`
`in Cancer Research 76
`
`Fortschritte der Krebsforschung
`Progres dans Ies recherches sur Ie cancer
`
`Edited by
`V. G. Allfrey, New York· M. Allgower, Basel
`I. Berenblum, Rehovot . F. Bergel, Jersey
`J. Bernard, Paris . W. Bernhard, Villejuif
`N. N. Blokhin, Moskva . H. E. Bock, Tiibingen
`W. Braun, New Brunswick . P. Bucalossi, Milano
`A. V. Chaklin, Moskva' M. Chorazy, Gliwice
`G. J. Cunningham, Richmond . G. Della Porta, Milano
`P. Denoix, Villejuif . R. Dulbecco, La Jolla
`H. Eagle, New York· R. Eker, Oslo
`R. A. Good, New York· P. Grabar, Paris
`R. J. C. Harris, Salisbury . E. Hecker, Heidelberg
`R. Herbeuval, Vandoeuvre . J. Higginson, Lyon
`W. C. Hueper, Fort Myers . H. Isliker, Lausanne
`J. Kieler, Kobenhavn . W. H. Kirsten, Chicago
`G. Klein, Stockholm . H. Koprowski, Philadelphia
`L. G. Koss, New York· R. A. Macbeth, Toronto
`G. Martz, Zurich
`. G. Mathe, Villejuif
`O. Muhlbock, Amsterdam' L. J. Old, New York
`V. R. Potter, Madison . A. B. Sabin, Charleston, s.c.
`L. Sachs, Rehovot . E. A. Saxen, Helsinki
`C. G. Schmidt, Essen' S. Spiegelman, New York
`W. Szybalski, Madison . H. Tagnon, Bruxelles
`A. Tissieres, Geneve . E. Uehlinger, Zurich
`R. W. Wissler, Chicago
`
`Editor in Chief" P. Rentchnick, Geneve
`Co-editor: H. J. Senn, St. Gallen
`
`NOVARTIS EXHIBIT 2044
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 26
`
`
`
`New Drugs
`in Cancer Chemotherapy
`
`Edited by
`S. K. Carter Y. Sakurai H. Umezawa
`
`With 133 Figures and 170 Tables
`
`S pringer-Verlag
`Berlin Heidelberg GmbH 1981
`
`NOVARTIS EXHIBIT 2044
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`Page 2 of 26
`
`
`
`U.S. Japan Joint Agreement on Cancer Research
`5th Annual Program Review Symposium
`San Francisco (USA), May 21- 22, 1979
`
`Dr. Stephen K. Carter
`Northern California Cancer Program,
`1801 Page Mill Road, Suite 200,
`Building B, Palo Alto, CA 94304 (USA)
`
`Dr. Yoshi Sakurai
`Cancer Chemotherapy Center, Japanese
`Foundation for Cancer Research,
`Kami-Ikebukuro 1-37-1, Toshima-ku,
`Tokyo 170 (Japan)
`
`Dr. Hamoa Umezawa
`Institute of Microbial Chemistry,
`14-23 Kamiosaki 3-Chome, Shinagawa-ku,
`Tokyo 141 (Japan)
`
`Sponsored by the Swiss League against Cancer
`
`ISBN 978-3-642-81565-2 (eBook)
`ISBN 978-3-642-81567-6
`DOI 10.1007/978-3-642-81565-2
`
`Library of Congress Cataloging in Publication Data. Main entry under title: New drugs
`in cancer chemotherapy. (Recent results in cancer research; 76) "U.S. Japan Joint
`Agreement on Cancer Research, 5th Annua1 Program Review Symposium, San Francisco
`(USA), May 21-22,1979. Sponsored by the Swiss League against Cancer." Includes
`bibliographical references and index.!. Cancer - Chemotherapy - Congresses. 2. Anti(cid:173)
`neoplasticagents - Congresses. 1. Carter, Stephen K. IL Sakurai, Yoshio. III. Umezawa,
`Hamao, 1914- IV. Schweizerische Nationalliga fur Krebsbekămpfung und Krebs(cid:173)
`forschung. V. Series. [DNLM: 1. Antineoplastic agents - Therapeutic use - Congresses.
`2. Neoplasms - Drug therapy - Congresses. WI REI 06P v. 76/ QZ 267 N532 1979]
`RC26l.R35 voL 76 [RC27I.C5] 616.99'4s 80-39739 [616.99'4061]
`This work is subject to copyright. All rights are reserved, whether the whole or
`part of the material is concerned, specifically those of translation, reprinting, re-use
`of illustrations, broadcasting, reproduction by photocopying machine Of similar means,
`and storage in data banks. Under § 54 of the German Copyright Law where copies
`are made for other than private use a fee is payable to 'Verwertungsgesellschaft Wort',
`Munich.
