C:m1rn T,ratmmt Jievit!ws ( 198 l) 8, G3-B7
`
`New antitumor substances of natural origin
`
`John Douros and Matthew Suffness
`
`Natural Products Branch, DetJelopmental Therapeutics Program,
`Division ef Cancer Trnatment, National Cancer Institute,
`Bethesda, lvlmyland 20205, U.S.A.
`
`Introduction
`
`Since 1956 the Cancer Chemotherapy National Service Center (CCNSC), now incor(cid:173)
`porated into the Developmental Therapeutics Program (DTP), has had a compre(cid:173)
`hensive drug development program which includes the screening of compounds obtained
`from natural products. The fermentation program. during the last four years has isolated
`and evaluated an average of 7500 organisms per year for their ability to produce new
`antineoplastic agents, but in 1979 approximately 15,000 organisms were screened.
`Since the inception of the program, approximately 180,000 culture filtrates have been
`tested in vivo against murinc tumors and 8.5 % of these have been found active ( I 0).
`A marked improvement in in vivo activity in recent years has been due to using in vitro
`pre-screen tests (only those broths active in the in vitro screen arc then tested in vivo)
`and isolating unusual organisms rather than just Streptomyces. Prior to 1975, no in
`vitro pre-screens were used by the CCNSC and primarily the isolation and fermentation
`of Streptomyces dominated the program. While Strcptomyccs 'Were the most prolific
`organisms for the production of novel antimicrobial antibiotics, this did not necessarily
`mean they would be the best producers of antineoplastic agents.
`Some of the in vitro prescrecns used in the NCI program and some contemplated tests
`arc shown in Table 1.
`There have been 1743 crystalline microbial metabolites screened in the program,
`with more than 1000 coming into the program, since 1975 (Table 2).Japancse companies,
`research institutes, and academia have supplied NCI with approximately 400 of these
`compounds during this time.
`Pure compounds which cntc1·ccl the NCI Natural Products Program for evaluation
`in the last yea,• include 233 antibiotics, 180 plant products and 20 animal products
`(Table 3)'. A total of 269 compounds have been assigned for tumor panel testing since
`1977 (Table 4) (8). Also, 432 compounds have .been selected for special testing based
`on some non-cancer biological activity or data regarding concentration of the agent in
`0305-7372/B 1 /0 I 0063 + 25 $02.00/0
`© 1981 Academic Pr<'"-'l.'i Inc. (London) Limited
`
`63
`
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`64
`
`J. DOUROS AND l\l. SUFFNESS
`
`TubJe I. Pre-screens-ill 1•itro
`
`In use
`
`Considered for future use
`
`P3B8 cytoxicity
`Ll210 cytotoxicity
`KB cytotoxicity (liquid, agar)
`Antitnctabolitcs or purines, pyrimidines,
`arnino acids and sugars
`Phage induction (lysogcnic, beta
`galactosiclase)
`Aminopcptidasc H inhibition
`cAl\1 P phosphodiesterase inhibit ion
`Protease inhibition
`Estcrase inhibition
`Antimicrobial activity (including yeasts
`and li.mgi)
`Diflcrcntial sensitivity of nonm,l 11s.
`tnutant bacterial strains
`
`Differential cell cytotoxicity
`Cell diffcrentiatim1
`Cell surface changes
`(a) Agglutination of plant lcctins
`(b) Binding or plant Jectins
`
`lnununogcn stimulation
`Ornithinc decarboxylasc inhibition
`Hypoxic cell
`
`Table 2. 1979 natural products program update
`
`Fermentati.;11
`Approximately 15,000 microbes isolated
`(a) Since inception of program 179,918 culture l>rolhs tested in 11ivo
`(b) 15,257 confirmed actives (in vim)
`(c) 1743 crystalline metabolites tested
`(cl) 127 new compounds in tumor panel
`(e) 11 new compounds in special testing
`
`Plant
`1500 to 3000 plant samples/year
`(a) 500-900 plant species
`(b) Since inception of program about 35,000 plant species,
`l 08,830 extracts
`4712
`(c) Plant extracts active
`1510
`(i) genera active
`3286
`(ii) species active
`(d) 64 plant compounds in tumor panel
`4 plant compounds in special testing
`(e) 2192 crystalline plant compounds tested
`
`Animal
`{a) Since inception of prngrnm 15,063 extracts screened
`(b) Animal extracts active
`651
`(i) genera active
`405
`(ii) species active
`552
`(c) 555 crystalline animal prodm:ts tested
`3 animal compounds in tunJor panel
`10 animal compounds in speci~ll testing
`
`Table 3. 1979 NCI-natural product acquisition·:;
`
`Contract
`
`Non-cont,act
`
`Total
`
`Antibiotics
`Plant products
`Animal products
`
`46
`40
`2
`
`187
`140
`18
`
`Grand ·total
`
`233
`180
`20
`
`433
`
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`NEW NATURAL ANTITUMOR SUBSTANCES
`
`fi5
`
`Table 4. 1979 natural products tumor panel status
`
`Fermentation
`
`Plant
`
`Animal
`
`Total
`
`Compounds assigned
`Testing incomplete
`Testing cc,mplctc
`Dropped status
`
`177
`127
`32
`18
`
`89
`64
`l(j
`9
`
`3
`3
`0
`0
`
`269
`19+
`48
`27
`
`a specific organ, e.g. a compound concentrating in the kidney would be tested against
`renal carcinoma in the mouse (Table 5).
