Seminars in
`Oncology
`
`
`
`HEALTH SCIENCES LiBHA
`UNIVERSITY OF WISCONSfivIY
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`Editors John W. Yarbro, MD, PhD - Michael]. Mastrangelo, MD
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`Horizon Exhibit 2031
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`j J5' on
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`Seminars in
`Oncology
`
`EDITORS
`John w. Yarbro, MD. PhD
`Michael Mastrangelo, MD
`
`in Oncology (ISSN 0093-7754} is published
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`

`

`Novel Therapeutic Agents for the Treatment
`of Myelodysplastic Syndromes
`
`Bruce D. Cheson. James A. Zwiebel.Janet Dancey. and Anthony Murgo
`
`Few chemotherapy agents have demonstrated activity
`in patients with myelodysplastic syndromes (MDS) and
`supportive management remains the standard of care.
`An increasing number of new drugs in development are
`being directed at specific molecular or biological tar-
`gets of these diseases. Topotecan, a topoisomerase I
`inhibitor, has shown single-agent activity and is now
`being combined with other agents.
`including cy-
`tarabine. The aminothiol amifostine induces responses
`in about 30% of patients: however, its role is still being
`clarified. Agents that inhibit histone deacetylase and
`target DNA hypermethylation. thus permitting dere-
`pression of normal genes, include 5-azacytidine. decita—
`bine. phenyibutyrate, and depsipeptide. Arsenic triox-
`ide has demonstrated impressive activity in acute
`promyelocytic leukemia and preclinical data suggest
`the potential for activity in M05. UCN-Dl
`is a novel
`agent that inhibits protein kinase C and other protein
`kinases important for progression through the G. and
`G; phases of the cell cycle. Dolastatin- l O has extremely
`potent in vitro activity against a variety of tumor cell
`lines. Since its dose-limiting toxicities include myelosup-
`pression.
`it
`is being studied in acute myelogenous
`leukemia (AML) and MDS. Ros may play a role in MDS,
`and activation of this gene and its signaling pathways
`may require farnesylation. Several l'arnesyi transferase
`inhibitors are now available for study in patients with
`MDS. An increasing body of data suggests a possible
`role for angiogenesis in MDS, and several antiangiogen-
`esis agents are in clinical trials, including thalidomide.
`SU54I6, and anti—vascular endothelial growth factor
`(VEGF) antibodies. Development of new drugs and
`regimens will be facilitated by recently developed stan-
`dardized response criteria. Future clinical trials should
`focus on rational combinations of these agents and
`others with the goal of curing patients with HDS.
`Semin Oncol 27:560-577. This is a US government work.
`There are no restrictions on its use.
`
`HE h‘iYELODYSPL/‘XSTIC syndromes (MUS)
`are a heterogeneous group of lieinutop:_iictic
`disorders characterized by pancyropenia. generally
`in the serrng of a hypcrcellular hone marrow. MUS
`
`
`
`From iliu Curler-r 'l'lici'upy Ei'aluurirm Program (UTE-Pl. iJii-i.
`Siuli (ll-Ctiilt'fll' Triromii'm Lind iJiuenosii. Nitriu'mi'ii Cancer institute.
`Bethesda. MD.
`requiem in Bruce ii. Clit’xnfl, MD. National
`Address n-pi'iiii
`{Euni'er lt’l.\lli](ii!. Executive Plum North—ii: loin Hi . lleil'iesdri. MD
`303"}
`This is a US firll’li'lTlTlidlil
`Iii-L].
`[TC-5‘3 -F?54/Llfll3FU4-LJCC i $L-‘ .DLUU
`illiii l0 i05_ilsriric.2LiCOJlri'-il
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`iltl'l'L“ill'iL'lliI1L\' on ii)
`
`ll-ifl‘li. Thine ilTL'
`
`560
`
`Page 3 of 20
`
`have historically been referred to as oligoblasric
`leukemia, refractory anemia. smoldering acute leu-
`kemia, or preleukemia.
