Multidrug Resistance in Acute Myeloid Leukemia Potential New .pdf

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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:                       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
they would be an effective single-cell       per cell (27). A possible drawback
killer (22). Auger electrons have a high-    with CD33 as the target is that these         1. Chang G. Multidrug resistance ABC transporters.
                                                                                              FEBS Lett. 2003;555:102–105.
linear-energy transfer and an even           levels can be decreased among differ-         2. Croop JM, Guild B, Gros P, Houseman DE.
smaller path length than do a-particles,     ent cells lines and in patient samples,          Genetics of multidrug resistance: relationship of
making Auger electrons also suitable         preventing enough Auger electrons                a coned gene to the complete multidrug resistant
                                                                                              phenotype. Cancer Res. 1987;47:5982–5988.
for the treatment of hematologic can-        from entering the nucleus to kill the         3. Hamada H, Tsuruo T. Characterization of the
cers. High antigen densities are essential   cell. To overcome these lower CD33               ATPase activity of the Mr 170,000 to 180,000
because a large number of decays is vital    levels of different targets, a higher            membrane glycoprotein (P-glycoprotein) associ-
                                                                                              ated with multidrug resistance in K562/ADM
for strong cytotoxicity (23). The dose,      specific activity may be needed to                cells. Cancer Res. 1988;48:4926–4932.
meaning what kills the cells, is de-         increase the percentage inside the            4. Wadkins RM, Roepe PD. Biophysical aspects of
pendent on the energy of the particle and    nucleus. However, this could reduce              P-glycoprotein-mediated multidrug resistance. Int
                                                                                              Rev Cytol. 1997;171:121–165.
the half-life. Unlike a- and b-radiation,    immunoreactivity. Another aspect to           5. Weisburg JH, Curcio M, Caron PC, et al. The
Auger emitters need to be attached to the    consider is the pharmacokinetics of              multidrug resistant phenotype confers immunolog-
individual tumor cells and enter the         the antibody with the attached poly-             ical resistance. J Exp Med. 1996;183:2699–2704.
                                                                                           6. Weisburg JH, Roepe PD, Dzekunov S, Scheinberg
nucleus. Optimum results with Auger          peptide chain; are they different from           DA. Intracellular pH and multidrug resistance
electron emitters were seen when they        those of the antibody alone? Pharma-             regulate complement-mediated cytotoxicity of nu-
were bound to the DNA, causing double-       cokinetics must be determined for these          cleated cells. J Biol Chem. 1999;274:10877–10888.
                                                                                           7. Hirose M, Hosoi E, Hamano S, Jalili A. Multidrug
stand breaks (24).                           novel constructs.                                resistance in hematological malignancy. J Med
   In the study by Kersemans et al.             The attachment of the NLS to the              Invest. 2003;50:126–135.
(13), the authors were able to specif-       antibody may invigorate interest in           8. McGrath MS, Rosenblum MG, Philips MR,
                                                                                              Scheinberg DA. Immunotoxin resistance in multi-
ically target the nucleus of the HL-60       radioimmunotherapy and seems to                  drug resistant cells. Cancer Res. 2003;63:72–79.
and HL-60-MX-1 cells by the addition         have many applications. The use of            9. Drach J, Gsur A, Hamilton G, et al. Involvement of
of the NLS onto the antibodies,              a-emitters on NLS-tagged antibodies              P-glycoprotein in the transmembrane transport of
                                                                                              IL-2, IL-4 and interferon-g in normal human T
making the increase in nuclear radio-        is noteworthy. The NLS-tagged anti-              lymphocytes. Blood. 1996;88:1747–1754.
activity 4- to 6-fold greater than that of   bodies could bring the isotope directly      10. Naito K, Takeshita A, Shigeno K, et al. Calichea-
the antibodies without the NLS. With         to the nucleus to ensure a ‘‘direct hit.’’       micin-conjugated humanized anti-CD33 monoclo-
                                                                                              nal antibody (gemtuzumab, zogamicin, CMA-676)
this increase in nuclear localized           Possible problems associated with                shows cytocidal effect on CD33-positive leukemia
radiation, survival of the targeted cells    a-particle emitters such as 212Bi and            cell lines, but is inactive on P-glycoprotein-express-
was significantly decreased. The au-          213Bi are the short half-lives, making it        ing sublines. Leukemia. 2000;14:1436–1443.
                                                                                          11. Linenberger ML, Hong T, Flowers D, et al. Multidrug-
thors also saw this increased cytotox-       difficult for an antibody to reach the            resistance phenotype and clinical response to
icity in the primary AML samples that        tumor cells in time to have an effect,           gemtuzumab ozogamicin. Blood. 2001;98:988–994.
expressed the different types of MDR         and the longer path lengths, affecting       12. Sievers EL, Larson RA, Stadtmauer EA, et al.
                                                                                              Efficacy and safety of gemtuzumab ozogamicin in
transporters (13). This result is excit-     some normal bystander cells (21). The            patients with CD33-positive acute myeloid leuke-
ing because other methods to over-           issue of short half-life could be solved         mia in first relapse. J Clin Oncol. 2001;19:3244–
come drug resistance in AML have             by using 225Ac, which has a half-life            3254.
                                                                                          13. Kersemans V, Cornelissen B, Minden MD,
fallen short. Unsuccessful results have      of 10.5 d (28). To reduce the killing of         Brandwein J, Reilly RM. Drug-resistant AML
been observed in clinical trials using       normal cells, the NLS on the antibody            cells and primary AML specimens are killed by
                                                                                              111In-anti-CD33 monoclonal antibodies modified
specific MDR1 inhibitors such as              would bring the a-particle directly to
                                                                                              with nuclear localizing peptide sequences. J Nucl
PSC-883 or quinine (25,26).                  the nucleus of the cancerous target,             Med. 2008;49:1546–1554.
   Given the dependence of cytotoxic-        and less antibody would be required.         14. Cassileth PA, Harrington DP, Appelbaum FR, et al.
ity on high levels of antibody binding,         The addition of the NLS to a radio-           Chemotherapy compared with autologous or alloge-
                                                                                              nic bone marrow transplantation in the manage-
it is necessary to determine whether         labeled antibody, allowing it to enter           ment of acute myeloid leukemia in first remission.
the samples of patients with AML             the nucleus and increase the killing of          N Engl J Med. 1998;339:1649–1656.