`The plant program evaluates approximately 1500-5000 plant extracts/year, which is
`equivalent to 500-900 plants/year. Since the program's initiation in 1957, about 35,000
`plant species and 108,830 extracts have been screened against murine tumors in vivo
`or for cell cytotoxicity against the KB (human nasopharynx) cell line. Approximately
`7192 crystalline plant materials have been tested in the program. At present, 80 plant
`compounds arc in special testing and 89 are in the tumor panel (Table 4).
`The smallest program has been the animal program and as yet no animal product
`has been evaluated by NCI in clinical trials. NCI has tested approximately 555 crystal(cid:173)
`line animal products and at present has 3 animal compounds in the tumor panel and
`43 animal-derived materials in special testing (Tables 4, 5).
`Many of the pure compounds screened have been isolated from the above-mentioned
`areas through NCI's extramural research program. NCI also has obtained many com(cid:173)
`pounds through its worldwide surveillance program that includes contacting industrial
`concerns, research institutes, universities, and individual scientists to acquire compounds
`of potential interest due to their novel structures or biological activities.
`Some of the more interesting drugs from this program will be reviewed. Most of the
`drugs discussed in the paper arc in preliminary stages of evaluation although several
`agents arc in early clinical trials.
`
`Methodology
`
`Compounds arc obtained by Lhc Natural Products Branch through contracts, grants,
`and through an extensive worldwide surveillance program.
`Pure compounds are tested initially against the P388 leukemia (in vivo pre-screen) at
`NCI unless there is biochemical data or anti tumor data which indicates that other testing
`would be more desirable. Analogs of known active compounds arc tested in direct
`comparison with the parent compound. Compounds which show preliminary activity
`arc retested for confirmation. Confirmed active compounds are reviewed for suitability
`for further testing in the NCI tumor panel (Table 6). Generally all compounds which
`show confirmed activity and arc structurally novel arc tested in the panel as are analogs
`·which show superior activity to their parent compounds.
`
`Table 5. 1979 natural products special testing status
`
`Fermentation
`
`Plant
`
`Animal
`
`Compounds assigned
`Dropped status
`
`309
`149
`
`80
`38
`
`43
`33
`
`Total
`
`432
`220
`
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`

`lit,
`
`J. IJ1 HJII.OS ,\NI) !\I. SUFFNESS
`
`Tul,le <i. Systcuis tested in hu1uu· pand
`
`'l't111111r.,
`
`I'S
`111
`t:1)
`CH
`l.E
`LL
`C21l2
`I.KIi:!
`1\IBll2
`<::ZG!i
`LKC:,
`.\·IBG:"1
`
`Co11lirrned T/(: ".,
`
`Initial
`·-·-·--------··· -··- ---·- ·••··· --·-·-- ~- ··-··-···
`1:.mt
`17.'i
`12:,
`l:iU
`!'~ IO
`<·I:.!
`~_; ,1 :.!
`~:;; 10
`I:.!:·,
`l .'iO
`1,w
`150
`"': :.w
`~ JO
`,;:;:w
`~~ 10
`,:: 'LO
`,;,;:w
`,,:; 211
`,.-;;;:w
`
`,:: -- IO
`-~ 10
`~ JO
`....,, 10
`,:·
`
`l'S---·P:'IIJB
`lymphocytic
`,.. Tumor ahlH·cviatio11s:
`leukemia; PA--- P'.Hlfl arlri.1111y<·i11 resist am; PV-- P:3U8
`,·i11crbti11e resistant; Pli--.. ·P3BH 1.-alanosi11c resistant;
`B 1---H I G m,·lanocarcinoma; (:Ii-- colon :>fi; CB--· colon
`:Ill; CD--CDUFI 111a111mary t11111or; CY----colon '.!G;
`CZ - colon 51 ; El\-l----epcmlymohla:.11,ma; LE-·-1, 1210
`I .L--- Lcwb
`lung ca1-ci11oma;
`leuk1:111i;i;
`lyn,phoid
`carcinoma; NI !---Novikoff
`ovari.111
`~l.':i--1\l.'i07ti
`lwpatwna; C:!G:l--.. -CX-1 colon renal cap,;ulc; C:.!G.'1-·(cid:173)
`CX-l colon n:11al capsule; C4G:">---CX-2 colon renal
`capsule; C!)G.'i---C:X-5 colon renal capi,ule; C:.!H2-(cid:173)
`CX-l colon x,:nngrafi; C9l l:!----CX-5 colon xenograft;
`l.KG.:i---LX-1 lung r<'nal capsule; LKH2--LX-l lung
`renal capsule;
`J\IBG:1---J\IX-2 breast
`xc110µ,'rali;
`!\IBH2-----!\IX-1 breast xc-nograft.
