Clinical Drug Resistance: The Role of Factors
`Other Than %Glycoprotein
`STANLEY B. KAYE, BSC, M.D., Glasgow, Scotland
`
`to
`is a major obstacle
`resistance
`drug
`Clinical
`it
`for cancer. When
`successful
`chemotherapy
`occurs,
`resistance
`to a wide
`range of agents
`is noted. This clinical observation
`should not
`be confused with so-called
`“multidrug
`resis-
`is a laboratory-based
`tance,” which
`phenome-
`non, whereby
`cross-resistance
`in experimen-
`tal models
`to structurally
`unrelated
`com-
`pounds
`is seen and
`is due
`to
`increased
`ex-
`pression
`of P-glycoprotein
`(PGP).
`In
`the ma-
`jority
`of cases of clinical
`drug
`resistance
`in
`solid
`tumors
`it is likely
`that other
`factors
`will play a major
`role. These other
`factors
`can be defined
`as pharmacologic
`or cellular.
`Pharmacologic
`factors
`are
`those
`that prevent
`an adequate
`degree of tumor
`cell exposure
`of dose and sched-
`and
`include
`considerations
`ule of drug, and also of drug metabolism,
`which may relate
`to concomitant
`medication
`and
`to genetic
`variations.
`Clinical maneuvers
`to circumvent
`drug
`resistance
`by increasing
`dose are so far of unproven
`value. Cellular
`cell
`factors
`are
`those
`that apply at the
`tumor
`itself, and
`it is probable
`that multiple mecha-
`nisms exist. These
`include
`considerations
`of
`drug uptake,
`activation/inactivation,
`and
`changes
`in target
`enzymes and
`in DNA
`repair
`processes. After DNA damage has occurred,
`key determinant
`of the sensitivity
`of the
`tumor
`cell
`is its ability
`to undergo
`apoptosis.
`It
`is conceivable
`that
`failure
`to engage
`this
`process
`is a key factor
`in resistance
`to a
`number
`of drug classes, although
`there
`is lit-
`tle clinical
`evidence
`to support
`this at pres-
`ent. However,
`the genetic
`controls
`for
`the
`process of apoptosis
`are now being unrav-
`eled, and
`if this notion
`proves
`correct,
`the
`possibility
`will exist
`for
`the design of more
`rational means of circumventing
`drug
`resis-
`tance
`to a wide
`range of agents.
`In the mean-
`time, strategies
`that should be pursued
`fur-
`ther
`in order
`to overcome
`this key clinical
`problem
`include
`further
`exploration
`of alter-
`
`a
`
`From
`
`the CRC Department
`
`01 MedIcal Oncology, University of Glasgow, Glas-
`
`Buldrng, Garscube Estate, Bearsden, Glasgow G61 1BD.
`
`or sequential
`nating
`new non-cross-resistant
`taxoids.
`
`and using
`drug schedules
`agents, such as
`
`T he use of drugs
`
`is a rela-
`cancer
`treating
`for
`Chemotherapy
`phenomenon.
`tively modern
`was first used in the 1940s following
`observations
`made during World War
`II.’ Clinicians
`quickly
`learned
`that cytotoxic
`drugs are nonspecific poi-
`sons, but by skillfully manipulating
`drug schedules,
`it was possible
`to capitalize on the remarkable
`ob-
`servation
`that
`recovery
`from
`the toxic side effects
`occurs more quickly
`in normal
`tissues than
`in cer-
`tain chemosensitive
`cancers.
`It has become clear,
`however,
`that
`the number of solid tumors
`that pos-
`sess such exquisite
`chemosensitivity
`is very
`lim-
`ited, and for the majority
`of common solid tumors,
`this sensitivity
`to drugs is eventually
`lost. Although
`temporary
`further
`benefits can be obtained by re-
`treatment
`with
`cytotoxic
`drugs,
`resistance
`to a
`wide
`range of agents generally
`becomes evitlellt
`and is ultimately
`fatal. This phenomenon
`remains a
`principal obstacle
`to successful
`treatment,
`and for
`clinicians it is particularly
`frustrating.
`(:ontrast,
`fol
`example,
`the management. of a young man with
`tes-
`ticular cancer with
`that of a patient with small-cell
`lung cancer. The response
`to treatment
`of widely
`metastatic
`testicular
`cancer
`is generally
`dramatic:
`more
`importantly,
`this
`is followed by permanent
`eradication of tumor and cure. In the case of small-
`cell lung cancer, however,
`impressive
`tumor
`re-
`sponses are usually not maintained
`long-term,
`and
`relapse after several months
`(or possibly years)
`is
`the norm
`rather
`than
`the exception.
