Cancer Treatment Reviews
`
`(1990)
`
`17, 109-I
`
`17
`
`and
`In vitro
`compounds
`
`in vivo evaluation
`in human
`tumor
`
`of US-N
`
`Heinz-Herbert
`Jacqueline
`
`Fiebig,*
`Plowman7
`
`Dietmar
`
`P. Berger,
`
`of Freiburg, Hugstetterstrasse 55, D- 7800
`of Internal Medicine, University
`*Department
`Freiburg, F.R.G., and tDeuelopmenta1
`Therapeutics Program, Division
`of Cancer Treatment,
`National Cancer Institute, Bethesda MD 20892, U.S.A.
`
`Introduction
`
`cytostatic
`of established
`or analogs
`activity
`for new drugs with antineoplastic
`The search
`objective
`of US-National
`increased
`efficacy and
`reduced
`toxicity was the major
`drugs with
`Cancer
`Institute
`screening
`projects. Between
`1975 and 1985 novel agents were
`tested
`in a
`‘compound-oriented’
`screening
`system based on initial
`in vivo testing
`in
`the mouse
`leukemia
`P388 and subsequent
`studies
`in a panel of five murine
`and
`three human
`tumor
`xenografts
`(10). This
`screening
`program
`was successful
`primarily
`in
`identifying
`compounds
`with
`clinical
`activity
`against
`leukemias
`and
`lymphomas
`(16).
`‘disease-oriented’
`a new
`Since 1985,
`the National
`Cancer
`Institute
`(NCI)
`
`h as eveloped d
`representative
`approach
`to drug
`screening,
`based on human
`tumor
`cell
`line panels
`partrcular
`tumor
`types
`(2). The objective
`of this
`type of screening
`is to identify
`compounds
`which
`exert selective
`effects on particular
`tumor
`types and
`to follow-up
`these
`leads
`in viva
`utilizing
`cell
`lines previously
`shown
`to be sensitive.
`the new NC1
`the old or
`in
`activity
`We have
`tested 28 compounds
`which
`displayed
`tumor
`xeno-
`primary
`screen
`in a combined
`in vitro/in
`viuo secondary
`screen using human
`grafts.
`First,
`large
`scale
`tests were
`performed
`in
`the clonogenic
`assay. Only
`the most
`sensitive
`tumors were subsequently
`studied
`in nude mice, where
`the in viuo pharmacological
`behaviour
`of a drug
`is considered.
`
`of
`
`Methods
`
`tumors
`(6-8). Human
`recently
`has been described
`in z&o test procedure
`in vitro and
`Our
`for all experiments.
`The human
`established
`in serial
`passage
`in nude mice were
`used
`origin
`of the
`tumors was confirmed
`by isoenzymatic
`and
`immunohistochemical
`methods.
`Tumor
`models were selected
`from a panel
`of 220 well characterized,
`regularly
`growing
`xenografts
`(9).
`were studied
`New compounds
`human
`bone marrow
`(CFU-GM)
`
`in uitro
`and
`
`for anticancer
`in
`the
`leukemia
`
`xenografts,
`tumor
`in human
`activity
`P388 using a modification
`of the
`
`03057372/90/2&3109+09
`
`$03.00/O
`
`0
`
`1990 Academic
`
`Press Limited
`
`109
`
`NPC02232984
`
`

