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EDITORIAL
Retinoid Resistance in Acute Promyelocytic Leukemia: New Mechanisms,
Strategies, and Implications
By Raymond P. Warrell, Jr
N
EOPLASTIC CELLS, through their various stages of
growth and differentiation, develop a certain imperviousness to the various environmental, immunologic,
toxicologic, and pharmacologic onslaughts to which they
are subjected. A general example of this problem is expression of multidrug resistance wherein the activity of a glycoprotein pump responsible for efflux of toxins from the cell is
increased, causing relative cross-resistance to a broad spectrum of compounds including anthracyclines, taxanes, and
vinca alkaloids.' Expression of multidrug resistance at the
time of diagnosis is associated with a substantially worse
outcome in patients with acute myeloid l e ~ k e m i a ,and
~?~
increased MDR gene expression accounts in part for the
progressively diminishing responsiveness of patients at the
time of relapse as they are subjected to repeated cycles of
drug combinations.
The recent success of using all-trans retinoic acid (RA) in
acute promyelocytic leukemia (APL)"7 has engendered interest due not only to the novelty of the drug but also to its
apparent mechanism of action whereby cells develop an
increasingly mature phenotype before their eventual elimi n a t i ~ n . ~As, ~ reported by both French and American
groups,'-'' the approach of using all-trans RA for remission
induction followed by anthracycline-based consolidation
has already achieved a significant increase in both relapsefree and overall survival in patients with APL. However,
this treatment sequence was less inspired than impelled by
early observations that despite near universal success in inducing remission, antileukemic responses induced by alltrans RA were brief in duration. Moreover, relapses that
have occurred while taking the drug have absolutely precluded another response. A final paradox was that leukemic
cells taken from relapsing patients appeared to retain sensitivity in vitro despite clinical resistance. In APL at least,
retinoid resistance has seemed to develop quite regularly
and rapidly.
Retinoids are critical regulators of numerous physiologic
actions including visual response, morphogenesis, and
various aspects of cellular differentiation," and their involvement is quite ancient from an evolutionary standpoint. Thus, it should come as no surprise that nature has
evolved several means of dealing with an excess of these
naturally occumng substances. A brief review of retinoid
pharmacology suggests several possible areas whereby this
process may arise12(Fig 1). All-trans RA normally circulates
in plasma in nanomolar concentrations, and it traverses the
cell membrane by passive diffusion across a concentration
gradient. However, any contribution of this plasma component to normal physiology seems unlikely because under
homeostatic conditions, cells probably derive whatever retinoic acid they require by intracellular conversion from preformed retinol. Whatever its source, cytoplasmic all-trans
RA can be bound to cellular retinoic acid binding proteins;
in myeloid cells, the predominant form is CRABP-11. While
Blood, Vol82, No 7 (October 1). 1993: pp 1949-1953
originally thought to perform a largely sequestory function,
recent data suggest that such binding facilitates presentation
of the retinoid to oxidative enzymes that catalyze conversion to inactive metabolite^.'^^^^ A second catabolic pathway may involve an interaction with lipid hydroperoxides
that generate free oxygen radicals that also result in oxidative i n a c t i v a t i ~ n . ' Only
~ , ~ ~ unbound retinoic acid that diffuses through the nuclear membrane is potentially effective
in transducing a response. In the nucleus, all-trans RA binds
to one of several retinoic acid receptors (RARs), members
of the steroid/thyroid superfamily of nuclear re~eptors'~;
to
date, a, p , and y subtypes have been characterized. When
activated by their ligand, RARs form dimers that then bind
to specific DNA segments known as retinoic acid response
elements (RAREs). Translation of mRNAs then control the
downstream activation of retinoid response genes that ultimately effect the retinoid response. The t( 15; 17) translocation in APL disrupts the gene encoding RAR-a which is
located on chromosome 17, causing its fusion to the PML
gene on chromosome 15.'8-20RAR-a has been directly implicated in granulocytoid maturation and differentiation,2'
and transfection of mutant PMLIRAR-a confers relative
retinoid resistance to HL60 cells in culture.22
With that background, there are several obvious regions
where retinoid resistance might arise, with the important
caveat that such resistance must necessarily be relative
rather than absolute. (It is difficult to envision a scenario of
complete insensitivity to an essential regulatory molecule
that normally functions in so many critical pathways.) In
APL, one obvious explanation is the generation of further
mutations in RAR-a. The utility of retinoids in causing differentiation of human leukemia was first suggested by Breitman et a123,24using HL60, a promyelocytic leukemia cell
line that was subsequently shown not to carry the 15;17
t r a n s l ~ c a t i o n .Several
~~
groups have now isolated mutant
HL60 subclones that are resistant to all-trans RA, and in
least one of these lines, an RAR-a mutation has been identified.z6(Other groups have reported isolation of RA-resistant
subclones of NB4 cells, a new line that stably carries the
15;17 tran~location?~
however, the mechanism[s] involved
have not yet been elucidated.) Nonetheless, it seems unFrom the Developmental Chemotherapy and Leukemia Services,
the Department of Medicine, Memorial Sloan-Kettering Cancer
Center, New York, NY.
