipotent progenitors such as blast colony-forming units and mixed
colonies. The colonies produced in response to IL-3 contain eosinophils,
basophils, neutrophils, mast cells, megakaryocytes, macrophages,
and erythroid cells.
Hematopoietic (HPGF) in the Pathogenesis of Acute Myeloid Leukemia
In recent years, our laboratory has investigated a series of questions
addressing the possible pathogenetic role of dysregulation of cytokine
expression in AML. The first question was, whether AML progenitor
cells require HPGF for proliferation ex vivo and, subsequently,
in vivo (see below). In 38 of 54 AML bone marrow samples tested,
there was a requirement for exogenous HPGF for growth in culture
while the remaining 16 cases demonstrated growth in culture in the
absence of exogenous HPGF ("autonomous growth"). After having demonstrated
HPGF dependency for the majority of cases, the second question addressed
the possible cellular sources of HPGF in AML. While unstillulated
normal blood and bone marrow cells under our experimental conditions
fail to release any HPGF or accumulate respective mRNAs, the majority
of AML samples were found to release HPGF and to accumulate HPGF
mRNA constitutively. Selected experiments were performed to study
if the addition of neutralizing anti-GM-CSF monoclonal antibody
was able to inhibit spontaneous colony growth of AML populations
which produced GM-CSF. Exposure resulted in a 20-70% reduction of
colony growth, whereas proliferation of AML cells which did not
express GM-CSF were not affected by anti-GM-CSF monoclonal antibodies.
This result suggests that GMCSF can be involved in an autocrine
mechanism which promotes proliferation of leukemic cells. Overall,
there appeared to be a correlation between the constitutive release
of HPG F and spontaneous ("autonomous") growth in culture .
Our series of 54 AML populations have also been analysed for the
expression of IL-2 and IL4 mRNA. None of the samples has been found
to produce these cytokines. Direct effects of CSFs and cytokines,
which are produced by AML populations have been investigated focussing
on growth regulation of leukemic cells. Whereas GM-CSF, G-CSF and
IL-3 added to the agar assays at concentrations of 50 ng/ml, induced
growth of leukemic colony forming units (L-CFU) in approximately
30-50% of the AML samples tested, M-CSF added at a concentration
of 1000/ml induced growth in only one AML cell population of 19
samples tested . IL-l-beta and TNF-alpha failed to promote growth
of leukemic cells via direct action . Since autocrine stimulation
could explain autonomous proliferation in vivo only in some patients
we investigated next, whether paracrine induction of HPGF could
contribute to AML progenitor cell proliferation. Whereas TNF-alpha
has been shown to exert inhibitory action on normal and malignant
hematopoiesis when added to cultures at high concentrations ,
we were interested in investigating if AML supernatants containing
TNF-alpha may induce CSF release by accessory cells present in the
bone marrow environment. Therefore, we added culture supernatants
containing TNFalpha constitutively secreted by AML cells to human
umbilical cord vein endothelial cells and performed Northern blot
analyses of exposed endothelial cells. TNF-alpha stimulated endothelial
cells were found to produce GM- and G-CSF mRNA and released these
proteins; this induction could be inhibited by pretreatment of AML
supernatants with anti- TNF monoclonal antibody prior to exposure
of endothelial cells. Other investigators demonstrated similar data
when exposing endothelial cells to AML supernatants containing IL-
1beta . IL-6 failed to induce endothelial cell production of
colony-stillulating factors . We then studied IL-I-beta and
GM-CSF, which are known to be potent function-inducing molecules
in myeloid cells [5,45], for their potential to induce CSF production
in CSF-negative AML populations. None of the AML samples tested
(n = 6) responded to these mediators with CSF production. Concentrations
for GM-CSF were chosen up to lOO ng/ml and for IL-I-beta up to 10
/ml. However , it has recently been reported that G M -CSF production
by AML blasts may be inducible with TNFalpha at a concentration
of 50 ng/ml . We were further interested to investigate the
CSF gene structure of AML populations constitutively producing the
respective CSF species. For each, G- and GM-CSF we analysed 10 AML
samples by Southern blot analysis using multiple restriction enzyme
digestions. None of the study samples showed a change of the G-
or GM-CSF gene structure as compared to germ line configuration.
