Download Ac-225 and her daughters: the many faces of Shiva

Cell Death and Differentiation (2002) 9, 593 ± 594
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News and Commentary
Ac-225 and her daughters: the many faces of Shiva
MR McDevitt1 and DA Scheinberg*,1
1
Program of Molecular Pharmacology and Chemistry, Sloan Kettering Institute,
New York, New York, USA, 10021
* Corresponding author: Tel: 212-639-5010,
E-mail: [email protected].
DOI: 10.1038/sj/cdd/4401047
Radioimmunotherapy (RIT) has evolved over a period of 20
years from the use of polyclonal antibodies conjugated to
long-ranged beta emitting halogen radionuclides such as I131 to the use of tumor specific monoclonal antibodies, their
fragments, or other tumor selective peptides employing
increasingly sophisticated radionuclides1,2 such as Bi-213,
At-211, Y-90, Lu-177, and Re-188 as the means to arm the
targeting moiety to render it selectively lethal to the tumor
cells. We have now reported methods for targeting tumor cells
with Ac-225 atomic nanogenerators.3
Ac-225 is an alpha particle emitting radionuclide with a
10.0 d half-life.4 Ac-225 yields several daughter radionuclides in its decay scheme (Figure 1a) and a net of four
alpha particle emissions. The parent and the daughters are
each individually lethal to cells. Actinium therefore can
serve as an atomic scale in vivo generator of alpha particle
emitting elements. Alpha particles are charged helium
nuclei that travel approximately 50 ± 80 micrometers (2 ± 4
typical cell diameters) and individually are able to kill a
target cell due to their deposition of 5 ± 8 MeV in a short
ionizing track, while largely sparing surrounding cells; it is
this characteristic that offers clear advantages to other
known forms of radiation as a means of selective cell kill.
Monoclonal antibodies that target a variety of different
cancer cells and that were internalized following binding to
cell surface antigenic molecules were modified to carry Ac225 atoms stably to the tumor cell.3 This work also
describes the use of these molecular-scale devices against
both disseminated and localized cancer models in mice and
some of the challenges that remain to be explored.
The field of radioimmunotherapy has benefited from
increasingly better identification of and understanding of the
biology of the tumor antigen ± antibody systems, the
availability of promising radiometals with unique characteristics, and subsequent development of radiometal ± chelate
chemistry necessary for their use. Appropriate radiometal ±
chelate chemistry is fundamental to success in this area,
providing stable attachment of the potentially toxic radiometal to the targeting molecule in order to deliver it to the
cell or into the cell without loss of it to metabolic or
catabolic pathways which might endanger the patient or
diminish the focus of the administered dose.5 Radiometals
typically will remain inside a cell when internalized, despite
cellular catabolic events. On the other hand, halogens, of
which radioiodine or radioastatine are examples, are often
rapidly excreted from the cell following catabolism 6
reducing the efficacy of the dose administered and
increasing doses to non-target tissues such as the thyroid,
stomach and urinary tract.
The requirement for reliable sources of pure reactive
radiometals, possessing emissions that are therapeutically,
diagnostically and dosimetrically useful, has resulted in the
development and study of a number of beta particle
emitting nuclides including Y-90, Lu-177, and Re-188 and
a number of alpha particle emitting radionuclides including
Bi-213, At-211, and Ac-225. Alpha particles have a far
shorter path length and a much higher linear energy
transfer than beta particles (Figure 1b); they have been
demonstrated to be significantly more selective and potent
in killing targeted cells.7 The therapeutic potential of Ac-225
and its decay daughters was unrealized in vivo due to the
varied chemical periodicity of the daughters, as no single
chelating agent would bind all of them. One proposed
solution to this problem was to bind the Ac-225 stably to an
appropriate chelate in order to deliver it to the tumor and
then rely on the antigen ± antibody complex to modulate
and efficiently transport the Ac-225 inside the cell. Once
inside, it was demonstrated that the Ac-225 and its
daughters remain internalized. Thus the daughters were
also utilized therapeutically and not released systemically
to accumulate in normal tissue.