`-J' 1 :10''.'., ir a cn1de ria111ral pn1duct extract or hroth
`
`Compounds demonstrating DN2 level activity in one or more tumor panel systems
`(Tahir 6) are reviewed for considcrntio11 for preclinical development (bulk prod11ction,
`liinnulatinn and loxicology). Decisions l,w selection for DN2A arc made hy the Decision
`Network ( DN) Committee which is made up of scientists expert in chemistry, natural
`products, screening, pharmacology, toxicolngy, phannaceutics, biochemistry and clinical
`1reatmen1. Selection is based on factors which include the spectrum and degree of anti-
`1 umor activity, the novelty of the :-,tructrn·e or superiority to the parent cornp6und, cost
`nf procurenient, possibility of fonnulation, and any biochemical and pharrnacnlogical
`data available, Compounds selected for further development at DN2A ai e returned to
`the D~ committee when procurement and formulation are complete (DN2B) and, if
`passed·;· pi~occecl to toxicology studies. vVhen toxic.:ology studies arc complete the con1-
`pound is again reviewed by the DN committee (DN3) and, if satisfactol'}', materials
`arc asst!mbled for an Tnvcstigational New Drug Application (rNDi. Upon approval of
`1hc IND by the Food and Drug Aclministrntion, Phase J clinical trials nre initiated.
`
`Per1nentation program
`
`In the frnnentatio11 contract program the first objective is to obtain a broad spectnun
`of different types of microorganisms, to ferment them under various ci:Jnditions, an<l to
`
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`NEW NATURAL ANTITUMOR SUBSTANCES
`
`ii7
`
`Tuhlc 7. Microo1·gunisrns isolated on unusun) carbon sourcc:s
`
`Srnue<! of carbon
`
`Isolates
`
`l11 vitro actives
`
`U11comn11H1 ca,holiydrat<·s
`S11hsti111tcd Sugars
`Carhoxylic adds
`Amin11 acids
`Fatly acids
`Lipids
`H ydrocarlmns
`·rerpenes
`
`I B~J
`:.n
`:,0
`WO
`77
`5B
`fi1
`10
`
`(j7 J
`
`22 ( I I.Ii'~•;,)
`ti ('.!6%)
`0
`10 (=>%)
`3 ('.L9%)
`lfj (27 .G'~;,)
`l'.i (20.3%)
`0
`
`70 ( I 0.-1''.,;,}
`
`test the hrot hs against various pre-screens (Tables I and 7). In addilion, comclabolism
`and biotrnnsfonnation techniques arc used on various substrates of interest to NCf lo sec
`if, by subtle microbial chemical modification, one can increase activity, lower toxicity,
`increase bioavailability, or lcmicr carcinogenicity (39). This work has just been iniliatcd
`and has started to yield sornc metabolites tliat arc now being isolated and appear to be
`novel.
`The techniques used to isolate organisms arc pollen baiting, enrichment, percolation,
`and sprinkle plate. In addition, substrates such as unusual sugars, purines, pyrirni<lincs,
`terpencs, arnino acids and hydrocarbons have been used ns sole sources of carbon for
`these organisms. 'rhc fonncntntion broths arc then evaluated againl'l various pr;:-scrcens.
`Active. broths arc rcfermcntcd and, if active again in the prc-sc,·ecn, arc tested in vivo
`against the P:1HB leukemia. An expansion of new pn:-scrcens is being contemplated for
`use in the entire natural products program with the hope of increasing productivity.
`If in vivo· activity is demonstrated in a broth and if presumptive chromatography
`indicates the presence of a novel compound, the active broth is then assigned to a
`chemist. The compound is isolated, idcntiiied, and is then tested in at lcasl four ad(cid:173)
`ditional murinc tumors if sufficient 1natcrial is available (7).
`Results obtained in 1979 indicate that the present approach 10 obtaining new cultures
`that produce novel antineoplastic agents is bcari11g fruit (Tables B, 9, 10). The final
`benefit of using .these various methods to obtain new drugs will be determined by how
`many of these materials have clinical cllicacy. [n order to obtain more novel fermen(cid:173)
`tation-derived compounds, the NCI has sponsored contracts at the 9 contractors listed
`i11 'fable l l.
`The l ·H fermentations currently undergoing chemical isolation studies indicate that
`the NCI program is obtaining more presumptive leads than ever. Prior to l 975 the
`program averaged about 18-22 fermentations undergoing isolation studies in any one
`year.
`
`Table IJ, 1!)79 fermentation statistics
`
`Company
`
`Cultm·cs
`formcntcd
`
`A
`n
`C
`
`H9·1
`42B9
`JO, l3't
`15,:117
`
`Active in l'itra
`
`15G (l7A 1!,{,)
`2501 (:18.3''.;,)
`93B ( 9.2,Xd
`3595 (23.1 '%)
`
`Tested
`in 1•ii:o
`
`IBO
`172
`809
`IIGI
`
`Active in 1.•fro
`
`·t-1 (24.4%)
`75 (43.6'!:,)
`61 (. 7.5'\,)
`180 (15.5'}~.)