`In 1952,
`the French-
`Americnn'Brirish (FAB) group presented a classifi—
`cation‘ modified in 1985, which currcnrhJ is the
`
`most widely used"? The FAB group separated
`M 175 into five categories: refractory anemia ( RA),
`RA with ringed sideroblasts (RARE), RA with
`excess blasts (RAEB), and RAEB in transform-a:
`tion (RAEBrT). The distinction between RAEB—T
`and acute invciogenous leukemia (AMLi is based
`on histi_-p;-1rhology. not clinical features. As a result.
`patients with MUS may exhibit a clinical picture
`consistent with AMI. with rapidly increasing num-
`bers of blasts, but without the requisite number to
`fulfill
`the criteria for
`the diagnosis of AML.‘
`Recently. a \X’orid Health Organization (WHO)
`steering comn'iitrec prniiposed changes to the MDS
`subtypes with the major modifications including
`reclassify-imp chronic myelomonncytic leukemia
`(CMMLl
`as
`a myeloproliierarive disorder and
`damnation},J the threshold For diagnosing AML from
`30% blasts to 309-3." This system may eventually
`replace the FAB.
`The likelihood ofri'amionnation to AML varies by
`FAB subtypefi'“: approximately 10% to 20% for RA or
`RARS. 20% to 30% for CMML‘ 40% to 50% for
`RAEB, and 60")?» to NW: For RAEFVT. Neverrheless.
`the MUS are unilbnnly Fatal, even widiout prog‘rrcssion
`to AML. because of infection and bleetlingfm'
`Over I'he years, a number oiscoring and prognos—
`tic. systems have been published to facilitate com—
`parisigins among reports of various treatments for
`MDS. Recently. the international Prognostic Scot-
`ing System (WES) has been widely adopted.“
`Factors taken into consideration included bone
`
`marrow blasts. cyrogenerics, and cytopenias. Groups
`were identified with relative risks For transforma-
`tion to AML and overall survival. Patients in the
`
`good cyrogenetics group were those with a normal
`karyolvpe; poor risk included patients with com-
`plex abnormalities or with an involved Cliffli‘l‘ifl'
`Some 7; intermediate-risk patients consisted of all
`others (Table i}.
`
`There are no curative therapies other than stem
`cell transplantation, which is an option for only 1'1
`subset oi‘ paiieiil‘s. Therefore, numerous therapies
`
`Seminars in Oncology Vol 1?. No 5 (October). 1000: pp 560—5}?
`
`Page 3 of 20
`
`

`

`NEW THERAPEUTIC AGENTS FDR M05
`
`5“
`
`
`
`Table | . International Prognostic Scoring System tor the Hyelodysplastic Syndromes
`
`Prognostic Variable
`
`Bone marrow blasts {to
`Karyotype
`Cytopenias (no. of lineages)
`
`Score
`
`D
`0.5
`LO
`|.5
`1i]
`
`S-ID
`<5
`Good
`intermediate
`
`D“
`In
`
`Poor
`
`| l-IO
`
`ll-SO
`
`NOTE. The total of the values for each prognostic variable is used to place patients in i of‘i risk groups: low. intermedlate- l. intermediate—2. and
`high. These risk groups have significantly dlfiarenr outcomes.
`
`have been and are being investigated to improve
`the outhUk for these patients. Drugs selected for
`study in MDS have typically been those with
`significant activity in AML. Thus. cytarabine has
`been most widely evaluated, dating back more
`than 30 years when Ellison er al'1 first reported
`complete remissions with doses of cytatabine as
`low as 10 mgme/‘d. Response rates were clearly
`dose-dependent. which encouraged the develop—
`ment of higher dose regimens. Subsequently. anec-
`dotal reports and small series were published in
`which cytarabine at 10% to 20% of the standard
`dose. administered either subcutaneously or by
`continuous intravenous infusion appeared to be
`effective in the treatment of AML and MDSJ-l'22
`
`Additional studies and a randomized phase 111 trial
`failed to support a major role for this therapy.”25
`Anthracyclines and related compounds have
`had been studied as single agents only to a limited
`extent.3"‘37 in a study in which hydroxyurea and
`etoposide were compared in patients with CMM L,
`response rates and survival were not impressive
`with either agent, but favored the Former.28 Other
`drugs that have been evaluated include 6-thiogua-
`nine and homoharringtonine. but both showed
`limited activity.“-m
`
`NEW AGENTS
`
`Several agents with unique mechanisms ofactiv—
`iry are currently or will soon be evaluated in
`clinical trials for patients with MDS.