Under our experimental conditions, many samples of AML blasts show
an activated. GM-CSF expression which is not seen in normal cells
of the myeloid lineage under the conditions tested. In order to
exclude lineage promiscuity of GM-CSF-producing AML samples, we
studied the presence of immunoglobulin gene and T -cell receptor
gene rearrangements. No AML sample, which produced GM-CSF, provided
evidence for rearrangements of illmunoglobuline genes (IGh) nor
of T -cell receptor genes. In another study with 69 patients with
AML we found that IGh-rearrangements appeared in 10 cases with an
additional kappa chain gene rearrangement in I case. Two patients
within this group showed rearrangements of the T -cell receptor
beta chain gene . In an effort to investigate the molecular
basis of constitutive cytokine expression in AML cells we have begun
to study the activated expression of point mutated RAS genes in
CSF- and cytokine-expressing AML populations. Fifty patients with
AML have been tested for the presence of activating point mutations
focussing on first and second nucleotides of codon 61 of N-RAS.
Mutations of the 7 positions that have been investigated have been
shown to be heterozygous, which was demonstrated by hybridization
of the normal allele with wild type probes. Most often we found
an association between IL6 expression in AML cells with N-RAS activation,
whereby the occurring mutations always involved exon I. There was
no clear correlation of N-RAS mutations with the expression of the
other growth factors investigated. The reported co-incidence of
alterations of myconcogenes with N-RAS oncogene was also investigated.
The 12.5 kb ECOR I band, which comprises the total coding region
of myc was unchanged and not amplified in all patients investigated
. Synthesis of factors with hematopoietic activity was also
studied in patients with acute lymphoblastic leukemia (ALL). Northern
blot analyses from 13 ALL did not reveal mRNA accumulation for G-CSF,
GM-CSF, M-CSF and IL-6. Only two T -ALL populations showed an accumulation
of IL-3 transcripts after prolonged autoradiography (unpublished).
In another model, we investigated the possible contribution of suppressor
cytokines to the suppression of normal hematopoiesis in patients
with leukemia. As a model, we chose Hairy Cell Leukemia (HCL), a
disease characterized by profound pancytopenia. Our studies demonstrated
constitutive mRNA accumulation and protein release of TNF-alpha
by HCL cells and not by other lymphoproliferative disorders .
The addition of neutralizing anti TNF monoclonal antibodies could
in part restore normal progenitor cell proliferation in culture.
in vivo correspond well to predictions based on in vitro studies
in that the ontogenetically latest acting growth factor, G-CSF,
induces the fastest rise, while IL-3, compatible with the role of
an early stem cell factor, requires approximately 10 days for white
blood cells to rise in the peripheral blood. In view of their pleiotropic
and in vitro- synergistic properties, HPGF can be expected to also
synergize in vivo, corresponding clinical trials are ongoing. In
addition to stimulating production of various lymphohematopoietic
cells, hematopoietic cytokines also lead to mobilization of progenitor
cells from bone marrow into peripheral blood facilitating harvest
by leukapheresis for subsequent stem cell transplantation [55,56].
Clinical studies have documented the effectiveness of recombinant
EPO in correction of anemia in patients with end-stage renal disease
 as well as in pre-dialysis patients . In these patients
only low levels of EPO can be demonstrated in serum. Although, pathogenetically,
anemia in tumor patients is not characterized by EPO deficiency,
we investigated whether exogenously administered EPO could stimulate
erythropoiesis in these patients and thus contribute to correcting
transfusiondependent anemia. The therapeutic effect of EPO in correcting
chemotherapy-induced anemia in patients with normal renal function
was demonstrated . EPO response was accompanied by a decrease
in serum ferritin. The requirement for red blood cell transfusion
was reduced or eliminated by EPO therapy. EPO was also shown to
be beneficial in the treatment of malignancy due to neoplastic bone
marrow infiltration . No side effects were noted during EPO
therapy. This is in contrast to results in patients with endstate
renal disease, in whom EPO therapy was associated with increases
in blood pressure and blood viscosity leading to significant morbidity
in some patients. This difference may possibly be explained by a
predisposition of patients with renal disease to vascular complications
and to their lack of functioning kidneys to regulate fluid balance
and thus blood viscosity due to increased red cell mass. Like GM-CSF,
G-CSF has been utilized in the prevention of chemotherapy-induced