`
`Submitted New active
`to chemists compounds
`
`70
`37
`40
`147
`
`6
`2
`2
`10
`
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`

`J. OOUROS ANU M. SUFFNESS
`
`Tuble 9. 3-ycnr nuturnl product screening statistics (one company)
`
`(:ultun:s screened
`Activt: i11 vitrlJ (Ll210 pn·scrcc11)
`Knowns 01· marginal producers
`Active fermentations in rivo T/C > 130
`I :m
`Active concentrates in llfru T/C >
`U11dergoing chemical fractio11atio11
`Nov,·! compounds isolated
`Compounds in tumor panel
`
`12,449
`2501
`11 tiO
`133/529 (25.1%)
`24:3/467 (52.()'i:,)
`37
`24-
`,5
`
`Table 10. 1979 ill 1•itrt1 results of one organization
`
`In vitro activity
`
`AntinH:tabolitc
`(nucleic acid precursors)
`Antimctabolitcs ·
`(specific amino acids)
`Antimct.tbolites
`(11uckic acid precursors
`and :specific amino acids)
`;\utimctabolites
`(Sugan;)
`.'>. arei•isiae 111111a11t
`''Conventional antimicrobial"
`and Ll2l0 cytotoxicity
`L 1210 cytotoxidty alone
`
`Number of
`in vitro leads
`
`Ju 11ivo actives
`
`32
`
`43
`
`G
`
`2
`
`53
`:!I I
`
`90
`
`437
`
`10 (31 'h,)
`
`3 ( 7%)
`
`I ( 17'\,)
`
`0
`
`2 ( 4%)
`23 (11%)
`
`65 (73'%)
`
`10~ (24%)
`
`Table l 1. Fermentation contracts 1~79
`
`General fermentation
`Bristol Mvers Co.
`l\tichigan· Stale Department or Ht•alth
`Microbial Chcrnistry Research Fo11ndation
`\Varner-Lambert
`Upjohn Company
`Frederick Cancer Research Ccnler
`!Jiolra11iformation
`University of Iowa
`Bdstol Myers Co.
`Literature suweilla11ce
`Univcrsit)• of Illinois
`
`The present contractors are investigating many fermentation beers that show good
`in viva activity against P388. These leads primarily come from the pre-screens and new
`isolation carbon sources (Table 7) and hopefully will yield many new antineoplastic
`agents.
`One additional meth~d of obtaining new fermentation leads which is being studied
`is mutational biosynthesis. Two types of mutants are used, auxotrophic and idiotrophic.
`Evahiation of this area of research is just bi'.!ginning but many of the contractors feel it
`could be; profitable and should yield new antincoplastic agents.
`
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`NEW NATURAL ANTITlJMOR SUBSTANCES
`
`69
`
`In addition 10 compounds obtained from NCI 's research program in 1979, approxi-
`111atcly 345 materials derived from natural products were added through a worldwide
`surveillance program. Several clinical and preclinical drugs derived by fermentation
`have been evaluated by NCJ through this surveillance program. Bleomycin, adriamycin,
`daunomycin an<l aclacinomycin arc examples of clinically active drugs that were brought
`into the program. At present, aphidicolin, cchinomycin, pepleomycin, macrornomycin,
`showdomyciu, bcstatin and others arc in various stages of preclinical testing (8).
`
`Plant and animal progra1ns
`
`The plant program ·which has been in existence since 1957 has undergone several
`important modifications in the last 2-3 years. vVc arc not only collecting plants ,vorld(cid:173)
`widc hut, through botanists around the world, obtain lists of all plants in a country.
`Our computer programs then select the plams ,vc have never had in our program or
`those ,vhich have only been tested a Jew times. In addition to our usual plant fraction(cid:173)
`ation program we also have a contract for preparation of aqueous extracts of fresh
`plants in order to determine whether dried plants and our organic solvent extraction
`system miss any potential antincoplastic agents (8). At the present time 64 plar..t
`products are being evaluated in the tumor panel and 4· in special testing. Since the
`inception of the program, 2192 crystalline plant-derived compounds have been evalu(cid:173)
`ated. \Vhilc the animal program is much smaller than the above-mentioned program,
`555 crystalline materials have been tested. The first animal products have now reached
`tumor panel testing with 3 being in the panel and 43 in special testing. Table 12
`indicates NCI's present contracts in the plant. and animal area.
`
`Table 12. Plant and animal contracts 1979
`
`Plant collectio11
`U.S. Department of Agriculture
`University of Hawaii
`Plant e:dractio11
`Raltech Scientific Services, l nc.
`Research Triangle I nstitutc
`Plant fra.:tio11atio11
`Arizona State University
`Central Drug Research Institute
`University of Illinois
`l;urduc University
`i\larine fractionation
`Arizona State llnivernily
`l.eucocyte i•1te1fero11
`\Varncr-I,amhert
`Fibrobl,ut interfero11
`Flow Laboratories, lnc.
`Plant tissue culture
`University of British Columbia
`Kyowa Bakko Kogyo Co.
`Pilot J1lm1t isolation
`Polyscicnccs, Inc.
`
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`70
`
`.J. DOUROS AND :r-.t. SUFFNESS
`
`Figme 1. Structure ofcotyknin A {NSC 319:ilm.
`
`0
`
`Figure 2. Structure ofrubransarol A (NSC 310385).