`

`110
`
`H.-H.
`
`FIEBIG
`
`ET
`
`AL.
`
`tumors
`(11). The most sensitive
`& Salmon
`by Hamburger
`assay as described
`clonogenic
`in vitro screening
`was done
`in
`four highly
`in Go. Primary
`were
`subsequently
`studied
`sensitive
`xenografts
`(small cell and
`large cell of the lung, breast and stomach),
`two resistant
`xenografts
`as well as the P388. Secondary
`in vitro screening
`was performed
`in a total of 14
`responsive
`and six resistant
`human
`tumor
`xenografts
`and
`in two
`to four marrow
`specimens.
`Compounds
`with a greater
`or similar
`effect on
`tumor
`cells
`in comparison
`to human
`bone
`marrow
`were subsequently
`studied
`in vivo in the
`two most sensitive
`xenografts
`transplanted
`subcutaneously
`into nude mice. The comparison
`of in vitro/in
`vivo activity
`enabled
`assess-
`ment of the relevant
`in vitro dose based on in vivo pharmacological
`behavior
`of a compound.
`If
`remission
`or at
`least no change was observed
`in vivo,
`the new compound
`undergoes
`disease-oriented
`testing
`usually
`in 40-60
`xenografts.
`Drugs were applied
`by continuous
`exposure
`until
`the end of the experiment.
`A compound
`was considered
`active,
`if it reduced
`colony
`formation
`of treated
`(T) groups
`to 30% or less of the control
`(C) group
`value.
`For
`in vivo experiments
`6-8-week-old
`female
`athymic
`nude mice of NMRI
`genetic
`background
`were
`used. Tumor
`slices averaging
`3 x 3 x0.5-1
`mm
`in diameter
`were
`implanted
`subcutaneously
`into both
`flanks of the animals.
`Treatment
`was started
`after 2-
`6 weeks when
`the median
`tumor diameter
`was 6-7 mm. The antitumor
`effect was evaluated
`following
`maximal
`tumor
`regression,
`in non-regressing
`tumors
`after
`3-4 weeks. Data
`evaluation
`was performed
`using specifically
`designed
`software. Relative
`tumor
`size (RTS)
`values were calculated
`for each single
`tumor
`by dividing
`the
`tumor
`size day X by
`the
`tumor
`size day 0 at the
`time of randomization.
`Median
`RTS values were used
`for
`further
`evaluation.
`Tumor
`doubling
`time
`(DT)
`of
`test and
`control
`groups was defined
`as the
`period
`required
`to reach
`a relative
`tumor
`size of 200%.
`The
`effect of
`treatment
`was
`classified
`as complete
`remission
`(RTS
`on day 21 or 28 < 10% of initial
`value),
`partial
`remission
`(1 l-500/,),
`minimal
`regression
`(5 l-75%),
`no change
`(7&1240/,)
`or progression
`( 2 125%). A tumor was considered
`to be sensitive,
`ifregression
`or no change was achieved.
`Additionally,
`tumor
`inhibition
`was evaluated
`in comparing
`the
`relative
`tumor
`size of
`treated with
`the control
`group.
`The
`specific
`growth
`delay
`(SGD)
`was calculated
`with
`regard
`to the
`tumor
`doubling
`time
`(DT)
`as described
`by Steel
`( 17).
`
`Results
`
`and discussion
`
`of interest which
`compounds
`Twenty-eight
`in vivo. A summary
`in uitro and
`were
`tested
`the clonogenic
`assay and
`in nude mice
`ipomeanol,
`oxanthrazole,
`penclomedine,
`given
`in detail
`below.
`
`screening
`from NC1 primary
`have emerged
`in human
`tumor
`xenografts
`in
`of the activity
`1. Results
`for hepsulfam,
`4-
`is given
`in Table
`pyrazine
`diazohydroxide
`and
`rapamycin
`are
`
`Hepsulfam
`
`(NSC-329680)
`
`to improve
`in an attempt
`1) was synthesized
`(Figure
`1,7-heptanediol-his-sulfamate
`The
`introduction
`of a more polar
`leaving
`group.
`through
`the antitumor
`efficacy
`of busulfan
`Hepsulfam
`showed a broader
`preclinical
`activity
`than busulfan
`in the NC1
`in vivo screening
`systems. Schedule
`dependency
`studies determined
`a single
`i.p. bolus
`injection
`as the most
`effective
`administration
`method.
`Cross-resistance
`of melphalan
`and
`cisplatin-resistant
`P388-sublines
`to hepsulfam
`was observed
`in vivo (18).
`Hepsulfam
`and busulfan were
`tested simultaneously
`
`xenografts
`
`in
`
`in human
`
`solid
`
`tumor
`
`NPC02232985
`
`

