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`PROCEEDINGS
`
`goth Annual Meeting of the
`American Association for Cancer Research
`April 10-14, 1999 e Philadelphia, PA
`VOLUME 40 et MARCH 1999
`
`CONTENTS
`(Arranged by Subject Category)
`
`:~B STRACTS
`pecial Multidisciplinary Sessions
`'l M ultidisciplinary and Translational Approaches to
`' Aerodigestive Cancers
`l
`\1 M ultidisciplinary and Translational Approaches to
`I Prostate Cancer
`l
`i arcinogenesis
`ONA Adducts, Protein Adducts, and Mutations
`carcinogen Metabolism
`Signaling Pathways in Tumor Promotion and
`Progression
`DNA Repair and Replication
`_I Hormones and Cancer
`Tobacco Carcinogenesis and Epidemiology
`Carcinogenesis in Experimental Models
`· ~netic Susceptibility in Experimental Models
`. i ~~asures of Human Cancer Susceptibility and Exposure
`.to Carcinogens
`, j Sgnal Transduction and Gene Expression in Ultraviolet
`\ ifand Chemical Carcinogenesis
`: 1 DUA Damage, Mutations, and Cellular Response
`'j ~markers of Premalignant and Malignant Lesions
`. , ..
`\ ! fJ!iA Adducts, Mutagenesis, and Repair
`Riactive Oxygen Species and Nitric Oxide
`! ~~.lecular and Enzymatic Determinants of
`lt arcmogenes1s
`.ic
`.
`.
`
`. ,, ~nd Tumor Biology
`
`t.
`
`} -,'
`
`' . .''el Therapies Targeting Angiogenesis
`· ' . stasis Models and Genetics
`,_
`'ii
`etics of Metastasis
`" f ptosis I
`'l',
`(';,ptosis II
`t·
`.
`h Factors and Receptors I
`" fr ular Signaling in Cancer Invasion and Metastasis
`;
`~ptosis Ill
`f
`(; ptosis JV
`, 'ulation of Angiogenic Factors
`ol of Apoptosis
`tosis V
`r-Host Interactions
`Factors and Receptors JI
`. l ·,:Tumor Interactions during Angiogenesis and
`t . erapeutic Approaches
`ion, Invasion, and Cellular Motility
`'
`-
`-·:; ',;genesis in Hormone Responsive Cancers
`. h Factors and Receptors Ill
`in Kinases in Tumor Progression/ Regression
`
`!"
`
`Page
`
`Cell and Tumor Biology (cont'd)
`
`Page
`
`Invasion: Its Regulation and Treatment
`Angiogenesis, Cell Signaling, and Gene
`Expression
`Cell Signaling in Tumor Progression
`Angiogenesis: Biology and Therapy
`Apoptosis VI: The Role of Mitochondria
`Metalloproteinases and Their Inhibitors
`Detection of Micrometastases
`Growth Factors and Receptors IV
`Interactions of Metastatic Cells with Their
`Environment: Genetic Implications
`Growth Factors and Receptors V
`
`Clinical Research
`
`Phase I Clinical Trials
`Phase I Trials of Novel Agents
`Lung Cancer I
`Head and Neck Cancer/Lung Cancer II
`Breast and Gynecologic Malignancies
`Prostate Cancer
`Bladder and Kidney Cancers
`Aerodigestive Cancers
`Gastrointestinal Cancer I: Colorectal and
`Hepatobiliary Cancers
`Gastrointestinal Cancer II: Hepatobiliary and Upper GI
`Tumors
`Molecular Pathogenesis and Tumor Progression
`Breast Cancer
`Gynecologic Malignancies
`Genitourinary Malignancies
`Melanoma/Sarcoma
`CNS and Pediatric Malignancies
`Lymphoma/Leukemia/Bone Marrow
`Transplantation
`Markers of Potential Clinical Utility
`
`Endocrinology/Preclinical and Clinical
`
`Endocrinology I
`Endocrinology II
`Retinoids and Their Signaling Pathways: Basic and
`Clinical Aspects
`Endocrinology Ill: Clinical and Translational Studies
`Endocrinology IV
`Hormones and Antihormones in the Regulation of Cell
`Growth and peath
`
`Epidemiology
`
`Cancer Epidemiology
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`316
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`337
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`343
`404
`491
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`524
`598
`603
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`718
`726
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`59
`157
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`308
`378
`613
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`636
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`39
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`202
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`408
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`44
`49
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`97
`153