`
`CH
`
`0
`
`0
`II
`N-C
`
`H
`
`...,..N--""(cid:173)
`H
`
`Fi_gure 3. Structure of CC-l0G."> (NSC 298223).
`
`Table 13. Antitu1nor activity ofCC-1065 (NSC 298223)
`
`Tumor*
`
`Activities
`
`~·~ T/Ct
`
`Opt. dose
`(µg/kg/inJJ
`
`PS
`190
`189
`BI
`C6
`150:f:
`(89)
`C8
`en
`42:t.
`LE
`14-1-
`(63:l:)
`C2G5
`(76:f:)
`LKG5
`(1s:n
`MBG5
`* For tumor abbreviations, sec footnote to Table 6.
`t Alt T/C values in parentheses arc inactive.
`:f: Not confirmed.
`
`30.00
`:i0.00
`S0.00
`50.00
`12.50
`10.00
`2!",.00
`50.00
`12.50
`
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`

`NEW NATUR.i\L ANTITUl\lOR SUBSTANCES
`
`OH
`
`0
`
`(JH
`
`0
`II
`C ·· 0 - CH 3
`
`CH 3
`
`0
`
`or
`
`0
`
`.. CH 3
`
`71
`
`G
`II
`C - 0
`
`- CH,
`
`OH
`
`0
`
`0
`0
`Figure 4. Structure of t<:1rac1·11omyci11 C (NSC 30~H51 ).
`
`0 H
`D I
`H
`9 0 -C -C~ •
`0
`'N
`I
`I
`II
`NH
`
`Cl
`Figure 5. Structure of acivicin (NSC 163501 ).
`
`Table 14. Antitumor activity ofacivicin (NSC 163501)
`
`Tumor*
`
`PS
`Bl
`C:6
`C:8
`CD
`LE
`I.L
`CY
`CZ
`l\1:,
`PA
`PY
`PG
`C2G5
`C4G5
`LKH2
`MBH2
`MBG5
`
`Activities
`
`Opt. dose
`(mg/kg/inj.)
`
`8
`2
`8
`·1.3
`4,32
`3.12, 6.25
`2.1
`23
`3.3
`120
`60
`32.4
`16
`8
`IG
`32
`8
`16
`
`% T/Ct
`
`250
`131
`14+
`( 13 I)
`23, G
`172, 223
`143
`( 104)
`126
`195
`147
`13:1
`177
`(157)
`(55)
`21
`3
`13
`
`• For tumor abbreviations, sec footnote to Table 6.
`t All T/C values in parentheses arc inactive.
`
`0
`
`Fi_,:11rt1 6. Structurn of hcrbimycin {NSC 305978).
`
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`72
`
`J. DOUR.OS .-\ND :\1. SliFFNESS
`
`TRblc 15. Antitumor activity of hcrbirn)·cin (NSC 305978)
`
`Activities
`
`~o T/Ct
`
`(IOl;)
`142
`( 103;)
`(95)
`
`Opl. dose
`(mg/kg/inj.)
`
`G.00
`0.75
`O.G2
`3.00
`
`PS
`131
`C8
`LE
`
`"' For tumor abbreviations, st·c footnote to Table 6.
`t All T/C values in parc111hcses arc inactive.
`! :--lot confirmed.
`
`Results
`
`The compounds discussed in this section arc potentially of interest to. NCI because of
`animal in vivo activity or unique structure and arc still being evaluated but have not
`reached the stage of being clinically useful.
`C:otylcnin A--NSC 319518 (Figure I) is a fermentation product (38). This glycosidc
`is an unusual compound which is undergoing special testing against 3 solid tumors and
`P388 leukemia. So far no activity has been observed.
`Rubransarol A-NSC 310385 (Figure 2) is a fermentation-derived quinone which
`was discovered by the Upjohn Company (16). Because of its structure and biological
`activity it was considered worthy of special testing. So far this compound has been
`inactive against the P388 leukemia and B 16 melanoma.
`CC-1065-NSC 298223 (Figure 3, Table 13) is a fermentation product which was
`discovered by the U pjohn Company ( 13). This benzodipyrrole recently passed Decision
`Network 2A and has been selected for preclinical development. This drug had good
`activity against P388 leukemia and B 16 melanoma and was slightly active against all
`the other murine tumors in the NCI panel except Lewis lung (LL). Formulation
`studies and bulk production are currently being pursued by the Ur.john Company.
`Tetracenomycin C--NSC 309451 (Figure 4) is a fermentation-derived naphthocenc
`(45) which was obtained from our worldwide surveillance program. This antibiotic is
`scheduled to be tested in the entire tumor panel based on its confirmed P388 activity.
`Acivicin-NSC: 163501 (Figure 5, Table 14) is an isoxazole that was isolated from a
`fermentation by the Upjohn Company and was formerly designated as AT-125 (12, 14,
`26). Acivicin acts as an antimetabolitc to glutarnine, histidine and asparagine (5, 15, 17).
`This compound has now entered Phase I clinical trials in the United States. The com(cid:173)
`pound has shown good activity against the murine lcuk«:rnias (P388-T/C > 200,
`LE-TiC 180) (27) and against the CD mammary tumor and the colon 26 tumor.