`

`at 100
`
`active
`
`-,
`
`at 10.0 pg/ml;
`
`+, active
`
`at 1.0 pg/ml;
`
`+ + , active
`
`bone-marrow.
`
`human
`
`ND
`1
`6
`
`3
`
`1
`
`2
`
`2
`
`ND
`
`1
`
`1
`
`1
`ND
`
`2
`3
`
`Progression
`
`Nude mice
`
`
`
`tumors
`in
`Active”
`
`I
`
`.
`
`& MEL
`
`REN
`SCLC
`SCLC
`
`ND
`0
`1
`ND
`
`SCLC
`
`116
`
`SCLC
`
`& MEL
`
`SCLC
`
`SCLC
`
`2
`0
`0
`0
`0
`94
`ND
`0
`0
`41
`0
`ND
`ND
`ND
`0
`ND
`ND
`
`& TES
`
`SCLC
`
`3
`
`for‘
`
`Selective
`
`P388
`
`ND
`3
`4
`ND
`
`79
`
`13
`41
`3
`7
`
`100
`ND
`98
`26
`1
`5
`4
`ND
`ND
`1
`ND
`ND
`4
`5
`
`(‘/o)
`
`‘T/C
`
`assay
`
`leukemia
`
`the P388 mouse
`
`and
`
`(CFU-GM)
`
`HBM
`
`Clonogenic
`
`+
`++++
`++++
`+++
`
`++++
`
`++++
`f-t
`+
`++++
`
`-
`+i
`-
`+
`+
`+++
`++++
`++++
`+
`++
`-
`+
`++t
`
`32
`38
`41
`33
`ND
`25
`ND
`24
`48
`24
`46
`41
`43
`19
`19
`24
`28
`42
`35
`21
`30
`23
`30
`13
`25
`42
`
`studied
`tumors
`No. of
`
`614383
`332598
`226080
`366 140
`361456
`328426
`338720
`349156
`349174
`336628
`381856
`30386 1
`349438
`329680
`606702
`343513
`356894
`262666
`375575
`357704
`817373
`339004
`602668
`339555
`320846
`303812
`
`no.
`
`NSC
`
`HBM,
`
`cancer;
`
`renal
`
`REN,
`
`cancer; MEL, melanoma;
`
`testicular
`
`TES,
`
`cancer;
`
`lung
`
`small-ccl1
`
`not done.
`
`ND,
`’ SCLC,
`
`KW.
`
`at 0.1 pg/ml;
`
`+ + + , active
`Britain.
`
`in Great
`
`in > 2076 of xenografts;
`Campaign
`
`Research
`
`at 0.01 pg/ml
`
`the Cancer
`the EORTC.
`
`by
`by
`
`< 30Yb)
`at present
`developed
`
`(T/C
`developed
`at present
`or no change.
`
`d + + + +, active
`’ Compounds
`‘Compounds
`p Regressions
`
`diazohydroxide
`
`Maleate”
`
`A4’
`
`Sulphonamide
`
`1’
`
`glycinateh
`
`SRI62-834
`Rhizoxir?
`Rapamycin
`Pyrazoloacridine
`Pyrazine
`Phyllanthoside
`Penclomedine
`Pancratistatin
`Oxanthrazole
`Merbarone
`LL-D49194a,”
`L-cystein-analog”
`4-Ipomeanol
`Hepsulfam
`Geneticin
`Dihydrolenperone
`Deoxyspergualin
`DABIS
`Cyclopentenyl
`cytosine
`Cyanomorpholino-Adriamycin
`Combretastatin
`Chloroquinoxaline
`Carmethizole”
`Bryostatin
`Batracylin
`Aphidicolin
`
`bone marrow
`
`human
`
`xenografts,
`
`tumor
`
`in human
`
`compounds
`
`of new
`
`Activity
`
`1.
`
`Table
`
`NPC02232986
`
`

`

`112
`
`H.-H.
`
`FIEBIG
`
`ET
`
`AL.
`
`NH
`
`-!-O-(CH
`2
`II
`0
`
`27 1
`
`0
`
`bl
`
`Hepsulfam
`
`(NSC-329680)
`
`,CH2CH2-NH-CH~C~-OH
`
`OH
`
`N-N
`
`1.7 HCI
`
`OH
`
`0
`
`NH-(CH&NHI
`
`Oxanthrazole
`
`(NSC-349174)
`
`C-CH,CHt-CH-CHa
`
`OH
`
`I
`0-CHI
`
`4-lpomeanol
`
`(NSC 349438)
`
`Penclomedine
`
`(NSC-338720)
`
`-No
`
`N=N-OH
`
`Dtazohydroxide
`Pymzine
`(NSC-361456)
`
`CHa
`
`CHs
`
`OH
`
`Rapamycin
`
`(NSC-226080)
`
`F+e
`
`1. Chemical
`
`structures
`
`of selected
`
`US-NC1
`
`compounds.
`
`activity
`spectrum
`showed broad
`assay, both compounds
`the clonogenic
`in vivo. In
`vilro and
`and a similar
`response profile. However,
`given
`the same dose level of 1 pg/ml
`at continuous
`drug exposure
`(Table
`2), hepsulfam
`was active
`in S/19 xenografts
`(32%) whereas
`busulfan
`reduced
`colony
`growth
`to a T/C < 30%
`in 2/10
`tumors
`(20%).
`LXFL
`xenograft
`cancer
`In vivo both
`compounds
`were
`tested against
`the
`large
`cell
`lung
`in
`‘no
`resulted
`therapy
`529. At a dose
`level of 150 mg/kg/day
`given day 1 i.p., busulfan
`change’
`on day 21. Hepsulfam-treated
`tumors
`regressed
`completely
`on day 21 and did
`not
`regrow
`within
`the observation
`period
`of 70 days
`(Table
`4). Further
`tests will
`be
`performed
`with
`this compound.
`
`NPC02232987
`
`