1406      THE JOURNAL    OF   NUCLEAR MEDICINE • Vol. 49 • No. 9 • September 2008
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    MRP activities using calcein-AM are prognostic            521–534.                                                   treatment of elderly patients with previously un-
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16. Goldenberg DM. Target therapy of cancer with              1215–1223.                                                 2654.
    radiolabeled antibodies. J Nucl Med. 2002;43:693–   22.   Burke JM, Jurcic JG, Scheinberg DA. Radio-             26. Solary E, Drenou B, Campos L, et al. Quinine as
    713.                                                      immunotherapy for acute leukemia. Cancer Con-              a multidrug resistance inhibitor: a phase 3 multicentric
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18. Todd WM. Acute myeloid leukemia and related               In vitro cytotoxicity of carcinoma cells with 111In-   27. Tanimoto M, Scheinberg DA, Cordon-Cardo C,
    conditions. Hematol Oncol Clin North Am. 2002;            labeled antibodies to HER-2. Mol Cancer Ther.              et al. Restricted expression of an early myeloid
    16:301–319.                                               2005;4:927–937.                                            and monocytic cell surface. Leukemia. 1989;3:339–
19. Andrews RG, Torok-Storb B, Bernstein ID.            24.   Buchegger F, Perillo-Adamer F, Dupertuis YM,               348.
    Myeloid-associated differentiation antigens on            Delaloye AB. Auger radiation target into DNA:          28. Miederer M, McDevitt MR, Sgouros G, et al.
    stem cells and their progeny identified by mono-           a therapy perspective. Eur J Nucl Med Mol                  Pharmacokinetics, dosimetry, and toxicity of the
    clonal antibodies. Blood. 1983;62:124–132.                Imaging. 2006;33:1352–1363.                                targetable atomic generator, 225Ac-HuM195, in
20. Griffin JD, Linch D, Sabbath K, et al. A mono-       25.   van der Holt B, Lowenberg B, Burnett AK, et al. The        nonhuman primates. J Nucl Med. 2004;45:129–
    clonal antibody reactive with normal and leukemic         value of the MDR1 reversal agent PSC-833 in                137.


    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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