`Clinically,
`the observation
`is that when drug re-
`sistance occurs, it applies
`to a wide range of struc-
`turally unrelated
`drugs.
`It
`is important
`that
`this
`clinical observation
`is not confused with
`the experi-
`mental observation
`that has been given
`the unfor-
`tunate
`title of “multidrug
`resistance.”
`This
`latter
`observation
`is a fascinating experimental
`phenome-
`non whereby drug resistance
`to a range of natural
`products appears
`to be mediated
`through
`increased
`expression of the membrane
`transport
`pump known
`as P-glycoprotein
`(PGP). Since
`its discovery
`in
`1976,” extensive studies have taken place to ascer-
`tain the clinical relevance of this phenomenon. This
`has been critically
`reviewed
`elsewhere,”
`but cur-
`rent
`information
`indicates
`that
`increased PGP ex-
`
`6A-4OS
`
`December 29. 1995 The American Journal of Medune Volume 99 (SUPPI 6A)
`
`Ex. 1092-0001
`
`

`

`of
`in the development
`pression could be relevant
`its
`drug
`resistance
`in hematologic
`cancers, while
`In-
`role in solid tumors seems much more
`limited.
`terestingly,
`increased expression of PGP correlates
`with a worse outcome
`for a number of cancers, in-
`cluding breast and colon cancer.4$6 However,
`there
`is little
`information
`from sequential studies
`to link
`this observation with
`cytotoxic
`drug
`resistance.
`Further
`studies are clearly
`required
`in order
`to
`clarify
`the prognostic
`importance
`and biological
`implications
`of increased PGP expression.
`The growth of cancers is characterized by genetic
`instability.6
`This implies
`that during
`the develop-
`ment of tumors, heterogeneous
`populations
`of cells
`will expand, expressing varying degrees of chemo-
`sensitivity
`according
`to a range of cellular
`factors.
`The impact of chemotherapy will be to exert power-
`ful selection pressures on these populations,
`allow-
`ing the outgrowth
`of the most chemoresistant.
`A
`further
`important
`factor
`is that as tumors grow,
`penetration
`of cytotoxic drugs
`into tumor cells may
`diminish because of changes in vascularity and oxy-
`genation. Taken together,
`these considerations
`indi-
`cate that several
`factors are likely to impact on the
`development
`of clinical drug
`resistance;
`further,
`it is highly probable
`that a number of these will
`coexist.
`WHAT ARE THE FACTORS UNDERLYING CLINICAL
`DRUG RESISTANCE?
`in clinical
`to be involved
`Factors
`that are likely
`drug
`resistance can be divided
`into pharmacologic
`and cellular
`factors.
`
`Pharmacologic Factors
`is ade-
`of chemosensitivity
`A key determinant
`i.e., the
`quate drug exposure at the site of action,
`tumor cell. Drug exposure
`is a function of both drug
`concentration
`and time. The major
`factor
`that con-
`trols drug exposure
`is the treatment
`regime used,
`i.e., the dose and/or
`infusion duration,
`and this
`is
`generally
`limited by considerations of normal
`tissue
`toxicity. Differences
`exist according
`to drug
`type;
`for example,
`the peak concentration
`is more critical
`than duration
`of exposure
`for alkylating
`agents
`(e.g., cyclophosphamide),
`whereas
`the
`reverse
`is
`the case for phase-specific drugs, such as antime-
`tabolites
`(e.g., methotrexate).
`Data
`from experi-
`mental models of drug resistance
`indicate
`the pres-
`ence of a relatively steep dose-response
`curve (par-
`ticularly
`for alkylating
`agents), and
`these have
`stimulated
`the design of various
`circumvention
`strategies. However,
`extrapolations
`to
`the prob-
`lems of clinical drug resistance are not straightfor-
`ward, although a number of clinical studies are now
`underway
`(see below).