Supported in part by Grants No. FD-R-000764from the Orphan
Products Division, Food and Drug Administration, CA-57645from
the National Cancer Institute, and EDT-47 from the American
Cancer Society.
Address correspondenceto Raymond P. Warrell.Jr, MD, Memorial Sloan-KetteringCancer Center, 127.5 York Ave. New York, NY
10021.
0 1993 by The American Society of Hematology.
0006-4971/93/8207-00S 1$3.00/0
1949
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1950
Fig 1. An example of biologic redundancy. Pharmacologic quantities of all-trans retinoic acid (RA) cross the cell membrane by passive diffusion. The drug can be bound by cellular retinoic acid binding proteins (CRABP) that may facilitate presentation to and
degradationby cytochromeP450 enzymes inthe endoplasmic reticulum. Alternatively, the drug can be oxidized to inactive metabolites by interaction with lipid hydroperoixdes. Only unbound drug is
able to diffuse into the cell nucleus, bind to the retinoic acid receptor (RAR), undergo dimerization with another RAR or with the retinoid "X" receptor (RXR), and generate the retinoid response. By
contrast, the isomer 9-cis retinoic acid can bind either RARs or
RXRs. RXRs have recently been shown to form heterodimers with
both vitamin D receptors (VDR) and thyroid hormone receptors
(TR).
likely that further acquired RAR-a mutations can explain
the clinical problem of retinoid resistance. First, clinical resistance appears almost universally and it develops quite
rapidly. Once established, it has proven unexpectedly longlived; however, most groups have reported that patients
with APL who have relapsed from a remission induced by
all-trans RA but who have not taken the drug for a number
of months can achieve a second remission induced by alltrans RA. Second, the described RAR-a mutations in human leukemic cell lines have arisen only under exceptionally artificial circumstances with the pressure of continuous
culture and subculture at high retinoic acid concentrations
(usually 2
mol/L). By contrast, the usual clinical dose
of all-trans RA achieves a peak plasma concentration >
mol/L only transiently (for 1 to 2 hours) which disappears
with a half-life of 40 minute^.^^^^^ For a genetic mutation
theory to hold, one also cannot postulate that RAR-CYmutations occur generally but rather only in APL cells (perhaps
because the previous translocation had increased the likelihood of spontaneous mutation). Moreover, the mutation
must either occur rapidly (to account for the brief remission
duration) or naturally (leading to a preferential growth advantage of cells that carry the additional defect). Finally, the
mutation cannot be stably camed because it does not appear that clinically induced resistance is permanent. The
combination of these unlikely postulates strongly suggests
that other mechanisms are operative.
RAYMOND P. WARRELL, JR
The unlikelihood of further mutations has yielded the
current leading hypothesis, namely that pharmacologic alterations in the metabolism of all-trans RA are responsible
for clinical retinoid resistance. At once, this hypothesis suggests changes that might occur rapidly and universally, and
that might be inducible in the presence of drug but yet reversible at some point after drug withdrawal. We had previously shown that continuous treatment of patients with
APL results in a progressive diminution of plasma drug concentrations and speculated that this decrease might eventuate in levels that were below some critical threshold that
would initiate ~ytodifferentiation.~'This induced decrease
is now known to be neither disease-specific to APL,3'-34nor
even ~pecies-specific;~~.~~
however, the mechanisms of the
induced decrease and the magnitude of its contribution to
clinical resistance are not entirely clear.