`
`© Springer-Verlag Berlin Heidelberg 1981
`Originally published by Springer-Verlag Berlin Heidelberg New York in 1981
`Softcover reprint of the hardcover 1 st edition 1981
`
`The use of registered names, trademarks, etc. in the publication does not imply,
`even in the absence of a specific statement, that such names are exempt from the
`relevant protective laws and regulations and therefore free for general use.
`Typesetting and printing: Cari Ritter-GmbH & Co.KG., Wiesbaden
`Binding: J. Schăffer OHG, Griinstadt
`2125/3140-543210
`
`NOVARTIS EXHIBIT 2044
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`
`
`Other New Drugs
`
`New Natural Products Under Development
`at the National Cancer Institute
`
`J. Douros and M. Suffness
`
`Natural Products Branch, Developmental Therapeutics Program, Division of Cancer
`Treatment, National Cancer Institute, USA - Bethesda, MD
`
`Summary
`
`Twenty-six new agents of natural products ongm which are under preclinical
`development as potential antitumor agents at the National Cancer Institute are
`discussed with reference to their sources, structures, antitumor activity, current status,
`and future potential as clinically effective drugs.
`
`Introduction
`
`Since 1956 the Cancer Chemotherapy National Service Center, now incorporated into
`the Developmental Therapeutics Program (DTP), Division of Cancer Treatment, has
`had a comprehensive drug development program that includes the screening of
`compounds obtained from natural products [7]. Since the inception of the program,
`approximately 178,802 microbial cultures have been isolated and fermented and
`103,272 plants extracted. The fermentation broths and plant extracts have been tested
`for their cell cytotoxicity and in vivo activity against various animal tumors using
`standard protocols [10]. During the last 3 years the fermentation broths in many cases
`have first been tested in various in vitro prescreens (e.g., enzyme inhibition, tubulin
`binding, phage induction, antimicrobial and antiyeast screens) [6]. Approximately 7
`years ago a concentrated effort to evaluate animal products (primarily marine) was
`initiated and to date 13,751 extracts have been screened and 0.7% showed confirmed
`in vivo activity.
`Many compounds have been isolated from the above-mentioned programs and in
`addition many natural products are obtained from the NCI worldwide surveillance
`program which includes agreements with industrial companies, research institutes,
`universities, and scientists. Some of the more interesting compounds in preclinical
`drug development that will be discussed are listed in Table 1. Many of the compounds
`discussed are analogs of earlier compounds which have been prepared in an effort to
`discover second generation drugs which retain the activity of the parent molecule and
`have less toxicity.
`
`S. K. Carter et al. (eds.), New Drugs in Cancer Chemotherapy
`© Springer-Verlag Berlin Heidelberg 1981
`
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`154
`
`J. Douros and M. Suffness
`
`Table 1. Natural products undergoing preclin(cid:173)
`ical drug development at NCI
`
`NCI No.
`
`107660
`244392
`296940
`276382
`294979
`279496
`208734
`269148
`265450
`526417
`122023
`237020
`234714
`285223
`226080
`298223
`216128
`283439
`141633
`163063
`125973
`269757
`269760
`266492
`157995
`266491
`
`Compound
`Actinomycin pip 1/3
`Azetomycin 1
`Actinomycin S3
`Pepleomycin
`Bleomycin BAPP
`Tallysomycin A
`Aclacinomycin A
`7-0-methyl nogarol
`Nogamycin
`Echinomycin
`Valinomycin
`Largomycin
`Aphidicolin
`Neothramycin
`Rapamycin
`CC-1065
`Borrelidin
`Eriofertopin
`Homoharringtonine
`Tripdiolide
`Taxol
`Baccharin
`Isobaccharin
`Phyllanthoside
`Fagaronine
`Psorospermin
`
`Methodology
`
`Natural products, when purified (> 90% ), are assigned NSC numbers which are
`identification codes used by NCI for all compounds studied. NCI prefers materials to
`be at least 98% pure before assigning NCS numbers; however, because proteins,
`peptides, polysaccharides, and some other antibiotics do not lend themselves to easy
`purification or are extremely costly to purify to a state of > 90% purity, they are
`assigned NSC numbers also. The various protocols for screening these drugs have been
`established by the Drug Evaluation Branch, NCI [10]. Normally the P388 leukemia
`assay in mice is the first in vivo test in which a natural product compound is evaluated.
`However, rational selection can result in using another in vivo tumor as the first screen
`if there is information on organ distribution, lipophilicity, selective tissue effects, or
`other antitumor data that indicate that other testing is preferable.
