Other New Drugs
`Other New Drugs
`
`New Natural Products Under Development
`New Natural Products Under Development
`at the National Cancer Institute
`at the National Cancer Institute
`
`J. Douros and M. Suffness
`J. Douros and M. Suffness
`
`Natural Products Branch, Developmental Therapeutics Program, Division of Cancer
`Natural Products Branch, Developmental Therapeutics Program, Division of Cancer
`Treatment, National Cancer Institute, USA - Bethesda, MD
`Treatment, National Cancer Institute, USA - Bethesda, MD
`
`Summary
`Summary
`
`Twenty-six new agents of natural products ongm which are under preclinical
`Twenty-six new agents of natural products ongm which are under preclinical
`development as potential antitumor agents at the National Cancer Institute are
`development as potential antitumor agents at the National Cancer Institute are
`discussed with reference to their sources, structures, antitumor activity, current status,
`discussed with reference to their sources, structures, antitumor activity, current status,
`and future potential as clinically effective drugs.
`and future potential as clinically effective drugs.
`
`Introduction
`Introduction
`
`Since 1956 the Cancer Chemotherapy National Service Center, now incorporated into
`Since 1956 the Cancer Chemotherapy National Service Center, now incorporated into
`the Developmental Therapeutics Program (DTP), Division of Cancer Treatment, has
`the Developmental Therapeutics Program (DTP), Division of Cancer Treatment, has
`had a comprehensive drug development program that includes the screening of
`had a comprehensive drug development program that includes the screening of
`compounds obtained from natural products [7]. Since the inception of the program,
`compounds obtained from natural products [7]. Since the inception of the program,
`approximately 178,802 microbial cultures have been isolated and fermented and
`approximately 178,802 microbial cultures have been isolated and fermented and
`103,272 plants extracted. The fermentation broths and plant extracts have been tested
`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
`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
`standard protocols [10]. During the last 3 years the fermentation broths in many cases
`have first been tested in various in vitro pre screens (e.g., enzyme inhibition, tubulin
`have first been tested in various in vitro pre screens (e.g., enzyme inhibition, tubulin
`binding, phage induction, antimicrobial and antiyeast screens) [6]. Approximately 7
`binding, phage induction, antimicrobial and antiyeast screens) [6]. Approximately 7
`years ago a concentrated effort to evaluate animal products (primarily marine) was
`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
`initiated and to date 13,751 extracts have been screened and 0.7% showed confirmed
`in vivo activity.
`in vivo activity.
`Many compounds have been isolated from the above-mentioned programs and in
`Many compounds have been isolated from the above-mentioned programs and in
`addition many natural products are obtained from the NCI worldwide surveillance
`addition many natural products are obtained from the NCI worldwide surveillance
`program which includes agreements with industrial companies, research institutes,
`program which includes agreements with industrial companies, research institutes,
`universities, and scientists. Some of the more interesting compounds in preclinical
`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
`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
`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
`discover second generation drugs which retain the activity of the parent molecule and
`have less toxicity.
`have less toxicity.
`
`S. K. Carter et al. (eds.), New Drugs in Cancer Chemotherapy
`© Springer-Verlag Berlin Heidelberg 1981
`
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`J. Douros and M. Suffness
`
`Table 1. Natural products undergoing preclin(cid:173)
`ical drug development at NCI
`
`Compound
`
`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
`
`Actinomycin pip 1/3
`Azetomycin 1
`Actinomycin S3
`Pepleomycin
`Bleomycin BAPP
`Tallysomycin A
`Aclacinomycin A
`7-0-methyl nogarol
`Nogamycin
`Echinomycin
`Valinomycin
`Largomycin
`Aphidicolin
`N eothram ycin
`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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`
`Table 2. Division of Cancer Treatment (OCT) panel of antiserum screens
`
`Tumor
`
`Parameter
`
`Activity
`criteria
`
`Route Tissue and level
`inocula- of inoculation
`tion
`
`Mouse colon 38 (CB)
`Mouse Breast (CD)
`Human colon xenograft
`Mouse breast xenograft
`Mouse lung xenograft
`Mouse B16
`melanosarcoma (B 16)
`Mouse Lewis lung
`carcinoma (LL)
`Mouse L1210 leukemia
`(LE)
`
`Tumor inhibition
`Tumor inhibition
`Tumor inhibition
`Tumor inhibition
`Tumor inhibition
`Survival
`
`TIC::::; 42%
`TIC::::; 42%
`TIC ::::; 42%
`TIC ::::; 42%
`TIC ::::; 42%
`TIC 2': 125%
`
`IP
`SC
`SC
`SC
`SC
`IP
`
`Brei
`Brei
`Fragment
`Fragment
`Fragment
`Brei
`
`1: 100
`5 x 106
`14mg
`14mg
`14mg
`1: 10
`
`Survival
`
`Survival
`
`TIC 2': 140%
`
`IP
`
`TIC 2': 125%
`
`IP
`
`Cells
`
`Cells
`
`105
`
`105
`
`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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`
`Fig. 1. Structure of
`actinomycin pip 1{J (NSC
`107660)
`
`Actinomycin pip lf3 (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 proline residue in the beta peptide chain is replaced with
`pipecolic acid. The production of actinomycin pip 1f3 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 1f3 is being compared with actinomycin D in gastrointestinal toxicity tests and in the
`NCI tumor panel. Actinomycin pip 1f3 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 1f3 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 D in that one of
`the prolines 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 1f3 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.