Clinically, systemic treatment with all-trans RA markedly increases expression of cytoplasmic retinoic acid binding proteins in leukemic cells.37In this issue of BLOOD,
Delva et aI3' report similar results but with two important
distinctions: first, they show that in the same patient
CRABP-I1 expression is increased at the time of relapse
compared with that patient's pretreatment levels; second
they show that while cells from relapsing and clinically resistant patients retain partial sensitivity to the cytodifferentiating actions of all-trans RA, a clear shift to the right has
occurred in the concentration-effect curve. Sensitivity was
retained at a favorite (albeit suprapharmacologic) concentration of
mol/L, but minimal effects were observed at
lo-' mol/L." In leukemic cells, an increased amount of
CRABP might rapidly bind an excess of cytoplasmic alltrans RA, thus preventing its transport to the nucleus and
facilitating its enzymatic catabolism. However, there are
some problems with accepting this phenomenon as a sole
explanation for resistance. Intuitively, one would expect
that the binding capacity of this protein in APL cells would
be rapidly saturable with continuous dosing and that the
excess would then freely spill into the nucleus. That objection is overcome by noting that increased CRABP expression does not occur in leukemic cells in isolation, but rather
as a generalized process in many tissues. Previous work had
shown that topical applications of all-trans markedly increases CRABP expression in skin.39Thus, one could envision the whole body as a "retinoid sponge" that might rapidly absorb the circulating retinoid from plasma. The work
of Delva et aI3' suggest an explanation that is complimentary to the previously described reduction in extracellular
drug levels that nonetheless yields the same effect, namely a
reduced intranuclear concentration of the ligand.
Some recent developments have increased the complexity of this picture. The pharmacology of all-trans RA has
now been examined in patients with a variety of diseases
and in normal subjects. It appears that there are extraordinarily wide differencesin constitutive rates of retinoid catabolism among individuals, and that these differences are
readily distinguished by administering test doses of all-trans
RA. We have pursued these tests in more than 80 subjects3'
(and R. Warrell, et al, unpublished data), and it is clear that
differences in catabolic rates occur without prior exposure
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1951
RETINOID RESISTANCE
to exogenous retinoids. In other words, some individuals
achieve very low plasma drug levels even with their first
dose, and in many cases, this accelerated rate also correlates
with reduced plasma concentrations of endogenous retin o i d ~ . There
~'
may well be both genetic and environmental
explanations for such metabolic differences, but it is clear
that clinical pharmacologic studies in small numbers of individuals can be quite misleading. It is tempting to speculate
that alterations in such rates create susceptibility to diseases
that might be reversed by retinoid treatment, or that individuals with a constitutively rapid rate of clearance might be
those who would most benefit from retinoid treatment (albeit in diseases other than APL). An increase in cytochrome
P450 enzyme activity may account in part for these differences, because nonspecific inhibitors of these enzymes such
as ketoconazole and liarozole significantly reduce both the
constitutive and inducible patterns of accelerated catabol i ~ m , ~ ' a, ~finding
, ~ ' that suggests they are both a manifestation of the same process. In addition, Muindi and Young'6
have shown that increases in lipid hydroperoxides (the alternate pathway in Fig 1) also can accelerate the oxidation of
all-trans RA, and that this process may also be inducible.
There is obviously a tremendous redundancy inherent in
these systems that act in concert to buffer intracytoplasmic
retinoid concentrations, but their net effect is the same:
modulation of the effective intranuclear retinoid concentration before ligand binding and receptor activation. A key
question is whether this knowledge can be usefully exploited
to contravene the problem of acquired retinoid resistance in
APL or other diseases for which such treatment may be
useful. Several possible strategies are outlined in Table 1. If
excess CRABP is the major problem as suggested by Delva
et al,38then use of a retinoid that does not bind CRABP yet
still generates the retinoid response may represent a useful
approach. In fact, however, one such compound has been
readily available for some time: 13-cis retinoic acid. Unfortunately, this agent does not appear to have substantial clinical
and in vitro it seems to require at least a log
higher concentration than all-trans RA to differentiate
freshly aspirated human APL cells in short-term culture."'
Intermittent treatment rather than the current practice of
continuous daily dosing represents another possible strategy. Adamson et al" recently showed that a drug-induced
elevation in CRABP levels decreased within 2 weeks of
stopping therapy in a small number ofpatients. Delva et a13'
suggest that relapsing APL patients might be tested for such
levels using reverse transcription and quantitative polymerase chain reaction analysis to indicate potential clinical responsiveness. However, two problems with this strategy are
that retinoid resistance is probably not mediated by increased CRABP alone, and that clinical resistance after withdrawal from all-trans RA dosing extends considerably
beyond the 2-week point (longer than 1 year in several of
our patients). Nonetheless, anecdotal evidence from several
patients with APL suggest that maximal cytodifferentiating
effects may be achieved within the first 2 weeks of treatment, and that additional therapy during induction may be
superfluous. This important lead (ie, the shortest duration
Table 1. Possible Clinical Strategies T o Overcome Acquired
Retinoid Resistance
Strategy
Liposomal encapsulation
Cytochrome P450 enzyme
inhibitors (ketoconazole,
liarozole, etc)
Low-dose retinoid treatment
RT-PCR for CRABP
Intermittent dosing
O2radical scavengers
Serial pharmacologic testing
Drug discovery
Alternative retinoid ligands
Possible Result
Parenteral formulation; increases
plasma levels
Decreased P450 oxidation
? Lower potential for inducing
accelerated catabolism
Allows treatment only when
CRABP levels are low
? Decreased metabolic induction;
? more rapid downregulation
of P450 and CRABP
? Decreased oxidation by
alternate pathway
Allows dosing only when high
plasma levels are achievable
Bypasses normal catabolic
pathway
May allow activation of retinoid
response by different
oathwavs
of therapy rather than the lowest possible dose) should be
explored further.