`
`Tiiptfisomemse l inhibitors
`
`Topotecan is a topoisomerase I inhibitor whose
`activity in acute leukemia led to its testing in
`MDS. The initial report included 47 patients with
`RAEB. RABBIT. or CMML.“ They were a poor'
`risk group. as demonstrated by the fact that the
`median age was 66 years. ?0% exhibited cytoge'
`netic abnormalities. and more than half were
`
`Page 4 of 20
`
`thrombocytopenic before topotecan therapy. Topo—
`tecan was delivered at a dose of 2 night-:3 as a
`continuous 24—hour infusion for 5 days. Treatment
`resulted in 28% complete remissions and an addi-
`tional 13% of patients who experienced significant
`hematologic improvement. All eight patients with
`cytogenetic abnormalities before treatment and
`who achieved a complete remission became cytoge'
`netically normal once in complete remission. The
`median remission duration was 7.5 months with
`
`38% of patients still alive 1 year following treat-
`ment. Whether chronic oral topotecan is effective
`is undergoing evaluation.
`The. same investigators have shown that combi‘
`nation of topotecan and cytarabine is extremely
`active in patients with MDS. Beran et 3133 reported
`on 86 patients with MDS and CMML. most of
`whom (66%) were previously untreated, but who
`were considered high risk based on age or cytoge—
`netic abnormalities. Topotecan was administered
`at a dose of 1.25 ingl'inI by continuous infusion
`daily for 5 days, and cytarabine at
`1 gg'm; by a
`2-hour
`infusion daily for
`5 days. A complete
`remission was attained in 56% of patients. with 7%
`treatmenturelated deaths and a median survival of
`
`60 weeks.” Preliminary results have been pub-
`lished of aggressive combination of topotecan.
`fludarabine. cytarahinc, and granulocyte colony—
`stimulating factor (G—CSF); there were 50% com—
`plete remissions and 40% partial remissions. and
`the regimen appeared to be well tolerated.33
`
`Amifostine
`
`Amifostine (Ethyol; Alta Pharmaceuticals, Paio
`Alto, CA) is a phosphorylated aminothiol that
`protects bone marrow progenitors and other nor—
`mal
`tissues from the toxicities associated with
`
`chemotherapy or radiation therapy. It was devel’
`oped by the Walter Reed Army Medical Institute
`
`Page 4 of 20
`
`

`

`561
`
`CHESON ET AL
`
`(thus. the military code name WR'ZHI) during
`the Cold War as part ofa classified research project
`to identify an agent that would protect military
`personnel from radiation in the event of nuclear
`war. Amifostine was found to afford greater protec-
`tion against radiation than more than 4.000 other
`compounds screened. Nevertheless, the Army ter—
`minated development of this compound in 1988
`because of its poor oral bioavailability and the
`prohibitive nausea. vomiting. diarrhea, and abdomi-
`nal cramps with the oral formulation.
`Further research was encouraged by the observa-
`tion that amifostine stimulates bematopoiesis in
`both animal models and in vitro studies. and that it
`
`enhances the formation of hematopoietic progeni—
`tors from MDS bone marrow. in the initial phase
`III] study.” the drug was administered at doses of
`100. 200. or 400 mgi’m1 three times per week or 740
`mg/m2 weekly for 3 weeks. These investigators
`treated 18 patients at a median age of 73 years.
`FAB types included RA {seven patients). BARS
`(n = 5). RAEB (n = 4). and RABBI—T (n = 2).
`Seventeen patients were anemic. 15 of whom were
`transfiision-dependent; 12 had an absolute neutro~
`phil count less than 1000pr and 14 were. thrombo-
`cytopenic. Hematologic improvement was ob-
`served in 83% with the three-times—a'weelt
`
`schedules. including either an increase in neutro—
`phils or a reduction in red blood cell transfusion
`requirements. More than 40% of patients had a rise
`in their platelet counts. However. there was accel-
`eration to AM]. in several patients with MEET.
`Although 61% of patients had clonal cytogenetic
`abnormalities before therapy.
`the abnormalities
`persisted even in patients with a hematologic.