`

`EVALUATION
`
`OF
`
`US-NC1
`
`COMPOUNDS
`
`113
`
`Table
`
`2.
`
`In vitro
`
`effect
`
`of hepsulfam
`
`(NSC-329680)
`
`us. busulfan
`
`Tumor
`histology
`
`Xenografts
`C&n
`Gastric
`Lung
`
`Ovarian
`Melanoma
`Various
`Active/total
`
`- NSCLC
`~ SCLC
`
`Hepsulfam
`
`(pg/mlj
`
`Busulfan
`
`(pg/ml)
`
`0.1
`
`1.0
`
`10.0
`
`0.1
`
`1.0
`
`10.0
`
`O/3”
`O/l
`O/7
`O/l
`o/2
`o/2
`O/3
`o/19
`0””
`
`O/3
`O/l
`317
`l/l
`o/2
`2/2
`O/3
`6/19
`32 O
`I,
`
`O/3
`O/l
`6/7
`l/l
`l/2
`‘w
`O/3
`IO/19
`53’1,
`
`o/2
`
`O/4
`
`O/l
`O/i
`o/2
`o/10
`0””
`
`O/2
`
`l/4
`
`O/l
`l/l
`o/2
`T/IO
`20 O,]
`
`o/2
`
`3/4
`
`O/l
`‘/’
`o/2
`4/10
`40”,,
`
`*Responsive
`
`(T/C
`
`< 30”;,)/total.
`
`Table
`
`3.
`
`Activity
`assay
`
`of
`in vitro
`
`selected
`
`US-NC1
`
`compounds
`
`in human
`
`tumor
`
`xenografts
`
`in
`
`the
`
`clonogenic
`
`Compound
`
`4-Ipomeanol
`
`Oxanthrazole
`
`R apamycin
`
`DOSC
`k/mY
`
`1.0
`10.0
`100.0
`1000.0
`0.1
`0.3
`1.0
`3.0
`10.0
`0.0001
`0.0003
`0.001
`0.003
`0.0 1
`0.03
`
`Xcnografts
`
`Responsive”
`
`Total
`
`(“,)
`
`Bone-marrow
`median
`T/C
`
`(“,J”
`
`P388
`‘l’/C
`(‘?,])
`
`o/34
`4/41
`IO/43
`8/8
`l/32
`9/43
`20/48
`25/36
`6/7
`2/31
`4/3 1
`14/41
`20/32
`23/33
`s/11
`
`0
`9
`26
`100
`
`3
`21
`42
`69
`85
`6
`13
`37
`63
`70
`73
`
`-
`
`I
`
`1
`+
`
`112
`115
`100
`89
`
`123
`95
`41
`1 +++
`1 +++
`I+++
`2
`tff
`l
`4 +++
`5 +++
`3 +++
`1 +++
`
`1
`-
`
`-
`
`91
`88
`94
`
`65
`
`0 +++
`
`ll+++
`I+++
`1+++
`
`< 30;,,.
`“T/C
`< T/C,
`“50”;,
`+ + + = T/C
`
`<
`
`non-toxic;
`loo,,
`highly
`
`+ = 3O”b < T/C
`toxic.
`
`4Ipomeanol
`
`(NSC-349438)
`
`< 50’:,, marginally
`
`toxic;
`
`+ + =
`
`lo”,
`
`< T/C
`
`< 30’>6,
`
`toxic;
`
`cytochrome
`a lung
`through
`bioactivated
`toxin
`1) is a pulmonary
`(Figure
`4-Ipomeanol
`is being developed
`for
`lung
`specificity,
`ipomeanol
`Because of its assumed
`P450 pathway.
`clinical
`trial by the Lung Cancer Drug Discovery
`Prqject
`of the NC1
`(5).
`the clono-
`in
`Ipomeanol
`was
`tested
`in human
`tumor
`xenografts
`of different
`histologies
`tumors
`(9%),
`genie
`assay. At a dose
`level of 10 pg/ m
`i 1 p omeanol
`was active
`in 4/41
`namely
`4/5 small-cell
`carcinomas
`of the lung
`(Table
`3). Bronchogenic
`carcinomas
`of large-
`cell
`(n = 4), squamous-ceI1
`(n = 1) or adenocarcinoma
`(n = 4) subtypes
`or tumors ofother
`histologies
`did
`not
`respond
`to
`ipomeanol.
`At
`the high
`dose of 100 pg/ml,
`ipomeanol
`in
`inhibited
`colony
`formation
`lo/43
`xenografts
`tested
`(26oj,).
`In vivo, ipomeanol
`was tested
`in three small-ceI1
`lung carcinomas
`previously
`shown
`to be sensitive
`in vitro. The maximally
`
`NPC02232988
`
`