neutropenia [61-65] and in the setting of autologous bone marrow
transplantation [66,67]. A dose-dependent increase in absolute neutrophil
counts and shortening of the neutropenic period was observed. At
higher doses up to a ten-fold increase in monocytes was also seen
. In most recent studies the incidence of severe infections
was reduced following these cycles of chemotherapy combined with
G-CSF. Neutropenia caused by marrow infiltration with low grade
lymphoma (hairy cell leukemia) also improved after treatment with
G-CSF  as with GM-CSF . Toxicities in G-CSF trials in general
have been limited consisting mainly of bone pain, presumably secondary
Hematopoietic Cytokines as Therapeutic Agents
In a series of phase I-IV clinical trials we have investigated
the in vivo biology of HPGF in man. G-CSF exclusively induces production
of neutrophils and bands . At doses up to 250 ug/m2 neutrophils
rise until day 10, while thereafter a decrease is observed in spite
of continued G-CSF administration, suggesting endogenous negative
feed-back mechanisms. GM-CSF induces proliferation of several white
blood cells: neutrophils and bands, predominantly, but also of eosinophils
and moncytes . Biological responses are not only dependent on
dose but also on routes of administration, since s.c. administration
almost exclusively induces neutrophils and bands, while continuous
i. v. administration also leads to expansion of eosinophil and monocyte
poopulations by GM-CSF. In contrast to G- and GM-CSF, IL-3 not only
promotes expansion of all white blood cell subpopulation but also
leads to increased reticulocyte and platelet counts (52-54). The
kinetics of white blood cell increases bone marrow expansion. This
adverse effect was seen in up to 25% of patients treated with an
intravenous bolus > 30 uuuuuug/kg body weight; with subcutaneous
administration and lower doses it was less frequently encountered.
In some patients reversible elevation of serum alkaline phosphatase
and lactic dehydrogenase have been noted as a result of increased
neutrophil turnover, and rarely evidence of overshooting neutrophil
activation such as the acute neutrophilic dermatosis (Sweet's syndrome)
has been observed . G-CSF is currently being tested by a number
of investigators for its usefulness in the treatment of neutropenic
disorders due to malignancies, cancer chemotherapy as well as in
congenital (Kostmann's syndrome), cyclic, or idiopathic neutropenia
[69- 71 ]. From the promising preliminary data it can be anticipated
that in the near future recombinant G-CSF will have a beneficial
impact on the natural history of these disorders. Although in vitro
findings suggested a possible role for inducing indirect and direct
antitumor effects, no such effects of GM-CSF have been observed
as yet in any of the clinical studies [72- 78]. Apart from its possible
role as antitumor agent, which requires further evaluation, GMCSF
shows activity in reducing chemotherapy associated neutropenia.
At higher doses (several-fold higher than required for amelioration
of chemotherapy induced neutropenia), the dose limiting toxicities
of GM-CSF reported were fever and, during continuous infusion into
small veins, thrombophlebitis [74,78]. Effects of GM-CSF were also
studied in the clinical setting of autologous bone marrow transplantation
[74,79]. It has been shown that GM-CSF accelerates the rate of neutrophil
recovery and increases the circulating pool of peripheral blood
hematopoietic progenitors. No difference was seen between GM-CSF
treated patients and control patients with respect to the first
appearance of neutrophils in the circulation . More recently,
the benefits of GM-CSF therapy was also demonstrated after allogeneic
bone marrow transplantation in situations of graft failure [81 ].
Administration of GM-CSF to patients with myelodysplastic syndrome
has been described to normalize red cell, white cell, and platelet
counts in some patients . More recent studies, however, have
not been able to confirm this optimistic report, demonstrating rises
in neutrophil counts only. At higher GM-CSF doses an increase in
leukemic blast cells in blood and bone marrow has been seen, indicating
that GM-CSF can stimulate the proliferation of human leukemic blast
cells as well as of normal hematopoietic cells in vivo [76,77,82].
Even a possible progression to frank leukemia has been observed
. Some ongoing studies are exploring the use of GM-CSF in acute
myeloblastic leukemia, by augmenting the proportion of malignant
cells recruited into the S-phase of the cell cycle and thus obtaining
enhanced cytotoxic effects with drugs such as Ara-C, that kill cycle-activated
cells [83,84]. The value of GM-CSF in the treatment of aplastic
anemia appears to be limited to those patients with residual hematopoiesis
as reported by Champlin and Nissen and their colleagues [85,86].