`response. No data regarding duration of response
`were provided. although responses were reported to
`persist during continuation therapy.
`List et 3135 reported the results of a subsequent
`multicenter trial of amifostine in 11? patients. 104
`of whom were evaluable at the time of presenta-
`tion. A neutrophil response occurred in 10 (33%)
`of 30 patients, and was considered major in nine
`and minor in the other. A red blood cell response
`was evaluable in 66 patients. and a major response
`occurred in seven. with three experiencing a minor
`response. A major improvement in platelet count
`was seen in seven of 2? patients. with a minor
`response in three others. and 21% of patients had
`an increase in the reticulocyte count. A decrease in
`mveloblasts and siderohlasts occurred in 28% and
`
`Page 5 of 20
`
`31%. respectively. The overall response rate was
`30%. which is significantly lowm than in the
`previous trial. Adverse events that were moderate
`or severe included fatigue (14%. 13%}. nausea
`(19%. 36%]. and vomiting (14%. 27%}.
`In a
`smaller series.” a single or multilincage response
`was noted in five of
`[2 patients (58%). The
`absolute ncutrophil count increased in 25% (by
`102 to 1.560i'pLJ. platelets in 50% (by 24,000 to
`49.000prl. reticulocytes in 25% {1.9% to 20”!“0}.
`and hemoglobin in 16913 (5.3 to 5.6 gde).
`In other reports. results with this agent were
`disappointingji'“ Hofmann ct 3133 described 32
`patients with RAIRARS (n = 1'6) and RAEB,’
`RAEB'T (n = 15) treated at a dose of 200 nlgl'n‘l2
`three times per week followed by a 3-week interval.
`for four courses. Limited benefit was observed even
`
`in patients with 10\ 1- or intermediate'risk disease
`by the [PSS.
`The role of amifostinc in MDS is still being
`clarified. Nevertheless. combinations of amifostiric
`
`with other agents such as E-amcyridine are being
`evaluated.
`
`Agents That Target Trtmsmprion
`
`Recent developments in understanding the mo-
`lecular basis
`for
`transcriptional
`repression and
`activation have presented new possibilities for
`cancer therapy. Two mechanisms of gene silencing.
`promoter hypen‘nethylarion and historic deacetyla'
`tion. appear
`to be interrelated. The utility of
`targeting DNA liypermcthi-‘lation and histone
`deacetylation is being explored clinically. Agents
`shown to inhibit historic deacetylasc in vitro
`include sodium phenylbutyrate. depsipeptide. hy‘
`brid polar compounds.W and MS—ZTvE75.‘m Hypo-
`methylatng agents include 5-azacytidine and 541311-
`l—deoxycytidinc. The exploration of these agents
`in the clinic. either alone or in combination with
`retinoids. derriethylation agents. and chemothera-
`peutic agents.
`is a novel and promising area of
`cancer therapeutics.
`5-Azacyridine and
`Hypomctliyluting agents.
`S-aza-E-'deoxycytidine are pyrimidine analogs that
`have been extensively evaluated in patients with
`MDS. These compounds are metabolized intracel-
`lularly to triphosphates and subsequently incorpo—
`rated into newly synthesized DNA. where they
`directly inhibit DNA synthesis and inhibit
`the
`activity of DNA iriethyltrnnsterase.
`the enzyme
`required for ‘J'-cytosine liit'thylatitiin of cytosine-
`
`Page 5 of 20
`
`

`

`NEW THERAPEUTIC AGENTS FOR MDS
`
`563
`
`guanosine (CpGl dinucleotides.“"H As a result.
`cytosine methylation is blocked in newly repli—
`cated DNA. but not
`in the DNA of resting or
`nondividing cells. Inhibition of methylation by
`iazacytidine and tlecitabine is associated with
`transcription of genes prevfiously silenced by meth‘
`ylation of promoter region CpG—tich islands. and
`with cellular phenotypic changes; these effects can
`occur at concentrations that are too low to inhibit
`
`DNA synthesis directly or to cause substantial
`cytotoxicity.“'4"fi The potential application of
`5-aracytidine and decitabine as inhibitors of DNA
`methylation and inducers of cell differentiation of
`normal and neoplastic. hematopoietic progenitor
`cells is an area ofactive investigationdi‘fi'ifi
`5rAzacytidine initially demonstrated activity in
`AMLfiM‘ but with considerable toxicity at doses
`required for response. Since the drug also induces
`in vitru cellular differentiation in association with
`
`it was of interest for
`hypomethylation of DNA,
`study in MDS. Chitamhar et al54 used a relatively
`low dose {10 to 35 ingfmlid for 14 days) to treat 13
`patients.