`Acivicin was also active against several P388 leukemia resist.int lines and showed good
`activity in the mammary xenografts (MX-1 and MB) (18).
`Herbimycin-NSC 305978 (Figure 6, Table 15) is a quinone isolated al Kitasato
`University from a fermentation (35, 36). This compound was in the special testing
`program and has shown Bl6 melanocarcinoma activity. Based on that activity it is
`now being tested in the NCI tumor panel.
`Cranornycin-like antibiotic--NSC 300886 (Table 16) was isolated by Warner(cid:173)
`Lambert Company from a fermentation. This compound is scheduled for tumor panel
`testing based on its BI 6 activity.
`
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`NEW NATURAL ANTJTUl'vlOR SUBSTANCES
`
`73
`
`Table 16. Anti tumor activity of CL-202A (NSC 300886)
`
`Tun1or*
`
`Activities
`
`% T/Ct
`
`Opt. <lose
`(mg/kg/inj.)
`
`120
`PS
`Bl
`136
`2
`C6
`I
`(98)
`CB
`(HS)
`0.12
`(52)
`CD
`l
`LE
`(108)
`2
`* For tun1or abbreviations, sec footnote to TabJc 6.
`t All T/C "'alucs in parentheses arc inactive.
`
`Table 17. Antitumor activity or CL-24F.HCL (NSC 287018
`
`Tun1or•
`
`Activities
`
`•};_, T/Ct
`
`Opt. dose
`(mg/kg/inj.)
`
`PS
`0.93
`188
`134
`Bl
`1
`0.25
`C6
`( 108)
`43
`C8
`I
`(95)
`CD
`I
`LE
`0.5
`130
`LL
`0.5
`130
`* For tu1nor abbreviations, sec footnote to Table 6.
`t All T/C values in parentheses are inactive.
`
`Table 18. Antitumor activity or ascidian compound
`(NSC 325319)
`
`Tumor*
`
`Activities
`
`% T/Ct
`
`Opt. dose
`(µg/kg/inj.}
`
`PS
`30
`171
`164
`160
`Bl
`CD
`40
`(55}
`LE
`133:f:
`20
`cs
`320
`(79t)
`* For tumor abbreviations, sec footnote to Table G.
`t All T/C values in parentheses are inactive.
`t Not confinncd.
`
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`

`74
`
`J. DOUROS AND M. SUFFNESS
`
`Figure 7. Structure of aplasmomycin (291329).
`
`Cranomycin-like antibiotic--NSC 287018 (Table l 7) was isolated by the Warner(cid:173)
`Lambert Company from a fermentation. It is different from NSC 300886 and, based
`on P388 activity, has been scheduled for the NCI tumor panel.
`Ascidian compound-NSC 325319 (Table 18) is a material isolated at the University
`of Houston from a tunicate. The compound is a depsipcptide whose structure is just
`being determined and this marine animal product is being tested in the C,!Itire NCI
`tumor panel. The compound has shown good activity against the Bl6 melanoma and
`has recently passed DN2A. This is the first. marine-derived product selected for pre(cid:173)
`clinical developri1ent.
`Apla~momycin-NSC 291329 (Figure 7) i-~ a boron complex isolated in the labora(cid:173)
`tories of the Institute of Microbial Chemistry in Japan from a marine Streptomyces
`(31, 34) and has shown minimal activity in B16. Because of its unusual structure and
`antiplasmodium activity it has been selected for some special testing.
`Sil~iromycin-NSC 291320 (Figure 8, Table 19) is an anthramycin analog isolated
`fron;i fermentations (2). This compound has met DN2 criteria in Bl6 and has shown
`activity in mammary carcinoma (CD). At present this compound is being evaluated
`in the NCI tumor panel.
`Neot,hramycins A and B-NSC 285223 (Figure 9, Table 20) are an anthramycin
`complex isolated from fermentation broths by Dr Umezawa's group in Japan (42).
`This complex has shown. less activity in murine tumors than sibiromycin. However,
`against the Novikoff rat hcpatoma, T/Cs of > 800 have been consistently obtained.
`
`0
`
`O=S=O
`
`CH3 -~
`HOH
`Figure 8. Structure of sibiromydn SO2-aclduct (NSC 291320).
`
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`

`NEW NATURAL ANTITUMOR SUBSTANCES
`
`75
`
`Table 19. Antitumor activity of' sibiromycin
`S02-adduct (NSC 291320)
`
`·1·umor*
`
`Activities
`
`'% T/Ct
`
`Opt. dose
`(µg/kg/inj.)
`
`PS
`173
`16.00
`Bl
`166
`4.00
`(50:j:)
`CB
`4.00
`2.00
`23:j:
`CD
`LE
`127
`32.00
`LL
`(130)
`16.00
`* For tun1or abbreviations, sec footnote to Table 6.
`t All T/C values in parentheses arc inactive.
`t Not confirtncd.
`
`Table 20. Antit:umor activity of ncothramycin
`(NSC 285223)
`
`Activities
`
`% T/Ct
`
`Opt. dnse
`{mg/kg/inj.)