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`347
`350
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`410
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`501
`507
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`623
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`740
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`65
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`163
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`West-Ward Exhibit 1085
`Gibbons Abs #2000
`Page 001
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`

`

`with longer treatment duration (Adler, et al., 1994; Au et al., 1998). The aim of this
`study is to compare the cytotoxicity of different exposure times of ET-743, a new
`marine natural product with promising antitumor activities, to assist clinical stud(cid:173)
`ies in finding a rational schedule for Phase U trials. Eighteen different types of
`tumor cells, three of them derived from pediatric tumors, and two non malignant
`cells were used and exposed to concentrations of ET-743 ranging from 0.0001 to
`0.1 µ.g/mg. For drug treatments and activity, a modification was used of the
`method described by Bergeron et al .. 1984. To detem1ine whether the higher
`activity observed for the longer treatments is due to a delayed exhibition of drug's
`effects and/or a reflection of cumulative effects that require a continuous drug
`exposure, cells were treated with ET-7 43 for 1, 3, 6, 8 & 24 hours and then either:
`(1) immediately processed for drug effect measurement (cell loss or immediate
`effect); or seeded again in drug-free medium, cultured and processed for drug
`effect measurement at 72 hours (cell inhibition or delayed effect). Data obtained
`and statistical analysis have shown that immediate and delayed effects have
`different pharmacodynamics. The immediate effect is higher with increasing
`exposure times up to 24 hours. For delayed effect, although short times expo(cid:173)
`sures presented lower IC 50's, the gain of sensitivity is more apparent between 3
`and 8 hours.
`
`#1996 Bisubstituted tricyclic chromophores as small molecule inhibitors
`of human te1omerase: Biological and modelling studies. 'Kelland, l.R.,
`'Gowan. S.M., 2Harrison. R.J .. 2Wood, A.A., 2Read, M.A., 2Dosanjh, H.S .. 2Perry,
`P.J .• 2Reszka, A.P., 20avies. R.T., and 2Neidle, S. 'CRC Centre for Cancer
`Therapeutics and 2CRC Biomolecular Structure Unit, Inst. of Cancer Research,
`Sutton, SM2 5NG, UK.
`Telomerase may provide a novel tumor-selective target for anticancer drug
`design. Our telomerase inhibitory strategy is aimed at the design of small mole(cid:173)
`cules capable of stabilising G-quadruplexes and thereby preventing 1he require(cid:173)
`ment of telomerase for a non-folded telomere DNA primer. A biological test
`cascade has been established where compounds are sought which possess a
`wide therapeutic index between potent cell-free telomerase inhibition (and no Taq
`polymerase inhibition) and low acute cytotoxicity against tumor cells. We initially
`observed activity with disubstituted amidoanthraquinones (AQs). We now show
`that potent activity 1s not specific to Aqs as other tricyclic compounds (acridine
`and fluorenones) inhibited human telomerase in an in vitro cell-free PCR-based
`assay (e.g., 50% inhibition at concentrations ranging from <1 to >50 µ.M).
`Parallel growth inhibition studies (96 h drug exposure, sulforhodamine B assay)
`have shown almost all compounds to be markedly less cytotoxic than doxorubi(cid:173)
`cin or mitoxantrone (mean IC~0 of approx 10 nM and 0.5 nM respectively) with
`IC50 values typically in the 0.5 to 25 µM range. Molecular modelling studies,
`performed on a human four-telomere intramolecular folded structure, have now
`detennined structures and energetics for ligand complexes. They have provided
`rationales for the observed structure-activity relationships, and a basis for struc·
`ture-aided drug design. Lead molecules are undergoing further in vitro (detection
`of telomere erosion in tumor cells) and in vivo evaluation for an1itumor effects.