`three of whom achieved a partial re-
`sponse. Cancer and Leukemia Group B (CALGBJ
`investigators35 conducted a phase II trial of Sara.
`cytidine at 75 trig/mild by continuous infusion for 7
`days every 28 days in 48 patients with MDS and
`noted 11% complete remissions and 25% partial
`remissions. Major toxicities included nausea and
`vomiting; one patient died of neutropenic sepsis.
`Subcutaneous administration resulted in slightly
`lower
`response rates—7% complete remissions.
`1?% partial remissions, and 14% with trilineage
`improvement. but less than a partial response.“
`These findings are similar to those achieved with
`low‘dose cytarabine.
`The CALGB recently reported the preliminary
`results ofa phase 111 randomized trial of S-aracyti-
`dine versus observation in 19] patients with MDS.”
`The patients were stratified by FAB subtype (19%
`RA. 4% EARS, 43% RAEB, 21% RAEB~T. 6%
`CMML}; patients with RA or RARS had.
`in
`addition. symptomatic cytopenias. S—Azacytidine
`was administered subcutaneously at a dose of 75
`mgz‘mzid for 7 days every 4 weeks for four cycles.
`Patients on the obsen-'ation arm could receive
`
`5-azacytidine upon progression. Hematologic re.
`sponses were significantly higher in patients ran:
`domired to receive S'azacytidine compared with
`observation (P < .0001): 6.3% (6% complete re-
`sponse. 10% partial response. and 479/6 improve'
`
`Page 6 of 20
`
`ment) versus 7% (all improvement. on complete or
`partial responses}. The median time to leukemic
`transformation or death was 22 months for patients
`on the treatment arm. compared with 12 months
`for
`the patients randomized to observation
`(P = .0034). The 12- and 24—month overall sur-
`
`vival rate was higher in patients randomized to
`receive azacytidine (70% and 41% versus 62% and
`25%. respectively). as was the median survival
`time (18 versus 14 months). but the differences
`
`were not yet significant. Treatment with S-azaeyti-
`dine was associated with subjective improvement
`in quality of life as measured by fatigue, dyspnea.
`physical functioning, posrtive affect. and psychov
`logic. distress-‘5‘ Whether S‘azacytidine improves
`overall survival or reduces transformation to leuke'
`
`rain will require additional follow—up evaluation.
`S-Aza-Z’deoxycytidine ldecitabine} is another
`hypomediylatlng agent with potent in vitro activ'
`ity. in earlier studies. decitabine administered as an
`intermittent intravenous infusion achieved brief
`
`responses in a small series of patients with MDS;
`however. the majority experienced life-threatening
`neutropenia andfor
`thrombocytopeniad" Wijer—
`mans et
`al‘r10 reviewed the experience with this
`agent in MDS and found a 54% response rate of 29
`elderly patients, although there were 17% toxic
`deaths. This drug is under development for MDS
`both in Europe and the United State-25.4""60
`Hisrorle dencctyiarion and DNA hypermethyiariori.
`Retinoids. other hormone receptors. and the Myc,’
`MadfMax network of growrh regulators exert their
`effects on gene expression by interacting with
`nuclear corepressor complexes that are present on
`the DNA of promoter regionsf‘l’“ Gene silencing
`occurs with the recruitment of histone deaeetylases
`and the formation of a nuclear corepressor-histone
`deacetylase complex {NCH DC). Histone deaceti,"
`lase catalyzes the removal of acetyl groups from
`historic proteins. inducing a conformation change
`that results in an environment unfavorable to gene
`transcription. A NCHDC has been found to play
`an important. role in acute promyelocytic leukemia
`{APL}. where the NCH DC is recruited by both the
`PML—RARa and PLZFvRARa fusion proteins.