`In most cases a material is tested initially against the P388 leukemia (PS) to determine
`toxicity data even though this may not be the test tumor of greatest interest. If
`reproducible activity is demonstrated in PS as evidenced by an increase in life span
`(ILS) of 20% or greater and if the compound has a novel structure, it is tested against a
`panel of tumors (Table 2). Close analogs of known compounds are tested under special
`
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`New Natural Products Under Development at the National Cancer Institute
`
`155
`
`Table 2. Division of Cancer Treatment (DCT) panel of antiserum screens
`
`Tumor
`
`Parameter
`
`Activity
`criteria
`
`Route Tissue and level
`inocula- of inoculation
`tion
`
`Tumor inhibition TIC:;; 42%
`IP
`Mouse colon 38 (CS)
`Tumor inhibition TIC:;; 42% SC
`Mouse Breast (CD)
`Human colon xenograft Tumor inhibition TIC:;; 42% SC
`Mouse breast xenograft Tumor inhibition TIC:;; 42% SC
`Tumor inhibition TIC:;; 42% SC
`Mouse lung xenograft
`TIC 2'. 125%
`Mouse B16
`Survival
`IP
`melanosarcoma (B 16)
`Mouse Lewis lung
`carcinoma (LL)
`Mouse L1210 leukemia
`(LE)
`
`Survival
`
`Survival
`
`TIC 2'.140%
`
`IP
`
`TIC 2'.125%
`
`IP
`
`Brei
`Brei
`Fragment
`Fragment
`Fragment
`Brei
`
`1: 100
`5 X 106
`14mg
`14mg
`14mg
`1: 10
`
`Cells
`
`Cells
`
`10s
`
`10s
`
`protocols in comparison with the parent compound. Rational bypass can be used to
`expedite testing in tumor panel systems or to screen against tumors that are not part of
`the tumor panel, including, for example, brain tumors for compounds that are known
`to cross the blood brain barrier or hormone dependent tumors for compounds with
`endocrine activity.
`If the compound has sufficient activity and is a novel structure or an analog deemed of
`interest to NCI, it will now be reviewed by the Decision Network (DN) Committee
`and, if approved, is scheduled for formulation studies. When a clinical formulation is
`obtained, the agent is tested for schedule dependency and oral route activity. The DN
`group then determines if the compound should progress into toxicology studies.
`While toxicology studies are being done, the pharmacology group determines
`pharmacokinetics and tissue distribution of this drug. The DN Committee reviews the
`toxicology results and determines if the drug is suitable for Phase I clinical trials. After
`Phase I trials are completed, the DN group again reviews the results and determines if
`the drug should be a candidate for Phase II clinical trials against the panel of human
`tumors selected by NCI:
`1. Breast
`2. Colon
`3. Lung
`4. Melanoma
`5. Acute leukemia
`6. Lymphoma, Hodgkin's disease
`
`Natural products, whether derived from microbes, plants, or animals, are all evaluated
`in the same way. Thorough discussions of the methodologies used in development of
`fermentation-derived compounds and plant-derived compounds are found in the paper
`by Douros [6] and Suffness and Douros [26].
`
`Results
`
`The following drugs derived from natural sources are now in some phase of preclinical
`drug development at NCI:
`
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`156
`
`J. Douros and M. Suffness
`
`CH3-CH
`
`CH-CH3
`
`Lo
`?i bL/
`
`3
`
`(DJ
`CH-C-NH-CH-C-N
`I
`II
`I
`NH O
`CH-C~
`I
`I
`
`?~
`?~
`w I w
`w I w
`6H/LI I
`I ILi
`?i r~~~;~0 (r-CH
`'~ <x:xX"' '~
`
`O-C-CH-N-C-CH2-N-CH3
`
`6H3
`
`CH3-N-CH2-C-N-CH-C-O
`
`oJ
`
`(DI
`LI
`N-C-CH-NH-C-CH
`II
`I
`I
`0 CH-C~
`NH
`I
`I
`
`CH3
`
`CH3
`
`Fig. 1. Structure of
`actinomycin pip 1/3 (NSC
`107660)
`
`Actinomycin pip 1(3 (NSC-107660) (Fig. 1) is a peptide antibiotic with a phenoxazine
`chromophore that is produced by Streptomyces parvulus. This antibiotic differs from
`actinomycin D in that the praline residue in the beta peptide chain is replaced with
`pipecolic acid. The production of actinomycin pip 1(3 and actinomycins in general by
`precursor feeding has been extensively studied by Katz and co-workers [8, 12].