Combinations of hematopoietic growth factors acting on early progenitors
with later-acting factors might have synergistic effects in accelerating
repopulation of the bone marrow and warrant further investigation
in this disease, possibly in combination with immunosuppression
agents. This approach is currently being tested in a clinical trial
(unpublished). Ultimately, GM-CSF may find a place in the treat
ment of other nonmalignant conditions characterized by leukopenia
(e.g. acquired immune deficiency syndrome)  or in the improvement
of host defense in infectious disease. In preclinical murine and
primate models, IL-3 has been shown to significantly elevate numbers
of circulating leukocytes. A phase 1/11 trial in patients with bone
marrow failure syndromes has revealed the following dose related
hematological responses: increases in platelet counts, absolute
leukocyte counts including neutrophils, monocytes, eosinophils,
lymphocytes, and, to a lesser extent, basophils, reticulocyte counts,
and bone marrow cellularity . Side effects included fever, flushing,
headache, and local irritation at the site of the subcutaneous injection
at higher doses ( > 250 ug/m²). More efficacy is to be expected
from the use of combinations of IL-3 with other late-acting hematopoietins
Hematopoietic Cytokines in the Treatment of Leukemias
The available data on the therapeutic use of HPGF in various leukemias
and other diseases infiltrating the bone marrow would suggest the
following conclusions. EPO will stimulate erythrocyte production
in settings of bone marrow infiltration by chronic lymphocytic leukemia
or multiple myeloma, after chemotherapy, but only occasionally,
if erythropoiesis is part of the neoplastic clone such as in MDS.
A similar interpretation is suggested by the data obtained with
GM-CSF in hairy cell leukemia (HCL): Since granulopoiesis is not
part of the leukemic clone, it should and does respond to exogenous
stimulation with CSF . Similarly, it would be expected that
neutrophil regeneration is accelerated by G- or GM-CSF after successful
induction chemotherapy in AML, when the leukemic cells are eliminated
and normal progenitor cells (PGC) available to respond [88,89].
As long as normal progenitor cells are available to respond, the
balance can be shifted from leukemic to normal PGC, possibly independent
of the suppressing mechanism (e.g. chemotherapy, TNF-alpha in HCL,
unknown in CLL). As expected, a more complex pattern of response
and non-response is seen in conditions where the cells targeted
by the respective HPGF are intrinsically abnormal. Treatment results
in myelodysplasia are variable, and even in patients that do respond
in one or more lineage as judged by peripheral blood counts, a clinical
benefit remains to be demonstrated. More recently, efforts to induce
leukemic PGC more sensitive to chemotherapy are under investigation
in several clinical trials [e.g. 91]. A third approach would be
suggested by the observations made in patients with MDS whose blast
cells expand during therapy. In these patients blasts tend to return
to baseline and occasionally less than baseline upon discontinuation
of cy to kine therapy. This observation would parallel in vitro
studies where leukemic cell lines can be adapted to cytokine containing
media, leading to cell death upon cytokine deprivation.
Cytokines in the Treatment of Chemotherapy Induced Cytopenia
With or Without Autologous or Allogeneic Stem Cell Rescue
Increased neutrophil recovery after intensive chemotherapy and
autologous or allogeneic stem cell rescue has been demonstrated
in a series of clinical studies (for review see ). Since hematopoietic
PGC are shifted from bone marrow to blood by chemotherapy, and even
more pronounced when followed by cytokine therapy, peripheral blood
PGC harvested under these conditions appear useful in further accelerating
white blood cell and especially platelet recovery after intensified
chemotherapy [55,56,93]. The question of dose intensification and
its relevance to improved therapeutic efficacy can now be studied
in an unprecedented way. While increased therapeutic efficacy remains
to be our overall goal, reduced morbidity and, in some cases, mortality
in cancer patients receiving cytotoxic therapy is a definitive and
important step in this direction. The future will see the evaluation
of novel cytokines alone as well as combinations of cytokines also
in non-neoplastic conditions, e.g. infectious diseases. Molecular
efforts correcting the pathophysiological defect or directly inducing
antitumor effects by gene transfer into tumor or host cells 
appear to be another promising step for cytokinebased treatments,
especially involving cytokine requiring paracrine secretion for
optimum activity and specificity.
I would like to thank my colleagues Drs. F. Herrman, A. Lindemann,
L. Kanz, W. Erugger, W. Oster, M. Lübbert, F. Rosenthal and many
others for working with me on the concepts discussed in this paper.
I am grateful to Ms. H. Vogel for excellent secretarial assistance.
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