`
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`#1997 Anti-tumor activity of prodrugs of triapine'", an inhibitor of ribo(cid:173)
`nucleotide reductase. Li. Z., Luo, X .. Chen, S.-H .. Li, X.·Y .. Li, J., Niu, C., Karra,
`S .. Wang, 0 .. Barrows, S .. Mao, J .• Doyle, T., King, I. and Zheng, L.-M. Vion
`Pharmaceuticals, Inc. New Haven, CT.
`TriapinerM (3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone),
`an inhibitor of ribonucleotide reductase, has good activities against a variety of
`experimental tumor models. To maximize its utility and to produce prodrugs with
`different rate of activation, a series of water-soluble phosphate prodrugs of
`Triapine"' was made. Two ot the phosphate prodrugs, l (para-phosphate) and II
`(orthophosphate), have been thoroughly evaluated. The water solubility of pro·
`drug I and II were 16 mg/ml and 11 mg/ml, respectively, whereas the parental
`ccmpound was <1mg/ml. Triapine™ was readily detectable when the prodrugs
`were incubated with alkaline phosphatase. Using the murine M109 lung carci(cid:173)
`noma model, we found prodrug II was more efficacious than prodrug I and the
`parental compound. Optimal anticancer activity of Triapine™ required a twice(cid:173)
`daily dosing schedule whereas prodrug II exhibited good antitumor activity with a
`once-a-day dosing schedule. Triapine™ prodrug II was also active against murine
`616 melanoma and the activity was compared to some of the anti-cancer agents
`currently used in clinics.
`
`#1998 Benzothiazolyl, benzoxazolyl, and benzimidazolyf hydrazones de(cid:173)
`rived from 2-acylpyridines: Synthesis and antitumor evaluation. Easmon, J.,
`Heimsch. G .. Pi.irstinger. G .. Margreiter. E .. Hofmann, J. Institute of Pharmaceu(cid:173)
`~cal Chemistry, lnnrain 52a, (J.£ .. G.H., G.P.), Institute of Medical Chemistry and
`Biochemistry, Fritz-Pregl-Strasse 3 (E.M .. J.H.), University of Innsbruck, A-6020
`lnnsbfl.Jck. Austria.
`In search of inhibitors of r1bonucleotide reductase, we considered it of high
`nterest to replace the th1ocarbamoyl [CS(NH2)) function of 2-acetylpyridine thio·
`semicarbazone with a benzothiazole ring (compound 1). Compound 1 and its
`congeners exhibited high cytotoxic activity in vitro against a panel of human
`tumor cell lines (Easmon, J., et al. Eur. J. Med. Chem. (1997), 32, 397-408). The
`i:ioisosteric replacement of the benzothiazole moiety by a benzoxazole or a
`benzimidazole ring resulted in compounds 2/3 which turned out to be more
`ll01ent than 1 by a factor of 30. In an extension to these studies, compounds
`'llhere the acetyl-CH3 was replaced by various alkyl, cycloalkyl, phenyl and
`
`PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 17
`
`pyridine moieties were synthesized. The novel 2-acylpyridine hydrazones inhib(cid:173)
`ited the proliferation of several human tumor cells (IC50 = 0.052-6.98 µM).
`induces apoptosis in Burkitt's lymphoma cells, and also are potent inhibitors of
`RNA synthesis. Financial assistance provided by the Austrian Science Foundation
`project no. P 12384-MOB.
`
`f'il N, ~NY)
`~NAy ~ X~
`CH3 H
`1: X = S (IC50 = 0.15 - 5.31 µM)
`2: X = 0 (IC50 = 0.006 - 0.23 µM)
`3: X = NH (IC50 = 0.005 - 0.68 µM)
`
`#1999 Pharmacological studies on two new classes of heterocyclic
`anticancer drug. Truong-Chiott, SA .. Haydar, S.N., Krapcho, P.A., and Hacker,
`M.P. University of Vermont, Burlington, VT 05405.