`There is interest in evaluation of a new actinomycin in clinical trial if the compound
`gives indication of a broader or different spectrum of activity, less toxicity, or a better
`chemotherapeutic index than actinomycin D. More than 100 actinomycins have been
`evaluated in NCI's program and three seem to have activities of interest. Actinomycin
`pip 1(3 is being compared with actinomycin D in gastrointestinal toxicity tests and in the
`NCI tumor panel. Actinomycin pip 1(3 has shown good activity in murine tumors
`against colon 38 (C8) giving 91 % inhibition, mammary carcinoma (CD) 99%
`inhibition, colon 26 (C6) 84% increased life span (ILS), B16 melanoma 66% ILS,
`L1210 leukemia (LE) 59% ILS, P388 leukemia (PS) 105% ILS. These activities are
`quite similar to those of actinomycin D. The critical data will be whether
`gastrointestinal toxicity is considerably less than that of actinomycin D and whether
`some xenograft activity is found with this analog. If actinomycin pip 1(3 is superior to
`actinomycin D in these tests it will be presented to DN. A comparison of the various
`actinomycin activities can be found in Table 3.
`
`Azetomycin I (NSC-244392) (Fig. 2) is an analog of actinomycin D and is also obtained
`by precursor fermentation [8]. This antibiotic differs from actinomycin Din that one of
`the pralines is replaced with azetidine. This compound has shown good activity against
`P388 giving 166% ILS, 51 % ILS against LE, 52% against B16, 100% inhibition of CD,
`57% ILS against C6 (Table 3). This drug has also shown activity against an
`actinomycin D-resistant leukemia. One additional actinomycin is being tested,
`actinomycin S3 (NSC-296940) [9]. The spectrum of antitumor activity in the few tests
`evaluated is inferior to that of actinomycin D (Table 3). The comparison of
`actinomycin D, azetomycin I, and actinomycin pip 1(3 antitumor data shows that thus
`far none has an advantage over the other and thus the comparative toxicity data
`becomes the crucial factor on whether one of the analogs is developed towards clinical
`trials.
`
`NOVARTIS EXHIBIT 2044
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`
`
`New Natural Products Under Development at the National Cancer Institute
`
`157
`
`Table 3. Typical activities of actinomycin derivatives in murine tumor systems•
`
`Tumor
`
`Actinomycin
`D
`NSC-3053
`
`Actinomycin
`pip 1{3
`NSC-107660
`
`Azetomycin
`I
`NSC-244392
`
`Actinomysin
`S3
`NSC-296940
`
`%TIC O.D.b %TIC O.D.b %TIC O.D.b
`
`%TIC O.D.b
`
`PS31 P388 lymphocytic leukemia 279
`LE21 L1210 lymphoid leukemia
`158
`B132 B16 melanocarcinoma
`200
`C631 Colon 26
`153
`C872 Colon 38
`22
`CD72 CD8F 1 mammary tumor
`0
`
`100
`60
`25
`500
`300
`300
`
`205
`159
`166
`184
`9
`1
`
`400
`750
`1100
`2880
`4500
`3000
`
`266
`151
`152
`157
`27
`0
`
`50
`300
`75
`750
`1200
`600
`
`72
`[115]C
`186
`d
`[110]°
`36
`
`10
`20
`10
`d
`20
`5
`
`a Data are typical for each system and testing is not in direct comparison
`b O.D., optimal dose in microgramslkg/inj
`] , activity criteria not met in this system
`c [
`, not tested
`d -
`
`?H3
`CH3-CH
`
`CH-CH3
`
`O -C-CH-N-C-CH2-N-CH3
`
`Lo
`5LI
`
`(DI ?i
`?i
`/L-threo'-.._
`(DI
`(LI
`N-C-CH-NH-C-CH
`CH-C-NH-CH-C-N
`I
`II
`I
`I
`I
`II
`0 CH-CH3
`NH
`NH O
`CH-CH3
`I
`I
`I
`I
`
`Fig. 2. Structure of
`azetomycin 1 (NSC 244392)
`
`CH3
`
`CH,
`
`Pepleomycin (NSC-276382). Many bleomycins have been tested by NCI and in Japan.
`In the last 18 months the Japanese have renewed NCI's interest in the bleomycins by
`presenting to NCI their data on several bleomycin analogs including pepleomycin and
`bleomycin BAPP (Figs. 3 and 4). Pepleomycin (Fig. 3), developed in Japan, differs
`from bleomycin in the terminal amine group. According to the Japanese data this drug
`shows less pulmonary toxicity in human clinical trials than does bleomycin, which
`would make this a second generation drug (less toxicity but equal activity) [22]. This
`drug is awaiting completion of pulmonary toxicity tests and tumor panel evaluation at
`NCI in direct comparison with bleomycin, and if results are favorable will be presented
`to DN late in 1979. Table 4 shows the data obtained with the various bleomycins that
`are presently of interest to NCI.