`which form as a consequence of chromosomal
`translocations 1(15;1?) and ti li;li’).
`respec~
`tively.“-’"°i A NCHDC is also recruited by ETC. 3
`component of the fusion product resulting from
`the t(8;21) chromosomal translocation in AML.“5-°°
`
`Moreover.
`
`inhibitors of histone deacetylase have
`
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`56-!
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`CH ESON ET AL
`
`been found to overcome transcriptional repression
`and to potentiate retinoid'induced differentiation
`of A PL and AMI. cells.“"'"”-"’” A clinical test of this
`
`observation was perfomiet] in a patient with APL
`who had become refractory to both chemotherapy
`and all-[mus retinoic acid (ATRA). Administra-
`tion of both ATRA and a histone deacctylase
`inhibitor, sodium phenylbutyrate {see below). re-
`sulted in a complete remission. The clinical re-
`sponse was associated with acetylation of histone
`proteins in the leukemic. cells.lo
`While methylation of CpO islands in gene
`promoter regions has long been known to be
`associated with gene silencing,
`it was not known
`how such DNA hypermethylation exerts its effect
`on gene transcription. Recent studies have shed
`light on both the role of DNA hypermethylarion
`in the inactivation of tumor suppressor genes. as
`well as the mechanism of transcriptional repres—
`sion. Examples of genes associated with CpG
`hypermethylarion include. among others. RB in
`retinoblasroma, VHL (the von Hippel'Lindau gene)
`in renal carcinoma, plolNK4A and pl5lNK4A
`(cyclin-dependent kinase inhibitorslI in solid tu-
`mors and in hematologic malignancies. and lIMLHl
`(a DNA mismatch repair gene) in colon cancer.“
`The mechanism of gene silencing by DNA hyper-
`methylation now appears to involve the recruit—
`ment of a NCHDC by the methyl'CpG-binding
`protein. MeCP2.73'73 ln fact. the combined admin—
`istration of a demethylating agent and a histone
`deacetylase inhibitor has been shown to synergize
`in reactivating genes that were silenced in cancer
`cells." This finding not only links the processes of
`DNA hyperrnethylation and histone deaceryla—
`tion. but also presents therapeutic targets for
`agents that are relatively nontoxic. or used at
`nontoxic doses.
`
`Phenylbutyrnte
`
`Phenylhutyrate (PB) is a low—molecular—weight
`phenyl—fatty acid that been used clinically to treat
`lnperat'urnonemia in children with inborn errors of
`urea synthesis?5 It also been shown to enhance
`fetal hemoglobin production in some patients with
`hemoglobinoparhies.li‘ A number of mechanisms
`have been proposed for the antitumor effect of PB.
`including (llI elimination of glutamine necessary
`for nucleic acid and protein synthesis in rapidly
`growing normal and tumor cell-5””; (2) inhibition
`of the mevalonate pathway til—cholesterol synthesis
`
`Page 7 of 20
`
`leading to interference of post~translational process—
`ing of proteins. modification of lipid metabolism.
`inhibition of protein isoptenylation. and regula—
`tion ofgene expression through DNA hypomethyl—
`ation it"s”: (3) activation of a peroxisome prolifera‘
`tor-activated receptor by PB. a transcriptional
`factor regulating lipid metabolism and cell growth“:
`and (4)
`regulation of gene expression through
`histone hyperacetylation via inhibition of nuclear
`histone deacetylrvses3‘3M
`PB has been shown to induce differentiation.
`
`tumor cytostasis1 and reversion of malignant pheno-
`type in several
`in vitro mtidttls.““'“5'“9 PB. as a
`histone deacetylase inhibitor. may have synergistic
`activity with ATRA in the treatment tafAPL.“5-‘ll"4°
`The PML-RAR fusion protein was shown to re-
`emit a transcriptional corepressot complex that
`includes a histone deacetylase. ATRA alone could
`partially dissociate the complex. allowing in-
`creased transcription, hut butytate {or other inhibiv
`tors of histone deacetylases) in combination with
`ATRA was able to completely abrogate [he inhibiv
`tion of transcription. In light ofthesc observations.