`Aza-benzothiopyranoindazoles and aza-benzothiopyranopyridines. recently
`developed and synthesized in our laboratory, are two novel classes of com(cid:173)
`pounds with impressive anti-tumor activity. They are structurally related to the
`Anthrapyrazoles and the Anthracyclines, but contain a heterocyclic rather than a
`carbocyclic ring. In vitro cytotoxicity data obtained from testing against L1210,
`S180 and S180/A10 cells demonstrated excellent antitumor activity with little er
`no cross resistance in the MOR cell line $180/AIO. Anti-tumor activity of com(cid:173)
`pounds from both classes was exquisitely sensitive to the location of the nitrogen
`within the heterocyctic ring, with the 9-azas superior to that of the 7 or 8 or
`non-azas. Ethidium bromide displacement assays using salmon spenn ONA were
`performed on four compounds (a 9-aza and an 8-aza from each class) to detect
`possible DNA-drug interaction. All four compounds were able to displace
`ethidium bromide from DNA and caused decreases in fluorescent intensities,
`indicating the existence of DNA-drug interaction and possibly DNA intercalation.
`To confirm that intercalation occurred, ligation assays of supercoiled DNA
`pBR322 in the presence and absence of drugs were conducted. All four com(cid:173)
`pounds interacted with ONA through intercalation. However, comparisions of
`results from cytotoxicity assays and ethidium bromide displacement assays
`suggested that DNA interaction may not be the primary mechanism for potency
`of our compounds. (Research was supported in part by a grant from Boehringer
`Mannheim Italia, Milan Italy).
`
`#2000 The effect of CCl-779, a novel macrolide anti-tumor agent, on the
`growth of human tumor cells in vitro and in nude mouse xenografts in vivo.
`Gibbons. J.J .. Oiscafani, C., Peterson, R .. Hernandez, R., Skotnicki, J .. and Frost,
`P. Oncology and lmmunoinflammatory Research, Wyeth·Ayerst Research, Pearl
`River, NY 10965.
`CCl-77g is a sirolimus analog formulated for intravenous use. The growth of
`human tumor cells was either sensitive (JC 50-1 nM) or relatively resistant
`(IC50>1.0µ.M) when co-cultured in vitro with CCl-779. Growth inhibitory effects
`were blocked by the FKBP inhibitory molecule ascomycin, suggesting that the
`mechanism of action of CCl-779 is similar lo sirolimus. Growth inhibited cells
`were arrested in the G1 phase of the cell cycle. POGF stimulation of the human
`glioblastoma line T98G was markedly inhibited (IC50-1pM) by CCl-779 in serum
`free medium. In vivo in nude mouse xenogratts, the growth of staged human
`glioblastoma (U87MG) tumors was blocked by a variety of dosing regimens
`(minimum effective dose 0.1-1.0 mg/kg). Staged tumors treated for 5 consecutive
`days with CCl·77g were still growth inhibited 14 days later. In contrast, the effect
`of the compound on immune function was lost as early as 1 day after drug
`withdrawal. Various histological tumor types (pancreas, breast. prostate) were
`also sensitive to CCl-779 in nude mouse xenogratts. The data suggests that
`CCl-77g will be an effective anti-tumor agent for several human tumor types when
`given via an intennittent dosing regimen. The compound currently is in Phase I
`trials in man.
`
`#2001 Highly potent anthracycline-based antitumor agents. Priebe, W ..
`Przewloka, T., Fokt, I., Ling, Y-H .. Perez-Soler, R. The University of Texas M.D.
`Anderson Cancer Center, Houston, TX 77030.
`New anthracyline-based agents designed to interact and crosslink with DNA in
`a base specific process have been synthesized. These analogs contain unique
`three ring system which is relatively stable. Synthesized compounds displayed
`activity significantly higher than that of parental daunorubicin or doxorubicin. In
`brief, in vitro the compound WP836 derived from doxorubicin was 500- to more
`than 100,000-fold more potent than doxorubicin in test perfonned in sensitive and
`multidrug resistant cell lines. Similarly, the increased activity was also noticed for
`analog WPaog obtained from daunorubicin. Other analogs were also designed
`and synthesized. Observed activity and-high potency indicate that the primar1
`mechanism of action of these analogs is different from doxorubicin and dauno(cid:173)
`rubicin.
`
`Proceedings of the American Association for Cancer Research ,. Volume 40 ° March .1999
`
`301
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`West-Ward Exhibit 1085
`Gibbons Abs #2000
`Page 002
`
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