`
`Bleomycin BAPP (NSC-294979) (Fig. 4) is another fermentation-derived analog of
`bleomycin that shows less pulmonary toxicity than bleomycin in the mouse test [22].
`
`r
`w I w
`w I w
`I fLI
`I
`cl ~-CH3 /cl H-CH3
`
`CH3-N-CH2-C-N-CH-C-O
`
`oJ
`
`tH/LI
`
`i:H3
`
`0
`cs, ¢:)~("' '~
`
`NOVARTIS EXHIBIT 2044
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`
`
`
`158
`
`J. Douros and M. Suffness
`
`~o
`
`H.,,
`CH,
`:c/
`,CH2~
`'"-""'"-: lJ
`
`NH2
`
`s
`
`H
`
`H
`
`0
`
`N
`
`NJ
`~H
`
`O~H2N~ I' ,NH2
`0
`½o "°:Cr'L ::I I
`H'-"' y
`CH, ~~o ":'
`cH,o <? CH,US I
`H0~01
`I
`\+:"
`°51~'"'
`"~~0;XJ:X::u,J's
`"7d,~l~j °"
`
`o,
`
`OH A
`
`o
`
`NH,
`
`Fig. 3. Structure of pepleomycin (NSC 276382)
`
`N:?' N
`
`O
`
`CH3
`
`~
`
`0
`
`o
`N~NHICH,i,NHICH2l,NHICH2l,CH3
`
`~H
`
`OH
`
`OH
`
`0
`
`OH A
`
`o
`
`NH,
`
`Fig. 4. Structure of bleomycin BAPP (NSC 294979)
`
`BAPP is being tested in comparison with bleomycin in the entire tumor panel. The
`antitumor data for bleomycin BAPP is presented in Table 4.
`
`Tallysomycin (NSC-279496) (Fig. 5) is a bleomycin analog similar to phleomycin that is
`being developed by Bristol Laboratories [13, 15]. The drug is being compared with
`bleomycin, bleomycin BAPP, and pepleomycin at NCI. The NCI Bleomycin Analog
`Committee will make recommendations to NCI scientists on the above analogs of
`bleomycin when testing is completed. Bristol Laboratories have several other
`derivatives of tallysomycin that are at present being evaluated against selected NCI
`murine tumor systems.
`
`NOVARTIS EXHIBIT 2044
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`
`New Natural Products Under Development at the National Cancer Institute
`
`159
`
`Table 4. Typical activities of bleomycin derivatives in murine tumor systems•
`
`Tumor
`
`Bleomycin
`NSC-125066
`
`Pepleomycin
`NSC-276382
`
`B!eomy-
`cin BAPP
`NSC-294979
`
`Tallysomycin
`A
`NSC-279496
`
`%TIC O.D.b %TIC O.D.b %TIC O.D.b
`
`%TIC O.D.b
`
`PS31 P388 lymphocytic leukemia
`LE21 L1210 lymphoid leukemia
`B132 B16 melanocarcinoma
`C631 Colon 26
`C872 Colon 38
`CD72 CD8F1 mammary tumor
`LL39 Lewis lung carcinoma
`
`12
`146
`[119]c
`2.5
`185
`8
`[119]c 15
`11
`64
`9
`32
`159
`32
`
`127
`[123]°
`184
`[121]c
`29
`16
`[138]c
`
`2
`1
`1
`8
`32
`16
`8
`
`10
`132
`[114]c 10
`158
`5
`161
`20
`[48]c 30
`64
`16
`d
`d
`
`[119]C
`[104]C
`_d
`
`_d
`12
`10
`d
`
`8
`4
`d
`
`d
`32
`32
`d
`
`a Data is typical for each system and testing is not in direct comparison
`b Optimal dose in mglkglinj
`c [ ], activity criteria not met in this system
`, not tested
`d
`-
`
`O=l,-OMe
`
`Fig. 6. Structure of
`aclacinomycin A (NSC 208734)
`
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`160
`
`J. Douros and M. Suffness
`
`Table 5. Antitumor activity of aclacinomycin A NSC-208734
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`PA
`C2G5
`C9G5
`C9H2
`LKG5
`LKH2
`MBG5
`MBH2
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Adriamycin resistant PS
`CX-1 Colon renal capsule
`CX-5 Colon renal capsule
`CX-5 Colon xenograft
`LX-1 Lung renal capsule
`LX-1 Lung xenograft
`MX-1 Breast renal capsule
`MX-1 Breast xenograft
`
`Activities
`
`% TIC"
`
`Opt. dose
`mg/kglinj.