`

`114
`
`H.-H.
`
`FIEBIG
`
`ET
`
`AL.
`
`tolerated
`showed
`Further
`
`treated
`tumors
`i.p. All
`l-4
`given on days
`as 12.5 mg/kg/day
`dose was determined
`indicating
`only
`limited
`effect of ipomeanol
`in vivo (Table
`4).
`progressive
`growth
`studies will be conducted
`using a weekly
`iv. schedule.
`
`Oxanthrazole
`
`(NSC-349174)
`
`anthra-
`1) is one of a series of 5-[ ( aminoalkyl)amino]-substituted
`(Figure
`Oxanthrazole
`It
`Co.
`Lambert
`(anthrapyrazoles)
`synthesized
`by the Warner
`[1,9-cdlpyrazol-6(2H)ones
`activity
`in various murine
`and human
`tumor models and was less
`showed
`broad
`spectrum
`cardiotoxic
`than doxorubicin
`in a cultured
`fetal mouse heart model
`(4).
`in
`assay
`Oxanthrazole
`was highly
`active
`in human
`tumor
`xenografts
`in
`the clonogenic
`to
`toxicity
`vitro. At a dose
`level of 0.3 pg/ml,
`9/43
`tumors
`(21%) were
`responsive
`without
`in
`inhibited
`human
`bone marrow
`(Table
`3). At 1 pg/ml
`tumor
`colony
`formation
`was
`In
`tumor-
`20/48
`xenografts,
`however,
`marginal
`bone-marrow
`toxicity
`was observed.
`tolerated
`bearing
`nude mice oxanthrazole
`was active
`in
`two xenografts
`at a maximally
`dose of 60 mg/kg/day
`given on days 1, 8 and 15 i.p.
`It effected
`a minor
`regression
`in a
`gastric
`cancer
`(GXF
`97) and a large-cell
`lung
`carcinoma
`(LXFL
`529). Five xenografts
`showed
`progressive
`growth
`and did not
`respond
`to oxanthrazole
`in vivo (Table
`4). Oxan-
`thrazole
`has completed
`clinical
`Phase
`I trials
`in
`the United
`States and has started Phase
`II evaluation.
`
`Penclomedine
`
`(NSC-338720)
`
`l), 3,5-dichloro-2,4,-dimethoxy-
`treat-
`prescreen.
`Intraperitoneal
`implanted
`CD8FI
`and MXl
`in
`only moderate
`activity
`was ob-
`with Melphalan
`and collateral
`
`(Figure
`penclomedine
`cr-picoline-derivative
`The synthetic
`6-(trichloromethyl)pyridine,
`was active
`in
`the P388
`ment
`caused
`tumor
`regressions
`in
`the subcutaneously
`the subrenal
`capsule
`assay.
`In non-breast
`tumor models
`served
`(14). Resistance
`studies
`indicated
`cross-resistance
`sensitivity
`with Amsacrine
`( 12).
`tumor-bearing
`in
`was tested only
`the compound
`As penclomedine
`needs bioactivation,
`as 150 mg/kg/
`dose was determined
`nude mice
`in vivo (Table
`4). The maximally
`tolerated
`xenograft MAXF
`401, penclomedine
`day given on days
`I,4 and 7 i.p.
`In
`the breast cancer
`the
`effected
`a complete
`remission
`on day 35. No
`regrowth
`was noted
`until
`the end of
`at a
`experiment
`on day 105. Activity
`was retained
`when
`penclomedine
`was given orally
`dose
`level of 300 mg/kg/day
`given on days 1, 4, 7 i.p. The
`large-cell
`lung
`cancer
`LXFL
`529 was resistant
`to penclomedine
`and grew progressively.
`
`Pyrarine diarohydroxide,
`
`PZDH
`
`(NSC-361456)
`
`program
`development
`of a congener
`1) is a product
`(Figure
`Pyrazine-2-diazohydroxide
`Branch
`initiated
`by the Drug Synthesis and Chemistry
`based on pyridine-2-diazohydroxide
`Broad
`was observed
`initially
`in
`the P388 prescreen.
`of
`the NCI.
`Its antitumor
`activity
`and
`spectrum
`activity
`was observed
`in various
`in vivo models
`including
`advanced-stage
`metastatic
`disease
`(13). PZDH may act via alkylation
`and needs bioactivation.
`Evaluation
`against
`leukemia
`sublines with acquired
`resistance
`to standard
`clinical
`drugs demonstrated
`cross-resistance
`with Melphalan.
`The
`in vitro cytotoxicity
`of PZDH
`is increased
`under
`acid
`and hypoxic
`conditions,
`which may
`favor
`selective
`toxicity
`to solid
`tumors
`in vivo (3).
`Pyrazine
`diazohydroxide
`was
`tested
`in
`three human
`tumor
`xenografts
`in nude mice
`
`NPC02232989
`
`