`
`SYMPOSIUM
`
`ON CHEMOTHERAPY
`
`/ KAYE
`
`TABLE I
`Some Cellular Mechanisms Described in Experimental
`Models of Drug Resistance witi Selected Examples
`
`Mechanism
`
`Drug
`
`Reference
`
`Defective/altered drug
`transport (including
`reduced receptor binding
`or membrane protein1
`Reduced intracellular
`activation, or Increased
`inactrJation (e.g., by
`glutathionel
`Reduced afhn~iy for, or acts~t~
`of rntracellular target enzymes
`
`i Increased repair capacity
`1
`I
`
`Met’lotrexate
`AlkylaMg agents
`Clsplatin
`Natural products
`Cytoslne arablnoside
`Clsplatln
`Anthracycllnes
`
`Methotrexate
`Sfluorouracil
`Toplsomerase I and II Mtors
`Alkylating agents
`Clsplatin
`Nltrosoureas
`
`1301
`1191
`I191
`1311
`1321
`1191
`1331
`
`1341
`1351
`1361
`1191
`1231
`I371
`
`Drug exposure may also be limited because of
`morphologic
`considerations,
`e.g., a tumor within
`the
`central
`nervous
`system, where
`the blood-brain
`barrier may prevent adequate exposure
`to pharma-
`cologic intervention.
`However, a more general
`limi-
`tation applies to cancer cells within poorly vascular-
`ized regions of large tumor masses; suboptimal ex-
`posure
`results
`from
`limited penetration
`and is fur-
`ther complicated
`by the development
`of hypoxic
`areas that can reduce
`the efficacy of a number of
`cytotoxic agentsa
`drug exposure at the
`In many cases, adequate
`tumor cell depends on conversion of the drug
`to its
`active
`form
`following administration.
`Examples
`in-
`clude alkylating
`agents, which depend on hepatic
`metabolism,
`involving
`the cytochrome P450 enzyme
`system,
`to the active species. The level of activity of
`this enzyme system
`is subject
`to considerable
`inter-
`patient variation, which may well be based on ge-
`netic differences.”
`
`Cellular Factors
`is
`cell exposure
`tumor
`Assuming
`that optimal
`the
`obtained,
`a number
`of
`factors pertaining
`to
`tumor cell itself may then be considered. These in-
`clude (a) defective
`drug
`transport
`across the cell
`membrane;
`(b) enhanced drug
`inactivation
`or re-
`duced drug activation;
`(c) altered
`levels of (or al-
`tered affinity
`for) a target enzyme;
`(d) enhanced
`level of repair of DNA damage. Examples
`for each
`of these have been
`identified
`for the major drug
`types using ex~e~irrLenta1 ~nzodels and are summa-
`I; when drug
`resistance arises elini-
`rized in Table
`tally,
`it seems likely
`that a number of mechanisms
`will come into play, but
`the extent
`to which
`these
`coexist has not yet been clarified.
`
`December
`
`29, 1995
`
`The American
`
`Journal of Medicine
`
`Volume 99 (suppl 6A)
`
`6A-41s
`
`Ex. 1092-0002
`
`

`

`SYftwOSluM ON CHEMOTHERAPY / KAYE
`
`agents.
`the effects of myelosuppressive
`against
`trials are now addressing
`the issue of the
`Clinical
`importance
`of dose escalation,
`which
`can be
`in
`achieved
`this way, and
`results
`are eagerly
`awaited. This applies particularly
`to those agents,
`such as alkylating
`agents, where preclinical
`and
`clinical data indicate a positive correlation between
`increasing
`response and dose’”
`(rather
`than dura-
`tion).
`It seems likely that
`the benefits,
`if any, of this
`approach will be seen
`in its
`integration
`into
`the
`management
`of chemosensitive
`cancers, e.g., lym-
`phoma,14
`rather
`than
`relatively
`resistant
`cancers,
`e.g., melanoma.‘”
`to the potential
`Data already available do point
`limitations
`of dose escalation over a modest dose
`range. Randomized
`trials in ovarian cancer in which
`the dose of cisplatin has been doubled
`in one arm
`have shown that although
`response and median sur-
`vival can be improved,
`long-term
`survival
`is not af-
`fected.‘”
`In order
`to make substantial
`improve-
`ments
`in treatment
`outcome,
`it may
`therefore
`be
`necessary
`to make much
`larger dose increments;
`using
`techniques mentioned
`above, doses can be
`escalated by a factor of at least 4 (for such drugs as
`carboplatin, etoposide, and cyclophosphamide)
`com-
`pared to standard
`regimens.