`
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`
`Table 3. Typical activities of actinomycin derivatives in murine tumor systemsa
`
`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 CD8F1 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]e
`186
`d
`[110]e
`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 micrograms/kg/inj
`e [ ], activity criteria not met in this system
`d - , not tested
`
`Fig. 2. Structure of
`azetomycin 1 (NSC 244392)
`
`Pepleomycin (NSC-276382). Many bleomycins have been tested by NCI and in Japan.
`In the last 18 months the Japanese have renewed Ncr'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 NCr.
`
`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].
`
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`158
`
`o
`
`OH
`
`o
`
`~~J{NH'
`J
`NH,J:/yO 0 HO~~~NH N-ylSJ
`CH3 ~~' ~CH3~ 9~CH3US)
`Hofd NJ
`I
`
`J. Douros and M. Suffness
`
`H:~~~
`NH-ICH'''-~ v
`
`H
`
`H
`
`N
`
`H
`
`OH ~OH
`OH A
`
`OH
`
`o
`
`o
`
`NH2
`
`Fig. 3. Structure of pepleomycin (NSC 276382)
`
`0
`°S:~JyNH'
`N=1'NH{C","NH{CH"'NHlCH'''CH'
`N~ N 0 CH,! 0
`NH~~O OH)::C:(U-)'S
`
`H
`
`H
`
`I
`
`N
`
`o
`
`OH
`
`OH
`
`o
`
`OH A
`
`o
`
`NH2
`
`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 NCr. The NCr Bleomycin Analog
`Committee will make recommendations to NCr 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 NCr
`murine tumor systems.
`
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`
`Table 4. Typical activities of bleomycin derivatives in murine tumor systemsa
`
`Tumor
`
`Bleomycin
`NSC-125066
`
`Pepleomycin
`NSC-276382
`
`Bleomy-
`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
`
`146
`[119]"
`185
`[119]C
`11
`9
`159
`
`12
`2.5
`8
`15
`64
`32
`32
`
`127
`[123]C
`184
`[121]C
`29
`16
`[138]C
`
`2
`1
`1
`8
`32
`16
`8
`
`132
`[114]C
`158
`161
`[48]C
`16
`d
`
`10
`10
`5
`20
`30
`64
`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 mg/kglin j
`c [ ], activity criteria not met in this system
`d -, not tested
`
`O=~-OMe
`
`HO
`
`Me
`
`0
`
`NMe2
`
`Fig. 6. Structure of
`ac1acinomycin A (NSC 208734)
`
`kO~
`·CJ~
`Uo
`
`Me
`
`OH
`
`0=
`
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`
`J. Douros and M. Suffness
`
`Table 5. Antitumor activity of ac1acinomycin 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-l Colon renal capsule
`CX-5 Colon renal capsule
`CX-5 Colon xenograft
`LX-l Lung renal capsule
`LX-l Lung xenograft
`MX-l Breast renal capsule
`MX-l Breast xenograft
`
`Activities
`
`% TIC'
`
`Opt. dose
`mg/kg/inj.
`
`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
`
`HO
`
`o
`
`HO
`
`OH
`
`O-Me
`
`Me
`
`OH
`
`Fig. 7. Structure of
`7-0-methylnogarol (7-0men) (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
`
`a 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
`
`CH3
`
`5N
`
`CH3
`
`HO
`
`OH
`
`HO
`
`CH3
`OH
`
`0
`OH
`0
`CH3~O~
`
`Fig. 8. Structure of nogamycin (Nogalomycin
`C) (NSC 265450)
`
`Table 7. Antitumor activity of nogamycin (nogalomycin C) NSC-265450
`
`tv
`
`CH30 OCH3
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`PA
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F 1 mammary
`Lewis lung carcinoma
`Adriamycin resistant P388
`
`a TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% T/ca
`
`193
`127
`357
`(102)
`(53)
`(57)
`(119)
`120
`
`Opt. dose
`mg/kglinj.