`

`remission,
`
`complete
`
`< 50%;
`
`lOO,& < RTS
`
`remission,
`
`partial
`
`< 75%;
`
`< RTS
`
`50%
`
`regression,
`
`< 1250/b; minor
`
`< RTS
`
`75%
`
`no change,
`
`< RTS;
`
`size at day 2 1 or day 28.
`
`125%
`
`tumor
`
`< 10%.
`b Progression,
`’ Relative
`
`RTS
`
`regression
`
`remission
`
`regression
`remission
`
`remission
`
`regression
`
`regression
`
`remission
`
`Minor
`No change
`Progression
`No change
`No change
`No change
`No change
`Complete
`Minor
`Partial
`Complete
`Progression
`Progression
`Progression
`Progression
`Progression
`Minor
`Progression
`Minor
`Progression
`Progression
`Progression
`Complete
`
`Activityb
`
`(%)”
`
`RTS
`
`74.4
`122.2
`201.3
`91.5
`119.7
`122.3
`120.2
`0.0
`69.7
`27.8
`4.8
`417.2
`206.1
`344.8
`230.2
`145.2
`60.4
`599.0
`72.2
`325.7
`352.5
`308.1
`0.0
`
`3.20
`4.49
`1.83
`5.20
`4.80
`2.96
`2.75
`>lO
`> 10
`> 10
`> 10
`0.88
`2.19
`0.24
`1.05
`3.07
`9.86
`0.20
`14.63
`0.07
`0.19
`0.20
`220
`
`delay
`Growth
`
`SCLC
`SCLC
`large-cell
`adeno
`
`large-cell
`
`large-cell
`
`SCLC
`SCLC
`large-cell
`squamous
`
`SCLC
`SCLC
`SCLC
`large-cell
`
`Breast
`Breast
`Lung,
`Lung,
`Lung,
`Lung,
`Gastric
`Breast
`Lung,
`Gastric
`Breast
`Lung,
`Renal
`Breast
`Lung,
`Lung,
`Lung,
`Lung,
`Gastric
`Lung,
`Lung,
`Lung,
`Lung,
`
`449
`401
`650
`538
`529
`629
`97
`
`40 1
`529
`97
`
`40 1
`529
`631
`
`857
`650
`605
`529
`397
`97
`650
`605
`538
`529
`
`MAXF
`MAXF
`LXFS
`LXFS
`LXFL
`LXFA
`GXF
`MAXF
`LXFL
`GXF
`MAXF
`LXFL
`RXF
`MAXF
`LXFS
`LXFS
`LXFL
`LXFE
`GXF
`LXFS
`LXFS
`LXFS
`LXFL
`
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`
`1-I
`l-4
`l-4
`l-4
`1-l
`I-4
`l-4
`1,8,15
`1,8,15
`1,8,15
`1,4,7
`1,4,7
`1,8,15
`1,8, 15
`1,8,15
`1,8,15
`1,8,15
`1,8,15
`1,8,15
`14
`1-I
`14
`1
`
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`150
`150
`60
`60
`60
`60
`60
`60
`60
`12.5
`12.5
`12.5
`150
`
`carcinoma
`Histology,
`
`Tumor
`
`Route
`
`(days)
`Schedule
`
`(w/k/day)
`Dose
`
`Application
`
`Rapamycin
`
`diazohydroxide
`Pyrazine
`
`Penclomedine
`
`Oxanthrazole
`
`4-Ipomeanol
`Hepsulfam
`
`Compound
`
`in &we
`
`xesografts
`
`ttumor
`
`in human
`
`compounds
`
`US-NC1
`
`of selected
`
`Activity
`
`4.
`
`Table
`
`NPC02232990
`
`