`the
`i.e.,
`to previously,
`Another
`factor alluded
`development
`of hypoxic cells within poorly vascu-
`larized tumor masses, can be addressed, not by dose
`escalation,
`but by specific drug design. Several
`forms of bioreductive
`agents, which are only acti-
`vated to cytotoxic species in areas of hypoxia, have
`now been developed,
`and early clinical
`trials of
`novel structures
`are encouraging.‘7
`Such agents
`might
`find their greatest clinical utility
`in eombina-
`tion with
`radiotherapy
`(or other
`forms of chemo-
`therapy)
`that would be capable of dealing with ade-
`quately oxygenated
`tumor cells.
`
`it is quite con-
`For the reasons given previously,
`ceivable
`that no single cellular
`factor will be identi-
`fied as being primarily
`responsible
`for any specific
`example of clinical drug
`resistance. However,
`it is
`now clear that
`the mechanism by which many struc-
`turally unrelated
`anti-cancer
`drugs have
`their ef-
`fects involves
`the process of programmed
`cell death
`or apoptosis.” The failure of cancer cells to engage
`this process could underly
`resistance
`to a number of
`drugs. Various genetic
`factors have been identified
`that control
`the process of apoptosis,
`including a
`range of genes, such as ~53, BCL2, and BAX.“’ The
`extent
`to which changes
`in levels of expression of
`any of these genes might provide a common mecha-
`nism for the development
`of clinical drug resistance
`requires urgent study.
`factors
`As described above, a number of cellular
`have been identified as being relevant
`to the devel-
`opment of resistance
`in experimental models. These
`include cell lines derived
`from patients with drug-
`resistant
`tumors, as well as cell lines in which drug
`resistance has been derived experimentally
`by con-
`tinued drug
`incubation
`in vitro. The resistance
`fac-
`tors (the ratio between sensitive and resistant
`in-
`hibitory drug concentrations)
`vary widely
`in these
`models, and
`for
`this
`reason
`in vivo models have
`been developed
`using both spontaneous murine
`tumors and human
`tumor xenografts. These can be
`useful
`for assessing means
`for modulation,
`but
`again
`their clinical relevance
`is unclear. A proper
`assessment of the cellular
`factors
`that underlie clin-
`ical drug
`resistance will
`therefore
`depend on an
`adequate body of information
`derived
`from clinical
`material.
`Ideally,
`tissue should be obtained
`from a
`cohort of patients before
`treatment
`and when dis-
`ease relapses. Patients
`should all receive similar
`chemotherapy
`protocols, and full clinical
`follow-up
`needs to be available. There are few studies
`in the
`literature
`that so far fulfill all these criteria.
`Cellular Factors
`HOW CAN CLINICAL DRUG RESISTANCE BE
`from clinical ma-
`Despite
`the lack of information
`CIRCUMVENTED?
`are being pursued
`terial, a number of strategies
`with
`the hope that at least some of the experimen-
`Pharmacologic Resistance
`the route
`for altering
`A number of options exist
`tal data describing cellular
`factors underlying
`resis-
`of administration
`of cytotoxic drugs, and these have
`tance do have clinical significance. A few examples
`II and described
`the potential
`to circumvent
`drug resistance
`that
`is
`of these are summarized
`in Table
`below.
`determined
`by limited drug access. Regional
`treat-
`of analogues of ex-
`TRANSPORT: The development
`ments, such as intrahepatic
`or intraperitoneal
`ther-
`isting cytotoxic
`agents has
`in some cases been
`apy, have been used extensively, and recent data do
`indicate an advantage
`for this approach
`in certain
`based on improved
`transport properties. One exam-
`circumstances.“~”
`However,
`these will not address
`ple
`is the antimetabolite
`lo-EDAM
`(lo-ethyl-lo-
`the issue of widespread
`systemic disease. An alter-
`dazaminopterin),
`which
`is an analogue of metho-
`native approach
`is the use of high doses of chemo-
`trexate.
`It shows enhanced
`transport
`into malig-
`therapy,
`and modern
`techniques
`allow
`this
`to be
`nant cells, as well as ,enhanced polyglutamation
`and
`employed safely because of the modulation
`of nor-
`therefore
`reduced drug efflux. Phase
`I trials
`re-
`mal
`tissue
`toxicity. Examples
`include
`the use of
`vealed
`dose-limiting
`diarrhea,
`leukopenia,
`and
`peripheral
`blood stem cells to protect bone marrow
`thrombocytopenia,ix
`and Phase
`II
`trials
`have
`6A-42S
`December
`29, 1995
`The American
`Journal of Medicine
`Volume 99 (suppl CA)
`
`Ex. 1092-0003
`
`

`

`lung cancer and
`
`in non-small-cell
`shown activity
`head and neck cancer.