`
`5
`1.25
`5
`5
`0.62
`10
`0.63
`10
`
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`
`J. Douros and M. Suffness
`
`yH3 ~ yH3
`
`b:~CH3
`IH ~ yH3 I
`
`8
`
`3
`
`-eND
`
`-..;;:
`
`CXN )
`
`I
`
`:,...
`A
`~ NO'""
`
`~
`~
`C-NH-CH-C-N-C-C-N-CH-C-O
`I
`(OJI
`(LJ
`/ (LJ
`(LJ
`C-NH-CH
`CH
`CH2
`H C-S' 's
`I
`I
`(OJCH-NH-C ~
`CH 2
`CH
`8
`I
`I
`I
`(LJ
`(LJ
`(LJI
`2
`O-C-CH-N-C-C-N-C-CH-NH-C
`I
`~
`A
`II InN //
`II
`I
`"
`I
`I
`o
`rH- CH3
`0
`CH3 0
`H CH3 0
`CH3
`CH3
`Fig. 9. Structure of echinomycin (NSC 526417)
`
`Table 8. Antitumor activity of echinomycin (quinomycin A) NSC-526417
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`LKG5
`MBH2
`C2G5
`C2H2
`C9G5
`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
`
`% T/ca
`
`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 TIC 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 C8. 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 (lCI), passed DN2 because of its excellent C6 activity (ILS 129%) [2, 3, 5].
`
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`163
`
`CH3
`
`'" /
`
`CH3 CH3
`
`CH3
`
`"" /
`
`CH 0
`CH 0
`C~ 0 H
`I
`II
`I
`I
`I
`I
`II
`I
`~
`~
`N-CH-C-O-CH--C-N-CH-C-O-CH-C
`I
`(0)
`(L)
`(L)
`(0)
`NH
`I
`H3C-CH--CH (0)
`I
`I
`CH3
`C=O
`I
`o
`I
`H3C-CH (L)
`I
`C=O
`I
`NH
`CH3
`'"
`I
`CH3
`CH3
`HC-CH IL)
`""/ /
`I
`CH3
`C=O
`CH
`I H
`6
`0 ""C{ H 0 CH3
`CH3
`0
`I
`II
`II
`I
`'"
`/
`I
`I
`I II
`HC-CH-O-C-CH-N-C-CH-O-C-CH-N-C--CH-CH
`II
`/
`(0)
`(L)
`(L)
`(0)
`(0)
`""
`CH3
`0
`CH3
`Fig. 10. Structure of valinomycin (NSC 122023)
`
`C=O
`
`CH3
`
`CH3
`
`CH3
`
`Table 9. Antitumor activity of valinomycin NSC-122023
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`C2G5
`C9H2
`C9GS
`LKH2
`LKGS
`MBH2
`MBGS
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F 1 mammary
`Lewis lung carcinoma
`CX-l colon renal capsule
`CX-S colon xenograft
`CX-S colon renal capsule
`LX-l lung xenograft
`LX-l lung renal capsule
`MX-l breast xenograft
`MX-l breast renal capsule
`
`Activities
`
`% T/ca
`
`Opt. dose
`mg/kg/inj.
`
`183
`131
`183
`200
`2S
`(49)
`14S
`(47)
`(64)
`(S4)
`(88)
`(99)
`(97)
`(S2)
`
`10
`S
`S
`3
`20
`1
`6
`40
`3
`5
`12
`5
`24
`20
`
`a TIC 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
`CD8Fj mammary
`Lewis lung carcinoma
`
`" TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% T/ca
`
`225
`(112)
`200
`184
`32
`18
`151
`
`Opt. dose
`mg/kg/inj.
`
`4.4
`1
`8
`4
`16
`8
`2
`
`H
`r---t---CH 2-OH
`.-----I--H
`
`H
`
`Fig. 11. Structure of aphidicolin (NSC 234714)
`
`Table 11. Antitumor activity of aphidicolin NSC-234714
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`MBH2
`LKG5
`LKH2
`C2G2
`C2H2
`C9G5
`C9H2
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F j 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
`mg/kg/inj.
`
`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
`
`NPC02232827
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`
`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 L12lO 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)
`
`HO N~ HO~N~
`~I N
`~I N
`CH3 - 4
`o
`
`H OH
`
`0
`
`HO
`
`H
`
`-;?'
`
`-;?'