`

`116
`
`H.-H.
`
`FIEBIG
`
`ET
`
`AL.
`
`on days 1, 8 and 15
`given
`dose was 100 mg/kg/day
`tolerated
`4). The maximum
`(Table
`In
`the gastric
`cancer
`tested.
`efficacy was observed
`in all
`tumors
`i.p. A high antineoplastic
`GXF
`97, a partial
`remission was achieved,
`the breast cancer model MAXF
`401 regressed
`completely
`28 days after
`the start of therapy.
`In
`the
`large-cell
`lung
`cancer LXFL
`529, a
`in vim.
`minor
`regression was observed. Overall,
`PZDH
`exerted high antineoplastic
`activity
`Phase
`I clinical
`trials
`should
`commence
`in
`the U.S.A.
`by mid-1990.
`
`Rapamycin (NE-226080)
`
`for
`selected
`i.c.
`implanted
`inhibits
`DNA
`
`its activity
`murine
`synthesis
`
`the clono-
`in
`(349:)
`were
`
`l), was originally
`(Figure
`rapamycin
`antibiotic
`The macrocyclic
`CD8FI murine mammary
`tumor
`and
`against
`the S.C. implanted
`ependymoblastoma.
`It was developed
`by Ayerst
`Laboratories
`and
`by interference
`with
`thymidine
`incorporation
`(4).
`potency
`In human
`tumor
`xenografts,
`rapamycin
`showed a high cytotoxic
`tumors
`genie assay
`in vitro
`(Table
`2). At a dose
`level of 0.001 pg/ml,
`14/41
`responsive;
`however,
`considerable
`bone-marrow
`toxicity was also noted.
`In viva, rapamycin
`4). The
`(Table
`was
`tested
`in seven xenografts
`of different
`histologies
`l-4
`i.p. Drug-
`maximum
`tolerated
`dose was determined
`as 100 mg/kg/day
`given on days
`induced mortality
`was observed
`generally
`about 2-3 weeks after drug application.
`A minor
`regression
`(relative
`tumor
`size 740,5 at day 2 1) was achieved
`in an adenocarcinoma
`of the
`breast. Five
`tumors
`showed
`‘no change’ with a median
`duration
`of 28 days, a small-cell
`lung
`cancer xenograft
`grew progressively.
`due
`Further
`development
`of rapamycin
`was stopped
`associated with
`the cremophor
`used
`in
`the experimental
`placed
`on
`the development
`of new analogs
`of rapamycin.
`
`to solubility
`formulation.
`
`problems
`Major
`
`toxicity
`and
`emphasis
`
`is
`
`References
`
`J. B., Safavy,
`antitumor
`
`A., Haugwitz,
`activity
`of pyrazine
`
`R. D. & Narayanan,
`diazohydroxide,
`
`V. L.
`sodium
`
`J. G. &
`A., Fine, D. L., Mayo,
`J. C. & Weisenburger,
`‘1‘. H., eds.,
`
`J,, Rampal,
`E. S., Plowman,
`1). C., Hand,
`1. Baker,
`and preclinical
`Synthesis,
`rhcmical
`stability,
`(1987)
`salt
`(NSC
`361456).
`Anti-Cancer
`Drug Des. 2: 297-309.
`D. A., Monks,
`2. Boyd, M. R., Shoemaker,
`R. H., Alley, M. C., Scudiero,
`Chabner,
`B. A.
`(1989)
`Drug
`development.
`In: Roth,
`J. A:, Ruckdeschel,
`Thoracic Oncolq~,
`Vol.
`7. Philadelphia:
`W. B. Saunders.
`Chapter
`51.
`In vitro cytotoxicity
`01
`(1988)
`3. Brodfuehrer,
`J,
`I., Moore,
`D. J,, Melder,
`D. C., Wilke,
`‘I’. J. & Powis, G.
`Inuert. A$‘ew
`pyrazine-2-diazohydroxide:
`sperificity
`for hypoxic
`cells and effects
`of microsomal
`coincubation.
`Drug3 6: 3-9.
`D. M. & Wodinsky,
`R. K., Silveira,
`4. Broome,
`M. G., Johnson,
`antibiotics:
`rapamycin
`(NSC
`226080)
`of two unique
`antitumor
`Ass. Cancer
`Res. 24: 32 1.
`5. Christian,
`M. C., Wit+
`& Boyd, M. R.
`(1989)
`81: 1133-l
`143.
`(1987)
`6. Fiebig,
`H. H.
`.\‘a~ Drugs 5: 78.
`H. & LGhr, G. W.
`J. R., Bieser, W. N., Henss,
`7. Fiebig,
`H. H., Schmid,
`tumor
`xenografts,
`murine
`tumors
`and human
`boor marrow.
`Potential
`Eur. J. Cancer Clin. Oncol. 23: 937-948.
`8. Fiebig, H. H., Winterhalter,
`B. R., Berger,
`
`Biochemical
`(1983)
`I.
`and macbecin
`II
`(NSC
`
`effects
`and biological
`330500).
`Proc. Am.
`
`R. E., Lcyland-Jones,
`4-Ipomeanol:
`a novel
`
`B., McLemore,
`investigational
`
`‘I‘. L., Grieshaber,
`new drug
`for
`lung
`
`B. A.
`C. K., Chabner,
`,Vatl Cancer Inst.
`cancer.
`J.
`
`Feasibility
`
`and usefulness
`
`of human
`
`tumor
`
`xenografts
`
`in secondary
`
`srreening.
`
`Inoest.
`
`Colony
`(1987)
`for anticancer
`
`human
`assay with
`drug
`development.
`
`D. P. & LGhr, G. W.
`
`(1988)
`
`Combined
`
`in vitro
`
`(clonogenic
`
`assay)
`
`NPC02232991
`
`