`
`236
`141
`148
`(123)
`40
`1
`(125)
`138
`9
`(76)
`(49)
`42
`(62)
`20
`(53)
`
`8
`25
`3
`12
`6
`15
`3
`15
`1
`2
`9.38
`2
`9.38
`2
`9.38
`
`• TIC values in parentheses do not meet minimum criteria for activity
`
`OH
`
`Me
`I
`Me-N
`
`0
`
`HO
`
`HO
`
`OH
`
`0-Me
`
`Me
`
`OH
`
`Fig. 7. Structure of
`7-O-methylnogarol (7-Omen) (NSC
`269148)
`
`Table 6. Antitumor activity of 7-0-methylnogarol NSC-269148
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`PA
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Adriamycin resistant P388
`
`• TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% TIC"
`
`240
`240
`209
`206
`21
`1
`187
`(116)
`
`Opt. dose
`mg/kg/inj.
`
`12.5
`12.5
`12.5
`25
`25
`25
`12.5
`30
`
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`
`Aclacinomycin A (NSC-208734) (Fig. 6) is a cinerubin-like anthracycline was isolated
`by Dr. Umezawa's research group at the Institute of Microbial Chemistry in Japan and
`has been developed by the Sanraku Ocean Company [23]. This compound is scheduled
`for clinical trials in the United States in 1979. The drug was chosen for clinical trials by
`NCI because it showed less alopecia and cardiotoxicity when evaluated in Phase I and
`Phase II clinical trials in Japan [25]. Phase III clinical studies in Japan have confirmed
`that this drug causes less cardiac toxicity than adriamycin and NCI's cardiac toxicity
`test in rabbits likewise indicated a lower cardiac toxicity. NCI feels that this is a second
`generation anthracycline that will provide clinical advantages over adriamycin due to
`less human cardiac toxicity and less alopecia. Aclacinomycin is highly active in NCI
`·
`murine tumor tests (Table 5).
`
`7-0-Methyl nogarol (NSC-269148) (Fig. 7) was obtained from the Upjohn microbial
`chemical biotransformation program [28]. This nogalomycin derivative showed broad
`activity against murine tumors (Table 6). Another nogalomycin analog from the
`Upjohn program is nogamycin (NSC-265450) (Fig. 8). This compound has shown
`superior activity to 7-0-methyl nogarol against B16 (Table 7).
`
`Echinomycin (NSC-526417) (Fig. 9) and valinomycin (NSC-122023) (Fig. 10) are two
`cyclic peptides presently of interest to NCI [21 ]. Echinomycin showed very selective
`
`Fig. 8. Structure of nogamycin (Nogalomycin
`C) (NSC 265450)
`
`HO
`
`0
`
`OH
`
`0
`
`CH30~
`CH3
`CH3
`
`CH3O OCH3
`
`Table 7. Antitumor activity of nogamycin (nogalomycin C) NSC-265450
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`PA
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Adriamycin resistant P388
`
`a T/C values in parentheses do not meet activity criteria
`
`Activities
`
`% T/Ca
`
`193
`127
`357
`(102)
`(53)
`(57)
`(119)
`120
`
`Opt. dose
`mg/kg/inj.
`
`5
`1.25
`5
`5
`0.62
`10
`0.63
`10
`
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`J. Douros and M. Suffness
`
`OCN)
`
`N
`
`fDJI
`1r-NH-CH
`
`I (Li
`CH
`H3c-s' \:H
`/Di¢H-NH-C-CNX)
`6H2
`I
`I
`(Li/ 2
`(Li
`IL)
`I
`0-C-CH-N-C-C-N-C-CH-NH-C
`1
`1
`11
`1
`11
`11
`1
`n
`0
`CH3 0 H CH3 0 CH3
`0
`yH-CH 3
`CH3
`Fig. 9. Structure of echinomycin (NSC 526417)
`
`,_,,_1::,_1_!~!-!"'-!:",i~O
`
`(Li
`
`(Li
`
`I
`CH2
`
`0
`
`g
`
`,-._
`~N
`
`I
`
`#
`
`Table 8. Antitumor activity of echinomycin (quinomycin A) NSC-526417
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`LKGS
`MBH2
`C2G5
`C2H2
`C9GS
`C9H2
`LKH2
`MBGS
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Lung renal capsule
`Breast xenograft
`Colon renal capsule
`Colon xenograft
`CX-5 colon renal capsule
`CX-5 Colon xenograft
`LX-1 lung xenograft
`Breast renal capsule
`
`Activities
`
`% TIC•
`
`2050.06
`126
`189
`(104)
`(123)
`(67)
`(111)
`(52)
`(54)
`21
`(78)
`(55)
`(56)
`(85)
`(55)
`
`Opt. dose
`mg/kg/inj.