`
`•
`
`CH3-0
`
`Table 12. Antitumor activity of neothramycin NSC-285223
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`EM
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8Fj mammary
`Lewis lung carcinoma
`Ependymoblastoma
`
`a TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% T/ca
`
`150
`126
`(119)
`(102)
`(62)
`(79)
`(121)
`(95)
`
`Opt. dose
`mg/kg/inj.
`
`4
`4
`4
`0.6
`1.1
`4
`1
`2
`
`OH
`
`O-CH3
`
`Fig. 13. Structure of rapamycin (NSC 226080)
`
`NPC02232828
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`J. Douros and M. Suffness
`
`Table 13. Antitumor activity of rapamycin NSC-226080
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`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
`
`OH
`
`Activities
`
`% T/ca
`
`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, B16, C6, C8, 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
`EriophyUum 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.
`
`NPC02232829
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`
`Table 14. Antitumor activity of borrelidin NSC-216128
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`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 TIC 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
`C8
`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
`
`% T/ca
`
`190
`148
`181
`150
`37
`38
`(104)
`120
`
`Opt. dose
`mglkg/inj.
`
`0.5
`3
`1
`3
`2
`16
`1.56
`
`Opt. dose
`mglkg/inj.
`
`0.01
`0.3
`0.01
`0.05
`0.1
`0.03
`0.04
`0.1
`
`HO ... ......
`
`o CH2
`II
`II
`
`CH2
`
`I
`I
`I
`I
`O-----t::-....
`
`Fig. 15. Structure of eriofertopin (NSC 283439)
`
`Homoharringtonine (NSC-141633) (Fig. 16) is a cephalotaxine ester isolated from
`Cephalotaxus harringtonia vaL drupacea [24]. This evergreen is a native of the China
`mainland and procurement of this plant has been difficult. At present several grams of
`homoharringtonine have been obtained from the People's Republic of China. This
`compound shows good activity against murine leukemia and is highly active against C8
`and CD tumors (Table 17). Some Lewis lung and colon capsule activity has been
`
`NPC02232830
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`J. Douros and M. Suffness
`
`Table 16 Anticancer activity of eriofertopin NSC-283439
`
`Tumor systems
`
`PS
`LE
`B16
`C8
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 38
`
`• TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% T/ca
`
`167
`129
`126
`(105)
`
`Opt. dose
`mglkglinj.
`
`20
`20
`20
`2.5
`
`CH3
`I
`CH3-C-(CH 2)3
`I
`:
`HO
`:
`: 0
`: II
`CH30-C-CH2-C-C-O.,
`,
`II
`- r - - - - ; (
`o
`OH
`
`<
`
`OCH3
`
`Fig. 16. Structure of homo harring to nine (NSC 141633)
`
`Table 17. Antitumor activity of homoharringtonine NSC-141633
`
`Tumor systems
`
`PS
`LE
`B16
`C6
`C8
`CD
`LL
`EM
`PA
`PV
`16
`CY
`CZ
`C2G5
`C9G5
`LKG5
`MB65
`
`P388 lymphocytic leukemia
`L1210 lymphoid leukemia
`B16 melanocarcinoma
`Colon 26
`Colon 38
`CD8F1 mammary
`Lewis lung carcinoma
`Ependymoblastoma
`Adriamycin resistant P388
`Vincristine resistant P388
`Mammary adenocarcinoma C3H
`Colon 36
`Colon 51
`CX-1 colon renal capsule
`CX-5 colon renal capsule
`LX-5 lung renal capsule
`Mx-1 breast renal capsule
`
`• TIC values in parentheses do not meet activity criteria
`
`Activities
`
`% TIC'
`
`Opt. dose
`mg/kg/inj.
`
`327
`150
`137
`(113)
`8
`7
`142
`(103)
`(103)
`(100)
`185
`181
`(106)
`38
`(44)
`(74)
`(103)
`
`1
`2
`2
`1
`4
`4
`0.5
`0.25
`1.2
`0.72
`1.9
`3
`1.2
`0.5
`2
`1
`1
`
`NPC02232831
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`
`observed. The drug has been reported to be active against various leukemias in clinical
`trials conducted in China [4]. Formulation studies are now underway at NCI.
`
`Tripdiolide (NSC-163063) (Fig. 17) is a diterpene triepoxide which was isolated from
`Tripterygium wilfordii in 1972 [16]. The selection of tripdiolide as a candidate for
`preclinical development was made on the basis of its activity in the L1210 leukemia
`system. Tripdiolide is also active against the B16 melanoma and the P388 leukemia
`(Table 18). A