`
`PS
`147
`4.00
`4.00
`( 119)
`Bl
`CB
`(62)
`1.10
`CD
`4.00
`(79:t:)
`EM
`(95,t)
`2.00
`LE
`4.00
`126
`(63:p
`LKG5
`16.00
`MBG5
`(159,t)
`2.00
`2.00
`NH
`810
`* For tumor abbreviations, see footnote to Table 6.
`t All T/C values in parentheses arc inactive.
`t Not confirmed.
`
`Table 21. Antitumor activity of rapamycin (NSC 226080)
`
`Tumor*
`
`Activities
`
`% T/Ct
`
`Opt. dose
`(mg/kg/inj.)
`
`PS
`141
`200.00
`159
`190.00
`Bl
`25.00
`C6
`(118:t)
`CB
`14
`400.00
`10:t:
`CD
`200.00
`EM
`219
`25.00
`LE
`( l 11)
`600.00
`LL
`(107:t)
`400.00
`6:t:
`C2G5
`100.00
`400.00
`LKG5
`(66:f:)
`MBG5
`(41-2:t)
`100.00
`* For tumor abb'rcviaticms, see footnote to Table 6.
`t AU T/C values in paren'i:heses are inactive.
`;t: Not confirmed.
`
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`

`76
`
`Ho:q;N~
`
`9"
`~ I
`
`N
`
`CH3-0
`
`J. DOUROS AND 1\1. SUFFNESS
`
`HO:q;N~
`CH3-0 O HO H
`
`~
`
`~ I
`
`N
`
`H OH
`O
`Figure 9. Structure of neolhramycin (NSC 285223).
`OH
`
`Q_i:
`0=!=:0°
`
`N
`
`HO;y
`CH;'"'-.._,
`
`0
`
`Figure iO. Structure of rapam>·cin (NSC 226080).
`CH3
`I
`CH
`\
`CH3
`
`0
`
`Figure 11. Structure of tripdiol~de (NSC 163063).
`
`CH1
`
`CH3
`
`"' /
`
`CH:i
`
`"' /
`
`CH3 CH,
`
`CH3
`
`"' /
`
`CH 0
`H
`CH 0
`CH O
`0 H
`!I
`I
`!
`II
`I
`I
`l
`ll
`I
`II
`N--CH ·- C-0-CH--C N--CH-C-0--CH-C
`I
`,._.,
`co,
`(DI
`(Ll
`NH
`I
`H3C-CH--CH!o}
`I
`I
`C ·, 0
`CH3
`I
`0
`I
`H3C ··· CH(Ll
`I
`C·~ 0
`I
`NH
`CH;i
`I
`"-.
`CHJ HC- CH !Ll
`/
`I
`CH3
`C ~ 0
`CH3
`CH.
`"-../.
`I
`O
`O CH;i
`CH H
`0
`0
`H
`I
`I
`!
`II
`II
`I
`I
`II
`HC-CH 0--C-CH-N•
`C ·· CH-0 ·-C-CH N--C--CH
`II
`{Ll
`lL}
`(O}
`\0}
`(D)
`0
`F~gtmt 12. Str1J,cture of valinomycin (NSC 122023).
`
`C"'-0
`
`CH3 "'
`
`/
`CH::1
`
`CH.:i
`"-. /
`CH
`
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`
`

`

`NEW NATURAl, ANTITU.MOR SUBSTANCES
`
`77
`
`Table 22. Antitumor activity of tripdiolide {NSC 163063)
`
`Tumor*
`
`PS
`HI
`C6
`LE
`LL
`
`Activities
`
`Opt. dose
`(µg/kg/ inj.)
`
`250
`100.
`250
`250
`25
`
`';;, T/Ct
`
`158
`134
`(103)
`207
`( 138)
`
`* J~or tumor abbreviations, sec: footnote to Table 6.
`t All T/C values in parentheses arc inactive.
`
`This complex is being evaluated in thc,~ntirc tumor panel and is presently undergoing
`Phase l dii1ical trials in Japan. The two components of the complex, neothratnycins A
`and B, can be separated but readily interconvert in aqueous systems to an equilibrium
`mixture.
`Rapamycin-NSC 226080 (Figure IO, Table 21) is a tricnc isolated by Aycrst
`Pharmaceuticals from Strcptomyccs fermentations ( l, 40, 41, 43). Originally this
`material was found to have good anti-Candida activity. Rapamycin was selected for
`further development at NCI based on its good activity against m.ammary (CD) and
`colon (C8) tumors and the brain tu_mor> ependymoblastoma (El\.1). Development of a
`suitable formulation is now underway which will be followed by toxicology studies.
`Tripdiolide-NSC 163063 (Figure 11, Table 22). This triepoxide diterpenc (20) has
`shown good activity against murine leukemias. Several thousand pounds of plant
`material are now being processed so sufficient material will be made available for
`formulation and toxicology.
`
`Table 23. Antitum.or activity of valinomycin {NSC 122023)
`
`Tumor*
`
`Activities
`
`Opt. dose
`(mg/kg/inj.)