`In experimentalmod-
`ACTIVATION/INACTIVATION:
`to
`els, such as ovarian cancer cell lines, resistance
`alkylating agents and cisplatin has been clearly re-
`lated to intracellular
`levels of glutathione,
`as well as
`metallathionen.‘”
`Glutathione
`(GSH) binds and in-
`activates such agents as cisplatin, and depletion of
`intracellular
`glutathione with
`the specific inhibitor
`of
`glutathione-S-transferase,
`buthionine
`sul-
`phoximine
`(BSO), has been shown to reverse exper-
`imental
`resistance
`to melphalan and to cisplatin
`in
`both
`in vitro and in vivo ovarian cancer models.“’
`Clinical
`trials with BSO have been initiated
`in Fox
`Chase Cancer Center and have confirmed
`the feasi-
`bility of obtaining significant
`reductions of intracel-
`lular GSH levels, as measured
`in peripheral mono-
`nuclear cells.21
`re-
`of agents,
`For a number
`TARGET
`ENZYMES:
`is a significant
`duced affinity
`for the target enzyme
`factor
`that
`limits activity. One of the main intracel-
`lular
`targets
`for 5fluorouracil
`(5FU)
`is the enzyme
`thymidylate
`synthase, which
`is bound by the 5FU
`nucleotide 5FdUMP.
`The tightness of this binding
`is greatly enhanced
`if intracellular
`concentrations
`of reduced
`folate are
`increased, and
`this can be
`achieved experimentally
`by the addition of leucovo-
`rin.22 Clinical trials of this approach have confirmed
`that
`the activity of 5FU can be enhanced
`in this
`way, and at least some elements of 5FU resistance
`may therefore be addressed.
`that
`indicate
`data
`Experimental
`DNA
`REPAIR:
`DNA adducts
`is
`enhanced
`repair of intracellular
`involved
`in resistance
`to cisplatin and alkylating
`agents. A number of intracellular
`enzymes are in-
`volved
`in DNA
`repair, and inhibition of their activ-
`ity clearly
`is a complex procedure. One of the en-
`zymes involved
`is DNA polymerase
`(a and 7) and
`the agent aphidocolin
`is a specific inhibitor
`of this
`enzyme.
`In experimental models aphidocolin
`is ca-
`pable of reversing
`cisplatin and alkylating
`agent
`resistanee,Zx and Phase I t,riaIs of aphidocolin have
`demonstrated
`the
`feasibility
`of achieving
`steady-
`state concentrations
`of drug
`that are equivalent
`to
`those that are active in vitr.oZ4
`
`SYMPOSIUM ON CHEMOTHERAPY / KAYE
`
`TABLE II
`Some Examples of Clinical Studies Aimed at
`Circumvention of Specific Resistance Mechanisms
`
`Mechanism
`
`Altered transport
`
`Actlvatlon/lnactlvatlon
`
`Altered affinity for
`target enzymes
`Increased repalr
`
`Drug
`
`Methotrexate
`
`Cisplatln
`Alkytatmg agents
`54uorouracil
`
`Examples
`
`Methotrexate analogues,
`[e.g., 1OEDAMl
`EGO
`lgltiathlone deple!ioni
`Leucovorin (binding to TS)
`
`Glsplahn
`
`Aphldocokn
`
`to resistant cells and
`rate
`function of the mutation
`the total number of tumor cells present. The prob-
`ability of cure equals e-‘r(M-l), where e is the base
`of natural
`logarithms,
`(Y is the mutation
`rate per cell
`generation,
`and M is the total number of cells pres-
`ent in the tumor. Put simply,
`this indicates
`that
`the
`larger
`the
`tumor
`in terms of numbers of cells or,
`alternatively,
`the higher
`the mutation
`rate,
`the
`lower
`is the probability
`of cure.
`Intuitively,
`this
`seems
`logical,
`i.e., that smaller
`tumors are more
`likely
`to be curable and that
`treatment
`needs to be
`initiated as soon as possible for this reason. The sec-
`ond
`inference
`from
`this model
`is that
`the best
`chance of cure lies with
`the use of combinations
`of
`agents
`that are non-cross-resistant.
`These can be
`used in a number of ways, and one that has been
`advocated most widely has been the use of alternat-
`ing sequences of non-cross-resistant
`combinations.
