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					                                                                                         INVITED              PERSPECTIVE


Multidrug Resistance in Acute Myeloid Leukemia:
Potential New Therapeutics
I  n acute myeloid leukemias (AMLs),
multidrug resistance (MDR) is fre-
                                                       Many investigators working to im-
                                                    prove cancer therapy have tried to use
                                                    various immunologic approaches to
                                                                                                     Although there have been significant
                                                                                                  advances in the treatment of AML, only
                                                                                                  20%230% of these patients reach long-
quently, but not always, caused by the              killing cancer cells because such ap-         term disease-free survival (14). The
MDR1 gene product, a 170- to 180-                   proaches might circumvent chemother-          addition of Pgp expression predicts an
kDa glycoprotein known as P-glyco-                  apeutic drug resistance. One of the           even poorer prognosis in the elderly,
protein (Pgp) or human MDR1 protein                 assumptions of an immunologic ap-             those patients who have relapsed, and
(1). It is characterized by broad re-               proach is that cells that are resistant to    patients with secondary AML (11,15).
sistance to several structurally, chemi-            chemotherapeutics should not be cross-           When considering radioimmunother-
cally, and pharmacologically distinct               resistant to immunotherapy because the        apy for the treatment of any type of
chemotherapeutic compounds. Many                    mechanisms of action are so widely            cancer, one must keep in mind three
theories explain how Pgp affects                    different. Unfortunately, several groups      important factors: the target tumor,
MDR, including the ‘‘drug pump’’                    have shown that MDR cells seem to be          isotope, and antibody (16). Because
model, in which Pgp hydrolyzes aden-                resistant to several forms of immuno-         leukemias are easily accessible and
osine triphosphate to actively pump                 logic therapies, including complement-        have well-defined differentiation anti-
drugs out of the cell (2,3). As many                mediated cytotoxicity (5,6), immunotoxin,     gens, they are ideal for the use of
MDR cells have been found to have                   gelonin attached to monoclonal anti-          radiolabeled antibodies (17). AML is
                                                    bodies (mAbs) (8), interleukin 2 (9),         characterized by the expression of
                                                    and drug immunoconjugates (10–12).            CD13, CD15, CD33, and CD117
               See page 1546
                                                       Another immunologic treatment is           (18). CD33 is a 67-kDa cell-surface
                                                    the use of mAbs to deliver radioisotopes      glycoprotein found on myeloid leuke-
increased intracellular pH and de-                  directly to the tumor cells. At the present   mia cells and on committed myelo-
creased plasma membrane potentials,                 time, the use of radiolabeled antibodies      monocytic and erythroid progenitor
another explanation of the MDR                      in the treatment of AML with Pgp              cells. It is not found on lymphoid,
mechanism of Pgp is the altered-                    expression has not been well studied, if      nonhematopoietic, or mature myeloid
partition model. This model takes into              at all. In this issue of The Journal of       cells, making CD33 a prime target for
account how the alterations in in-                  Nuclear Medicine, Kersemans et al. (13)       antibody binding (19,20).
tracellular pH and membrane potential               use a strategy to overcome MDR using             Different isotopes have been at-
that accompany the overexpression of                mAbs that have been labeled with 111In        tached to antibodies based on their
Pgp indirectly affect the partitioning              modified with a nuclear localizing             half-life and the type of particle they
of the drugs, but Pgp does not directly             sequence (NLS). They showed that the          emit. For single-cell kill, with the least
pump the drugs out of the cell (4–6).               addition of the peptide sequence              cytotoxicity to normal cells, the ideal
Other drug-resistance proteins, which               CGYGPKKKRKVGG, which contains                 isotope emission should have a path
are associated with hematologic can-                the NLS PKKKRKV of SV-40 large                length that is the same as that of the
cers that use similar mechanisms,                   T-antigens, allowed the antibody to be        target cells (21). 90Y and 131I emit
include the MDR-associated protein,                 internalized and to translocate to the        b-particles, which have a relatively long
the lung resistance protein, and the                nucleus. Once in the nucleus, Auger elec-     range and a low linear-energy transfer.
breast cancer resistance protein (7).               trons from the 111In were cytotoxic to the    Unfortunately, these properties make
                                                    parental HL60 cell line and drug-resistant    b-particles an excellent choice for solid
                                                    (mitoxantrone-insensitive) HL60-MX-1          tumors but not for hematologic cancers,
                                                    cell line and to the primary AML speci-       in which antibodies cannot bind to all
  Received May 12, 2008; revision accepted                                                        the tumors cells at sufficient levels (21).
May 16, 2008.
                                                    mens that were expressing a diversity of
  For correspondence or reprints contact: Jeffrey   MDR phenotypes. These results suggest         This long particle range results in the
H. Weisburg, Stern College for Women, Yeshiva
University, New York, NY 10016.
                                                    that 111In-anti-CD33 mAbs that are mod-       irradiation of target tumor cells as well
  E-mail: jweisburg@yahoo.com                       ified with an NLS may be a new treatment       as surrounding cells, causing normal
  COPYRIGHT ª 2008 by the Society of Nuclear
Medicine, Inc.
                                                    for patients who have drug-resistant          cells to be killed. Alpha-particles, on
  DOI: 10.2967/jnumed.107.050153                    myeloid leukemias.                            the other hand, have a shorter range