Internalization of the radionuclide increases the probability that an ensuing particulate alpha emission will
traverse the interior of the cell. Furthermore, the multiple
alpha emissions from the Ac-225 nanogenerator source
further increase the chances of a cytotoxic event occurring.
In a variety of cancer models studied in vitro, a specific
antibody that is labeled with Ac-225 is approximately 1000
times more potent on a mCi basis than the same antibody
labeled with Bi-213 which emits only a single alpha and
which has a 46 min half-life. This time is so short that only
a fraction of the administered atoms will be internalized into
target cells. The increased potency may be thus rationalized by both the 313-fold longer Ac-225 half-life and the
four net alphas emitted.
Cellular responses to alpha particle exposure have been
characterized and include gene mutation, chromosomal
aberrations, cell cycle arrest, the induction of micronuclei
and sister chromatid exchanges, lethality8 and the induction
of apoptosis.9 The exact mechanisms by which alpha
particles damage cells have not been determined. Obvious
possibilities include direct alpha particle interaction with
DNA and hydroxyl radical interactions, with DNA promoted
by the high energy particle track through the cell yielding a
significant number of ionizing events. Less obvious is the
biological production of reactive oxygen species, superoxide and hydrogen peroxide, following exposure of human
News and Commentary
594
A
B
Figure 1 (A) The decay scheme of Actinium-225, showing half-lives and
major emissions. (B) Differences in the radiobiology and geometry of beta and
alpha particles. The left side shows the long-ranged, low energy deposition of
the beta particle from an antibody targeted to a cluster of tumor cells in the
vasculature. Nearly all of the energy is deposited in the normal tissue and not
in the targeted cell. The right side shows a high linear energy transfer (LET)
alpha particle emitted from a radiometal chelate conjugated antibody, in which
most of the energy is retained within the target, yielding little bystander
damage and the unique capability of single cell kill. With the several alpha
emitting daughters internalized within the target cell, the effect is amplified
cells to alphas, which has been shown to mediate DNA
damage indirectly in the absence of direct alpha hits on the
cell.8,10 The induction of apoptosis may be initiated in some
cell types as a result of passive DNA damage following
alpha exposure8 and contribute to the overall cytotoxicity.
Microvascular endothelial apoptosis has been demonstrated to be the primary lesion leading to stem cell
Cell Death and Differentiation
damage in mice following radiation exposure11 and this
may be a factor in vivo.
A surprising phenomena that we have observed is the
resistance of a drug resistant leukemia cell line, RV+, to
alpha particles. Exposure of RV+ and HL60 leukemia cells
to either Bi-213 or Ac-225 labeled HuM195 (both of these
cell lines express the CD33 antigen in similar amounts and
both internalize the radiolabeled HuM195 antibody with
similar kinetics) demonstrate a marked difference in the
LD50 of radiolabeled construct necessary to kill cells. This
phenomena necessitates further exploration since it may
have implications for effectiveness of RIT of drug resistant
cancers, commonly found in humans, and the mechanism
of relative radioresistance to targeted alphas, an observation not previously described.
The extraordinary potency of alpha emissions predicts
that use of Ac-225 labeled antibodies clinically in humans
will utilize extremely low amounts of radioactivity, perhaps a
fraction of a milliCurie (approximately 4E6 disintegrations
per second). Furthermore, Ac-225 is more potent and
specific than other radionuclides and may prove more lethal
to tumor cells and other diseases when attached to an
optimal targeting vehicle. Little is known now about the
biology, chemistry or pharmacology of drugs based on Ac225, and future efforts involving Ac-225 should include
investigations into its mechanisms of action and resistance,
its chemistry and daughter properties, better targeting and
pretargeting vehicles for cancers and other diseases, the
role of tumor vascular targeting, and intrathecal and
intraperitoneal regional therapeutic approaches in patients.
Acknowledgement
DA Scheinberg is a Doris Duke Distinguished Clinical Science Professor.
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