`an APL patient who experienced multiple relapses
`after ATRA treatment was treated with PE in
`
`combination with ATRA under compassionate
`release. and achieved a complete remission.To
`
`Depsipeptlde
`
`Depsipeptide (NSC 6301736) is a hicyclic pep-
`tide originally isolated from Cliromobactcnum l-‘lOlfl'
`ceum, strain 968, by Fujisawa Pharmaceutical Co
`(Osaka. Japan). In the original observations. depsi-
`peptide selectively decreased the mRNA expres-
`sion of the c-myc oncogene and inhibited the
`growth of the Harms—transformed NIH3T3 clonal
`cell
`line. Ras-l. but had no effect on Ha-ms
`
`rnRNA expressiond'1 It did not affect DNA synthe'
`sis. but caused cell cycle arrest at GDIGI. Recently,
`it has been shown to be a historic tleacetvlase
`inhibitor.“
`
`incubation of
`Byrd et al demonstrated that
`chronic lymphocytic leukemia cells with depsipep—
`tide resulted in an alteration in apoptosis-associ—
`ated proteins: an increase in Boat with no change in
`Bel-2. and a decrease in p27 expression.“
`in collaboration with Fujisawa Pharmaceutical
`Co. the National Cancer institute (NCll is cur.
`
`rently sponsoring two phase l trials ofdepsipeptide
`administered as a 4-hour intravenous infusion. In
`
`one trial. a once—weekly infusion schedule (days 1.
`
`Page 7 of 20
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`NEW THERAPEUTIC AGENTS FOR NUS
`
`555
`
`8. and 15 every 28 days} is used, while the other
`trial evaluates a EWice-weekly (days 1 and 5 every
`3i days} schedule.
`
`MS—27'375
`
`MS-27-275 is a benzamicle derivative that was
`
`synthesized by Mitsui Pharmaceuticals (Tokyo,
`Japan) in a search for novel antitumor agents.“
`The compound was found to have histone deacety-
`lase activity in vitro at micromolar concentrations.
`In addition. when administered orally, MS—27-2?5
`inhibited the growth of a number of tumor xeno'
`grafts. The NCI,
`in collaboration with Mitsui
`Pharmaceuticals. plans to sponsor phase I trials of
`this agent in the near future.
`
`Hybrid Polar Compounds
`
`Hexamcthylene bisacetamide (HMBA) was the
`first of the class of hybrid polar compounds to be
`evaluated as an antitumor agent
`in MUS and
`AML. The limited clinical activity that was ob-
`served was attributed to the inability to achieve
`the plasma concentrations that were required to
`induce differentiation in cells in vitro and to
`
`doseriimiting thrombocytopeniaf-J‘l Subsequently,
`Richon et all” described compounds structurally
`related to HMBA, but which exhibited 3-ng
`greater potency in inducing terminal differentiav
`tion and apoptosis in transformed cell iines.
`in
`addition. these compounds possess historic deacety'
`lase inhibitory activity at micromolar COHCGHLTB'
`tions. Recently, one such compound, M‘carboxy-
`cinnamic acid bishydroxamide {CHI—1A), was found
`to induce apoptosis in human neuroblastoma. and
`the effect was associated with CD95ICD95 ligand
`expression by the tumor cells.95 These agents
`should be entering into early clinical trials in the
`near future.
`
`Arsenic Trioxide
`
`Arsenic was used as a medicinal 2,400 years ago
`in the time of the ancient Greeks and Romans.
`
`Paul Ehrlich used organic arsenicals for the treat—
`ment of syphilis. Arsenicals are still included as
`ingredients
`in folk remedies of some cultures,
`particularly in China and other parts of Asia.
`Arsenic was widely used to treat syphilis before the
`advent of penicillin, and the organic arseiiical
`melarsoprol
`is a recognized treatment
`for
`the
`Ineningoencephalitic stage of African trypanoso.
`miasis."“ Fowler's solution (1% arsenic trioxide in
`
`Page 8 of 20
`
`potassium bicarbonatel. formulated in the 13th
`
`century to treat a variety ofinfectious and neoplas-
`tic disorders. was reported by US physicians in the
`19305 to be useful
`in the treatment of chronic
`
`myelogenous leukemia {CIVIL}. and more recently
`by hematoiogists in China to treat various forms of
`leukemia, including CML.“
`