                                                            AML MDR        AND   POTENTIAL NEW THERAPEUTICS • Weisburg                1405
(about the size range of 3–5 times that      have levels of antigen that are compa-       multidrug-resistant cells, is promising.
of the target cells) than b-particles and    rable to those expressed in the cell         The results demonstrated in the article
a much higher linear energy transfer.        lines. Kersemans et al. (13) reported        by Kersemans et al. (13) show that
Only one a-particle is needed to cross       that the HL-60 and HL-60-MX-1 cells          there may be a treatment to overcome
the nucleus to induce cell death by          contained 3–4 · 104 CD33 per cell.           MDR in AML and perhaps other types
causing double-strand breaks in the          With this number of sites per cell, they     of hematologic cancers.
DNA, making a-particles more efficient        determined that at a specific activity of
than b-particles at killing a single cell.   8 MBq/mg, 10% of the radioactivity is
                                                                                                                      Jeffrey H. Weisburg
The shorter range of a-particles is          localized to the cell surface, 70% is in                                    Yeshiva University
beneficial in 2 ways. First, nonspecific       the cytoplasm, and 20% is in the                                          New York, New York
cytotoxicity to nearby healthy cells         nucleus. It has been previously re-
should be reduced, and second, because       ported that myeloid and monocytic
the path length of a-particles is shorter,   leukemias contain only 1 · 104 CD33
                                                                                          REFERENCES
they would be an effective single-cell       per cell (27). A possible drawback
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                                                                                              nal antibody (gemtuzumab, zogamicin, CMA-676)
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                                                                                              with nuclear localizing peptide sequences. J Nucl
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1406      THE JOURNAL    OF   NUCLEAR MEDICINE • Vol. 49 • No. 9 • September 2008
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                                                                              Erratum

    In the article ‘‘SPECT/CT,’’ by Buck et al. (J Nucl Med. 2008;49:1305–1319), the legends of Figures 1, 5, and 6 contain
    errors. In the legend of Figure 1, ‘‘99mTc-iodobenzamide’’ should be ‘‘123I-ioflupane (DaTSCAN [GE Healthcare]).’’ In
    the legend of Figure 5, panel B is described as a 99mTc-MIBI scan but is in fact a 99mTc-pertechnetate scan. In the legend
    of Figure 6, ‘‘99mTc-MIBG’’ should be ‘‘123I-MIBG.’’ The authors regret the errors.




                                                                     AML MDR            AND    POTENTIAL NEW THERAPEUTICS • Weisburg                                    1407

				
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