`
`183
`lO
`PS
`5
`183
`Bl
`3
`200
`C6
`20
`25
`CB
`1
`(49)
`CD
`5
`LE
`131
`6
`145
`LL
`40
`(H)
`C2G5
`3
`(64)
`C9H2
`(54)
`5
`C9G5
`12
`{88)
`LKH2
`5
`(99)
`LKG5
`24
`(97)
`MBH2
`20
`(52)
`MBGS
`* For tumor abbre~iations, see footi1ote to Table 6.
`t All T/C values in parentheses are inactive.
`
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`

`78
`
`J. DOUR.OS AND M. SUFFNESS
`
`H
`--------CH2-0H
`.----+-•H
`
`Figure 13. Structure of aphidicolin (NSC 23,n 14).
`
`------
`CH3 0 CH-1
`H O
`
`· H c-s' 's
`
`I
`~
`t-NH-tH---~-~---l ~ ·--~-=--CH--~-0
`""' .,.9NX)
`(D) I
`I
`CH;,
`C-NH- CH
`(O)t::H-NH-C \~ I . --.;;:
`I
`I
`8
`CH;,
`1
`1
`•
`(L)/
`(L)
`(L)
`I
`0-C-CH-N-C-C-N-C-CH-'-NH--C.
`ii
`II
`I
`I
`I
`I
`!I
`!I
`0
`CH3 0
`H
`CH3 0
`CH3
`0.
`fH-CH3
`"'
`CH3
`Fft;ure 14. Structure of cchinomycin (NSC 526417).
`
`(XN )
`
`N
`
`g
`
`(LI
`
`3
`
`/(LI
`CH
`
`CH.,
`
`-
`
`CH
`
`~:~-CH3
`0
`
`(Ll
`
`,-...
`............. N
`
`.,_,.,,,
`
`Figure 16. Structure of 7-0-mcthylnogarol (7-0MEN) (NSC 269148).
`
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`

`NE'W NATURAL ANTITUMOR SUBSTANCES
`
`79
`
`Table 24. Antitumor activity of aphidicolin (NSC 234714}
`
`Activities
`
`% T/Ct
`
`Opt. dose
`(mg/kg/inj.)
`
`155
`PS
`75
`( 176)
`Bl
`150
`200
`C6
`229
`(65)
`CB
`100
`CD
`400
`(44)
`LE
`100
`( 122)
`LL
`( 126)
`lCO
`400
`Ml3H2
`(83)
`LKG5
`100
`26
`200
`LKH2
`(86)
`C2G2
`50
`(73)
`400
`(95)
`C2H2
`200
`C9G5
`(45)
`(78)
`200
`C9H2
`* For tu1nor abbreviations, see footnote to Table 6.
`t All T/C values in parentheses are inactive.
`
`Table 25. Anti-tumor activity oi echinomycin
`(quwomycin A) (NSC 526417)
`
`Tun1or*
`
`PS
`Bl
`C6
`CB
`CD
`LE
`LL
`3LKG5
`3M.Bl:l2
`3C2G5
`C2H2
`C9G5
`C9H2
`LKH2
`MBGS
`l\.lBH2
`
`Activities
`
`% T/Ct
`
`Opt. dose
`(mg/kg/inj.)
`
`205
`189
`(104)
`(l 23)
`(67)
`126
`( l l l)
`(52)
`(54-)
`2l
`(78)
`(55)
`(56)
`(85)
`(55)
`(66)
`
`0.06
`0.12
`0.06
`0.015
`0.0075
`0.03
`0.015
`0.12
`0.03
`0.24
`0.03
`0.12
`0.1
`0. t
`0.24
`0. 1
`
`* For tumor abbreviations, sec footnote to Table 6.
`t All T/C values in parentheses arc inactive.
`
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`

`80
`
`J. DOUR.OS AND M. SUFFNESS
`
`0
`
`Figure 17. Structure ofnybomycin acetate (NSC 157004).
`
`OH
`I
`
`0
`
`1 H O
`0
`O-C-CH=C-CH3
`II
`I
`0
`CH3
`
`F(gurc 18. Structure of 6a-senccioyloxy-chaparrinone (NSC 290494).
`
`F(g1m: 19. Structure of pepleomycin (NSC 276382).
`
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`

`NEW NATURAL J\NTlTUMOR SUBSTANCES
`
`Bl
`
`Table 26. Antitomor activity ofbaccharin (NSC 269757)
`
`Tumor*
`
`PS
`Bl
`C6
`CB
`CD
`LE
`LL
`M5
`PA
`
`Activities
`
`% T/Ct
`
`Opt. dose
`(mg/kg/inj.)
`
`311
`158
`(123)
`(66)
`(76)
`157
`( 105)
`131
`158
`
`10
`2.5
`3.2.f
`20
`20
`40
`5
`0.75
`7.2
`
`* For tumor abbreviations, see footnote to Table 6.
`t All T/C values in parentheses are inactive.
`
`Valinomycin-NSC 122023 (Fjgure 12, Table 23). This fermentation product is
`now undergoing formulation studies. vVhile quite active against murinc tumors, no
`activity against human tumors in nude mice has been observed.
`Aphidicolin-NSC 234714 (Figure 13, Table 24) is a diterpene fermentation product
`isolated by ICl (3, 6) which has potent antiviral act