`A number of clinical trials have been pursued along
`these
`lines, and unfortunately
`the majority
`have
`proved
`negative.
`For
`instance,
`alternating
`se-
`quences of chemotherapy
`in small-cell
`lung can-
`cer,“’ advanced breast cancer,27 and Hodgkin’s dis-
`ease2s have indicated no clear evidence of superior-
`ity over conventional
`sequences. Part of the expla-
`nation may
`lie in the
`relative
`lack of non-cross-
`resistance of the combinations
`involved.
`Over the past few years one of the most promis-
`ing developments
`in new drug discovery has been
`the identification
`of taxoids.“’ These are agents that
`act to stabilize
`the microtubule.
`and they have wide
`activity
`in experimental models. Clear act.ivity has
`been seen
`in drug-resistant
`models
`for both
`the
`Alternative Strategies
`resistance has
`of drug
`The clinical significance
`taxoids
`that are now clinically available: paclitaxel
`been appreciated
`for several years. One approach
`to
`(taxol) and docetaxel
`(taxotere). Most
`importantly,
`circumvention
`has been to construct mathematical
`both these agents have demonstrated
`clear activity
`models that might
`lead to the generation of hypoth-
`in the clinic
`in patients who have drug-resistant
`eses that could be tested clinically. The most widely
`cancers, such as ovarian and breast cancer. Re-
`used of these
`is the Goldie-Coldman model, which
`sponse rates
`in breast cancer have ranged up to
`was first published
`in 1979.‘” This is based on the
`50% for patients whose disease is progressing
`on
`assumption
`that drug-resistant
`cancer cells arise as
`therapy with anthracyclines,
`whereas
`in patients
`a consequence of spontaneous mutation. The model
`with ovarian cancer whose disease
`is progressing
`allows the prediction of the probabjljty
`of cure as a
`on cisplatin or earboplatin,
`response
`for both
`rates
`December
`29, 1995
`The American
`Journal of Medicine
`Volume 99 (suppl 6A)
`6A-43S
`
`Ex. 1092-0004
`
`

`

`Am J Med
`
`SYM~OS~IJM ON CH~MOTIMAPY
`
`/ KAYE
`
`agents have been in the range of 20%. It is conceiv-
`able that
`these agents do represent
`truly non-cross-
`resistant
`drugs;
`for
`this
`reason,
`the strategy
`of
`employing alternating
`non-cross-resistant
`combina-
`tions that
`include
`taxoids should now be revisited.
`
`FUTUREPROSPECTS
`is likely
`It is evident
`that clinical drug resistance
`to relate
`to a number of factors
`that probably coex-
`ist. Circumvention
`is therefore
`likely
`to be a com-
`plex process and might well need the simultaneous
`use of strategies
`to overcome
`pharmacologic,
`as
`well as cellular,
`factors.
`It
`is generally
`accepted
`that DNA
`is the main target
`for many clinically use-
`ful drugs. For the future
`it will be important
`to pur-
`sue the notion
`that
`resistance
`to a number of these
`relates
`to failure of treated cells to engage
`the pro-
`cess of programmed
`cell death, or apoptosis. The
`genetic
`factors
`that control entry
`into apoptosis
`in-
`clude
`the presence of functional
`p53 protein,
`the
`activity of which can be reduced by altered expres-
`sion of members
`of other gene
`families, such as
`BCL2 and BAX.
`In addition, mutations
`of the p53
`gene are widely seen in resistant cancer cells, and it
`is therefore possible that
`the failure of these cells to
`undergo apoptosis
`relates, at least partly,
`to inacti-
`vation of the p53 gene. Attempts
`to reverse
`this
`process experimentally
`are underway. Clearly,
`it is
`important
`to confirm
`that
`the failure of cells to un-
`dergo apoptosis
`is relevant
`to the clinical problem
`of drug
`resistance,
`and
`this will
`require
`careful
`studies using new functional assays. If these prove
`to be positive,
`it may then be possible
`to advocate
`methods
`for resistance circumvention
`that can be
`widely used and
`that may at least
`indirectly
`ad-
`dress the clinical phenomenon
`of drug resistance
`to
`a number of structurally
`unrelated drugs.
`
`in treatment of neoplasbc disease. JAMA 1946:
`
`in Chrnese
`
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`of multidrug
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`resis
`
`Ex. 1092-0005
`
`