Several strategies have sought to overcome the induced
decrease in plasma drug levels. The simplest approach
would be to administer a larger quantity of drug by the
intravenous route. This approach has been constrained to
date by the lack of a suitable pharmaceutical formulation;
however, a liposomally encapsulated form of all-trans RA
has recently become a ~ a i l a b l e ?and
~ while probably impractical for extended therapy it should provide a critical
test of the pharmacologic theory of acquired resistance. Another approach is to use pharmacologic inhibitors of cytochrome P450 oxidative enzymes. While short-term treatment with both ketoconazole and liarozole can attenuate
the induced increase in catabolic rate^,^',^'*^' these combinations have not yet been shown to sustain high plasma levels
on an extended basis. A combination with interferon-cu is
theoretically appealing both for a possible additive effect of
the two agents as well as the activity of interferon to affect
the P450 p a t h ~ a y . ~ ~
Although
,~'
one report clearly suggested reversal of acquired re~istance,~'
another report has
shown acceleration of leukemia by this approach.49Combinations of putatively differentiating agents surely represent
a fruitful area for clinical testing but not necessarily for the
purpose of overcoming retinoid resistance. It was originally
believed that lower doses of all-trans RA might decrease
induced resistance and avoid other undesirable effects such
as excessive leukocytosis and the "retinoic acid syndr~me"'~;however, this has not proven to be the case.5'
Finally, it must be recognized that none of the aforementioned strategies may prove successful; therefore, drug discovery using novel screening systems such as NB4 or fresh
human leukemic cells in short-term culture may represent
the most promising approach. Although HL60 has provided
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RAYMOND P. WARRELL, JR
1952
tremendous insights into leukemogenesis a n d myeloid differentiation, as a predictive model for h u m a n neoplasia it
has proven somewhat less than representative. For APL, the
availability of systems that stably carry the relevant chromosomal translocation should provide a considerably more informative result. T h e first agents that should be tested include alternative retinoids, such as 9-cis retinoic acid, an
agent that binds to both RARs and retinoid “X” receptors
(RXRS).’*-’~Other possibilities include agents that selectively activate specific retinoid receptors such as RAR-@,
R A R - Y , or
~ ~the R X R S . ’ ~
T h e problem of retinoid resistance i n APL extends well
beyond this particular disease a n d applies to the prospects
for “differentiation therapy” as a method of cancer treatment. Single agents such as retinoids m a y affect neoplastic
cells at only a specific point i n their life cycle. Myeloid cells
appear to require all-trans RA at the promyelocyte stage
a n d will arrest there if there is a block; however, leukemic
progenitors at an earlier stage may well be insensitive, b u t at
that stage they retain t h e capacity for self-renewal. If this is a
general case, then treatment on an indefinite basis will be
required absent some other intervention (eg, use of a cytotoxic drug or generation o f an i m m u n e response). If so, then
resistance to the agent must absolutely not occur, otherwise
t h e clinical response will inevitably prove short-lived, as indeed it has in APL. T h a t resistance t o all-trans RA occurs so
rapidly and uniformly does not bode well for the prospects
of extending this type of treatment, and this feature m a y
well represent an absolute constraint on the utility of the
approach. T h e cytodifferentiating activity of all-trans retinoic acid in myeloid cells was observed nearly 14 years ago,
and over the succeeding time this pathway has hardly been
unexplored. Therefore, it is quite sobering to recognize that
a form of genetic therapy, so exquisitely targeted to the specific molecular defect i n a small disease, can be so readily
undermined by the most trivial aspects of clinical pharmacology. O n e can hope that this case will prove exceptional,
lest the enormous efforts devoted toward intervention in
other molecular pathways be similarly confounded.
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From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
1993 82: 1949-1953
Retinoid resistance in acute promyelocytic leukemia: new
mechanisms, strategies, and implications [editorial; comment]
RP Jr Warrell
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