`
`0.03
`0.12
`0.06
`0.015
`0.0075
`0.015
`0.12
`0.03
`0.24
`0.03
`0.012
`0.1
`0.1
`0.24
`
`a T/C values in parentheses do not meet activity criteria
`
`activity, being highly active against B16 and P388 and showing activity against the
`colon renal capsule xenograft (Table 8). Valinomycin shows superior activity against
`the murine tumors to echinomycin. Murine antitumor data for valinomycin is
`presented in Table 9.
`
`Largomycin (NSC-237020), a protein originally isolated in Japan [29, 30, 31], was
`obtained through the NCI literature surveillance program and is highly active against
`murine tumors (Table 10). Largomycin is one of the few natural products showing
`activity against the Lewis lung carcinoma. In addition, activity was observed against C6
`and CS. Production methods for this drug are being developed at the Frederick Cancer
`Research Center (FCRC).
`
`Aphidicolin (NSC-234714) (Fig. 11), which was obtained from Imperial Chemical
`Industries (ICI), passed DN2 because of its excellent C6 activity (ILS 129%) [2, 3, 5).
`
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`163
`
`CH3
`
`C=O
`
`CH3
`
`CH3
`
`CH3 CH3
`CH3
`""/
`"-._/
`CH 0
`CH O
`0 H
`CH3
`I
`II
`l
`ll
`II
`I
`ll
`I
`I
`I
`N-CH-C-O-CH--C-N--CH-C-0-CH-C
`I
`(D)
`(LI
`(LI
`(DI
`NH
`I
`H3C-CH--CH (DI
`I
`I
`CH3
`C=O
`I
`0
`I
`H3C-CH /LI
`I
`C=O
`I
`NH
`CH3
`I
`"-..
`HC-CH ILi
`CH3
`CH3
`/
`I
`"'--/
`CH3
`C=O
`CH
`6
`I H
`o "'--c{ H o CH3
`o
`CH3
`/
`I
`I
`II
`II
`I
`I II
`I
`"-..
`HC-CH-0-C-CH-N-C-CH-0-C-CH-N-C--CH-CH
`II
`(DI
`(LI
`(LI
`(DI
`(DI
`/
`""
`CH3
`0
`CH3
`Fig. 10. Structure of valinomycin (NSC 122023)
`
`CH3
`
`Table 9. Antitumor activity of valinomycin NSC-122023
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`C2G5
`C9H2
`C9G5
`LKH2
`LKG5
`MBH2
`MBG5
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`CX-1 colon renal capsule
`CX-5 colon xenograft
`CX-5 colon renal capsule
`LX-1 lung xenograft
`LX-1 lung renal capsule
`MX-1 breast xenograft
`MX-1 breast renal capsule
`
`Activities
`
`% TIC"
`
`Opt. dose
`mg/kg/inj.
`
`183
`131
`183
`200
`25
`(49)
`145
`(47)
`(64)
`(54)
`(88)
`(99)
`(97)
`(52)
`
`10
`5
`5
`3
`20
`1
`6
`40
`3
`5
`12
`5
`24
`20
`
`a T/C values in parentheses do not meet activity criteria
`
`This diterpene has been superior to the seven analogs tested against C6 and is
`scheduled for formulation studies. Aphidicolin also showed activity against the lung
`renal capsule xenograft, B16, and P388 (Table 11). Aphidicolin was originally selected
`for screening because of its antiviral activity.
`
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`J. Douros and M. Suffness
`
`Table 10. Antitumor activity of largomycin NSC-237020
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F 1 mammary
`Lewis lung carcinoma
`
`a TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% TIC"
`
`225
`(112)
`200
`184
`32
`18
`151
`
`Opt. dose
`mg/kglinj.
`
`4.4
`1
`8
`4
`16
`8
`2
`
`H
`--~----CH 2-0H
`~--+--H
`
`Fig. 11. Structure of aphidicolin (NSC 234714)
`
`Table 11. Antitumor activity of aphidicolin NSC-234714
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`MBH2
`LKG5
`LKH2
`C2G2
`C2H2
`C9G5
`C9H2
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F 1 mammary
`Lewis lung carcinoma
`Breast xenograft
`Lung renal capsule
`LX-1 lung xenograft
`CX-1 colon renal capsule
`CX-1 colon xenograft
`CX-5 colon renal capsule
`CX-5 colon xenograft
`
`a TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% TIC"
`
`Opt. dose
`mglkglinj.
`
`155
`(122)
`176
`229
`(65)
`(44)
`(126)
`(83)
`26
`(86)
`(73)
`(95)
`(45)
`(78)
`
`75
`100
`150
`200
`100
`400
`100
`400
`100
`200
`50
`400
`200
`200
`
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`165
`
`Neothramycin (NSC-285223) (Fig. 12) is an anthramycin-like compound obtained
`from Japan. Our results are similar to those of the Meiji Seika Company and at the
`present time NCI is evaluating this compound against rat tumors. The Japanese
`indicated that neothramycin was superior to most drugs against rat tumors but that it is
`only marginally active against mouse tumors. This drug has shown minimal activity
`against P388 and L1210 leukemias in mice and has shown no activity in any other
`murine tumor systems (Table 12).
