Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4387-4388
CORRESPONDENCE
Erythropoietin Prevents the Development of
Interleukin-12-Induced Anemia and Thrombocytopenia But Does Not
Decrease Its Antitumor Activity in Mice
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LETTER |
To the Editor:
It has recently been shown in preclinical studies that local or
systemic treatment with interleukin-12 (IL-12) produces profound antitumor effects causing regression of established tumors and tumor
metastases.1,2 The antitumor activity of IL-12 is to a
large extent mediated by interferon-
(IFN-) secreted in increased amounts by T cells and natural killer (NK) cells.1
IL-12 had initially been viewed as a synergistic hematopoietic growth
factor in vitro.3 However, when administered in vivo to
mice it caused a dose-dependent suppression of bone marrow hematopoiesis.4 Similarly, in phase I trial of IL-12 in
patients with advanced malignancies it caused anemia, thrombocytopenia, lymphopenia, and neutropenia.5
There is substantial evidence that cytokines (mainly IFN-) released
during IL-12 treatment are implicated in the suppression of bone marrow
hematopoiesis. However, both neutralization with monoclonal
antibodies1 and reducing the release of IFN- (by means
of predosing with IL-12)6,7 result in attenuation of the
antitumor activity of IL-12, and thus cannot be considered as good
methods to prevent the suppression of bone marrow hematopoiesis. In our
previous experiments we showed that application of granulocyte colony-stimulating factor (G-CSF) results in correction of
IL-12-induced granulocytopenia.8 However, coadministration
of G-CSF with IL-12 led to even stronger suppression of thrombopoiesis.
Moreover, as has been reported in a recent issue of BLOOD,
pretreatment with IL-12 does not ameliorate the thrombocytopenia
observed during subsequent administration of IL-12 to either humans or
mice.7
Because erythropoietin (Epo) is used in the treatment of anemia of
cancer,9 and has also been shown to occasionally correct thrombocytopenia,10 we decided to evaluate whether it could prevent the development of some of the side effects induced by IL-12
treatment.
Administration of IL-12 (kindly provided by Genetics Institute, Boston,
MA) at a daily dose of 0.1 µg for 7 consecutive days resulted in
anemia and thrombocytopenia (Table 1). Epo
(rhuErythropoietin, Eprex, Cilag) administered at two daily doses of 20 U for 7 consecutive days nonsignificantly increased the level of
hemoglobin as compared with controls. In accordance with our
expectations, application of Epo prevented the development of
IL-12-induced anemia. Additionally, unexpectedly Epo was also found to
prevent IL-12-induced decrease in platelet count. However, taking into
account the somewhat weaker thrombopoietic activity of Epo in
humans11 as compared with mice, it remains to be seen
whether Epo could be effective in correcting IL-12-induced
thrombocytopenia in tumor patients.
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Table 1.
The Influence of IL-12 and/or Epo on the Number
of Platelets and the Hemoglobin Concentration in Peripheral
Blood
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Because hematopoietic growth factors may occasionally stimulate the
growth of neoplasms, including solid tumors,12,13 we decided to examine the influence of Epo application on the growth of
MmB16 melanoma. Epo did not influence tumor growth when given alone and
did not decrease the antitumor activity of IL-12 in this particular
tumor model (Fig 1A and B).
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| Fig 1.
The effects of treatment with IL-12 and/or Epo on
MmB16 melanoma growth in B6D2F1 mice. Mice were inoculated with 1 × 106 melanoma cells into the footpad of the right hind limb
and treated with the intratumoral injections (days 7 to 13, arrows) of
IL-12 (0.1 µg/injection), Epo (20 U/injection; twice daily), or IL-12 in combination with Epo (the same doses). Tumor volume was determined as described previously.15 (A) A pilot study with four
B6D2F1 mice per group. * P < .05: IL-12- and IL-12+
Epo-treated mice versus controls;  , IL-12 + Epo;  , IL-12;  ,
control. (B) Additional experiment with five to six B6D2F1 mice in each
of the groups. * P < .05: IL-12- and IL-12+ Epo-treated
mice versus controls and Epo-treated mice; ** P < .01: IL-12- and IL-12 + Epo-treated mice versus controls
and Epo-treated mice (Student's t-test); , IL-12 + Epo;
, IL-12;  , Epo; , control.
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As the antitumor activity of IL-12 may by potentiated by administration
of some of the chemotherapeutics,14 it might be anticipated
that IL-12 together with Epo could be successfully included into some
of the combined chemoimmunotherapy schedules.
Jakub Go
b
Radosaw Zago
don
Tomasz Stokosa
Witold Lasek
Marek Jakóbisiak
Department of
Immunology
Institute of Biostructure
Medical University of Warsaw,
Poland
Zygmunt Pojda
Department of Radiation
Hematology
WIHiE, Warsaw, Poland
Eugeniusz Machaj
Department of Experimental Hematology
Maria
Skodowska-Curie Memorial Cancer Center
Institute of Oncology,
Warsaw, Poland
| |
ACKNOWLEDGMENT |
Supported by Grant No. 6 P207 058 07 from the State Committee for
Scientific Research (K.B.N), Poland. Tomasz Stokosa is a recipient
of the Foundation for Polish Science Award.
| |
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