`

`EVALUATION
`
`OF
`
`US-NC1
`
`COMPOUNDS
`
`117
`
`with
`
`human
`
`tumor
`
`xenografts
`
`for anticancer
`
`drug
`
`development.
`
`Proc. Am. Ass.
`
`uiao test procedure
`in &o/in
`(1989) C ombined
`Strahlenther. Onkol.
`165: 522-524.
`implications
`for clinical
`evaluations.
`
`its
`
`Recent
`
`in uiuo test procedure
`and
`Cancer
`Res. 29: 493.
`9. Fiebig, H. H.,
`IYinterhalter,
`with
`human
`tumor
`xenografts
`10. Goldin,
`A. & Venditti,
`J. M.
`Results Cancer RPS. 70. 5-20.
`11. Hamburger,
`A. W. & Salmon,
`463.
`D.,J.,
`J., Dykes.
`S. D. Jr., Plowman,
`12. Harrison,
`and schedule
`dependence
`and cross-resistancr
`Am. Ass. Cancer Res. 30: 577.
`(1990)
`D. P. Jr.
`W. R. & Griswold,
`1). J., Wand,
`J., Dykes,
`13. Harrison,
`S. D. Jr.,
`Plowman,
`diazohydroxide
`natural
`metastases,
`and cross-resistance
`of pyrazine
`dependence,
`activity
`against
`in Go. Cancer Chemother. Pharmacol.
`25: 425-9.
`models
`salt, NSC
`361456)
`in preclinical
`14. Plowman,
`J., Harrison,
`S. D., Dykes,
`D. J,, Paull, K. D., Narayanan,
`V. L., Tobol,
`Griswold,
`D. P.
`(1989)
`Preclinical
`antitumor
`activity
`of an a-Pirolinc
`derivative,
`Cancer Res. 49: 1909-1915.
`338720),
`on human
`and murine
`tumors.
`15. Plowman,
`J. &Jackson,
`R. C.
`(1985)
`Anthrapyrazoles,
`a new class of intercalating
`Cancer Res. 45: 5532-5539.
`broad
`spectrum
`activity
`against murine
`tumors.
`predictivity
`16. Staquct,
`M. J., Byar, D. P., Green,
`S. B. & Rozencwcig,
`M.
`(1983)
`Clinical
`tumor
`systems
`in
`the selection
`of new drugs
`for solid
`tumors:
`rationale
`for a three-stage
`Rep. 67: 753-765.
`immune-suppressed
`The
`(1982)
`M. J.
`V. D. & Pcckham,
`17. Steel, G. G., Courtcnay,
`J., ed., The Nude Mouse
`in Experimental
`In: Fogh,
`host
`for heterotransplantation.
`Academic
`Press.
`pp. 207-227.
`New York:
`J., Paull, K. D., Narayanan,
`18. Wand, W. R., Plowman,
`& Griswold,
`D. P., Jr.
`(1988)
`J., Laster,
`W. R., Jr.
`329680).
`Pm. Am. Assoc. Cancer Res. 29: 333.
`
`D. P., Lijhr, G. W.
`B. R., Berger,
`drug
`development.
`for anticancer
`(1980)
`The new NC1 screen
`and
`
`S. E. (19771
`
`Primary
`
`bioassay
`
`of human
`
`tumor
`
`stun
`
`cells. Science 197: 461-
`
`\V. R. & Griswold,
`Lvand,
`of penclomedine
`(NSC
`
`(1989)
`D. P. Jr.
`338720)
`in preclinical
`
`Treatment
`models.
`
`route
`1%~.
`
`Schedule
`(sodium
`
`H. K., Martin,
`Penclomedine
`
`J. &
`(NSC
`
`agents with
`
`high-level,
`
`of
`strategy.
`
`transplantable
`Cancer Treat.
`
`as an altcrnativc
`mouse
`and Clinical Resrarch,
`Vol. 2,
`
`D. M., Harrison,
`V. L., Bailey,
`Preclinical
`antitumor
`activity
`
`D.
`S. D. J., Dykes,
`of hepsulfam
`(NSC
`
`NPC02232992
`
`