`
`Rapamycin (NSC-226080) (Fig. 13) was obtained from Ayerst Laboratories where it
`was originally developed as an anti-Candida drug. This triene fermentation product
`has shown marked activity against ependymoblastoma, mammary, colon 38, and colon
`26 tumors (Table 13). This drug is undergoing formulation studies and hopefully will
`be available for toxicologic evaluations in late 1979. It passed DN in April, 1979 and is
`
`Fig. 12. Structure of
`neothramycin (NSC 285223)
`
`1/"'
`HO N~
`::::,.... I
`N
`•
`
`rn,-4
`
`O
`
`H OH
`
`1/"'
`HO N~
`::::,.... I
`N
`
`°~-4
`
`O
`
`HO
`
`H
`
`Table 12. Antitumor activity of neothramycin NSC-285223
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`EM
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Ependymoblastoma
`
`a TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% TIC"
`
`150
`126
`(119)
`(102)
`(62)
`(79)
`(121)
`(95)
`
`Opt. dose
`mg/kglinj.
`
`4
`4
`4
`0.6
`1.1
`4
`1
`2
`
`OH
`
`0-CH,
`
`Fig. 13. Structure of rapamycin (NSC 226080)
`
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`
`Table 13. Antitumor activity of rapamycin NSC-226080
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`EM
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Ependymoblastoma
`
`• TIC values in parentheses do not meet activity criteria
`
`OH
`
`Activities
`
`% TIC•
`
`142
`(120)
`146
`159, 205
`26, 19
`29, 4
`(107)
`243, 211
`
`Opt. dose
`mg/kg/inj.
`
`25
`400
`12.5
`12.5, 6.25
`25, 25
`12.5, 12.5
`400
`200, 50
`
`Me
`
`HO
`
`Fig. 14. Structure of borreledin (NSC 216128)
`
`at present being tested in the entire tumor panel (Table 17). NCI is trying to obtain a
`clinical formulation for this highly insoluble material. The drug was identified as being
`of potential interest from our worldwide surveillance program.
`
`Borrelidin (NSC-216128) (Fig. 14) was obtained from Bristol Laboratories fermen(cid:173)
`tations [1, 14]. This compound has shown activity against Lewis lung, CD mammary,
`B16, and P388 (Table 14). At present this macrocylic lactone is being evaluated in the
`tumor panel.
`
`CC-1065 (NSC-298223) is an Upjohn fermentation product which is undergoing
`structure elucidation studies [11]. Sufficient structural information has been obtained
`to insure that this is a novel antitumor agent. This highly toxic material is quite
`effective against murine tumors (Table 15). The drug has been found active against PS,
`LE, Bl6, C6, CS, and CD and minimally active against an adriamycin-resistant
`leukemia. It is currently being evaluated in NCI xenograft tumors.
`The following drugs of preclinical interest are higher plant products:
`
`Eriofertopin (NSC-283439) (Fig. 15), a sesquiterpene lactone, has been isolated from
`Eriophyllum confertiflorum which is found in California [18]. This compound has
`shown activity against both murine leukemias and B16 (Table 16). At present it is
`scheduled for tumor panel testing.
`
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`
`Table 14. Antitumor activity of borrelidin NSC-216128
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`
`Activities
`
`% T/Ca
`
`169
`(109)
`159
`(111)
`(69)
`14
`154
`
`a T/C values in parentheses do not meet activity criteria
`
`Table 15. Antitumor activity of CC-1065 (U-56314) NSC-298223
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`cs
`CD
`LL
`PA
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Adriamycin restistant P388
`
`a TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% TIC•
`
`190
`148
`181
`150
`37
`38
`(104)
`120
`
`Opt. dose
`mg/kg/inj.
`
`0.5
`3
`1
`3
`2
`16
`1.56
`
`Opt. dose
`mg/kglinj.
`
`0.01
`0.3
`0.01
`0.05
`0.1
`0.03
`0.04
`0.1
`
`0 CH2
`II
`II
`O-C-C-CH 3
`
`Fig. 15. Structure of eriofertopin (NSC 283439)
`
`Homoharringtonine (NSC-141633) (Fig. 16) is a cephalotaxine ester isolated from
`Cephalotaxus harringtonia var. drupacea [24]. This evergreen is a native of the China
`mainland and procurement of this plant has been difficult. At prese