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`HEALTH SCIENCES LIBRARY
`
`UNIVERSITYOFWISCONSIN
`SIXTY-SIXTH
`annual meeting
`of the
`American Association
`for Cancer Research
`
`PROCEEDINGS
`
`ELEVENTH
`annual meeting
`of the
`American Society
`of Clinical Cheoay
`MAY AIT, IG/
`San Diego, California
`
`
`
`Volume 16: March 19/5
`
`CELGENE 2096
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`Proceedings of the
`American Association for Cancer Research
`and
`American Society of Clinical Oncology
`
`Sidney Weinhouse, Editor
`
`Margaret Foti, Managing Editor
`
`
`AMERICAN ASSOCIATION FOR CANCER RESEARCH, INC.
`
`OFFICERS
`
`(1974-1975)
`
`President, Van R. Potter
`
`Vice President, Charlotte Friend
`
`Secretary-Treasurer, Hugh J. Creech
`
`BOARD OF DIRECTORS
`
`Term Expiring May 1975
`
`ThomasC. Hall
`G. A. LePage
`
`Carl G. Baker
`Paul Calabresi
`
`Term Expiring May 1976
`
`Van R. Potter
`Frank M. Schabel, Jr.
`
`Charlotte Friend
`Ludwik Gross
`
`Term Expiring May 1977
`
`SeymourS. Cohen
`George H. Hitchings
`
`Mortimer L. Mendelsohn
`Elizabeth C. Miller
`
`Hugh J. Creech
`
`Sidney Weinhouse
`
`Ex Officio
`
`AMERICAN SOCIETY OF CLINICAL ONCOLOGY, INC.
`
`OFFICERS
`
`(1974-1975)
`
`President, Rose Ruth Ellison
`
`President Elect, Joseph R. Bertino
`
`Immediate Past President, Bayard D. Clarkson
`
`Secretary-Treasurer, Audrey E. Evans
`
`BOARD OF DIRECTORS
`
`Daniel Bergsagel
`
`Vincent T. DeVita
`
`Albert H. Owens,Jr.
`
`
`Copyright 1975 by Cancer Research, Inc. Published for Cancer Research, Inc., and the
`American Association for Cancer Research, Inc., by The Williams & Wilkins Co., Baltimore,
`Md. 21202, and included in subscriptions to the journal CANCER RESEARCH.
`
`

`

`AACR Abstracts, 1975
`
`205 CYTOTOXICITY OF COPPER AND IRON
`COMPLEXES OF 5-SUBSTITUTED-2-
`FORMYLPYRIDINE THIOSEMICARBAZONES (HL).
`D. H. Petering, W. Antholine, J. M.
`Knight, and H. G. Petering, Department
`of Chemistry, University of Wisconsin-
`Milwaukee, Milwaukee, WI 53201 and
`Department of Environmental Health,
`University of Cincinnati, Cincinnati,
`OH 45219.
`The cytotoxicity of metal com-
`plexes of HL against Ehrlich ascites
`tumor cells has been examined. Short
`in vitro incubation of cells and drugs
`followed by implantation of cells into
`mice and observations of tumor growth
`was used to assess cytotoxic effects.
`Using 5x10% cells/ml and 2 mg/ml of the
`iron complexes,
`the following order of
`activities was observed, beginning with
`the least active complex, OH < -OCOCH;
`~ -N(CH3)2 < H < -CH3 ~ -Cl
`~
`-CF3.
`The
`last two complexes completely prevent
`tumor development over long periods.
`At 0.1 mg/ml copper complexes of 5-H
`and 5-CH; completely inhibit trans-
`plantation.
`In contrast,
`2 mg/ml of
`the 5-H ligand has less effect than
`either its iron or copper complex.
`These results indicate that metal com-
`plexes of HL as well as parent ligands
`need to be examined for their anti-
`tumor properties.
`(Supported by NCI
`CA 16156.)
`
`206 MORPHOLOGICAL MODIFICATION OF A VIRUS-
`INDUCED LYMPHATIC LEUKEMIA BY THYMECTOMY
`AND ANTILYMPHOCYTE SERUM.
`Steven L. Dresler,
`Peter J. Dawson, and A. Howard Fieldsteel.
`Univ. Oregon Med. Sch., Portland, Ore. 97201
`and Stanford Research Inst., Menlo Park,
`Ca. 94025.
`Since most human lymphocytic leukemias in
`contrast to murine leukemias possess B-cell
`markers, we attempted to induce with virus a
`murine leukemia of B-cell origin. Groups of
`BALB/c mice were thymectomized at 5-7 days of
`age,
`treated with antilymphocyte serum (ALS) on
`days 7, 8 and 9 and inoculated on day 8 with
`lymphatic leukemia virus (LLV-F)
`isolated from
`Friend virus. Control animals were either thy-
`mectomized and given ALS (and no virus) or were
`sham-thymectomized and inoculated with virus.
`Control animals developed lymphocytic leukemia
`involving thymus, periarteriolar sheaths of
`spleen, portal areas of liver,
`lymph nodes and
`bone marrow.
`Immunofluorescence showed 6 anti-
`gen on leukemic lymphocytes and absence of
`immunoglobulins.
`In thymectomized mice,
`leu-
`kemia developed later and involved the splenic
`red pulp, hepatic sinusoids and bone marrow.
`Lymph nodes and periarteriolar sheaths of the
`spleen were spared. Cytologically the cells
`were different and lacked both T and B cell
`determinants. Possible explanations are the
`transformation of a different clone of lympho-
`cytes by LLV-F,
`the unmasking of trace amounts
`of Friend virus or the presence of another leu-
`kemia virus.
`Supported by grants CA-15072 and CA-07868
`from the National Cancer Institute.
`
`207 PHASE I STUDY OF 5-AZACYTIDINE USING 24 HRS
`CONTINUOUS INFUSION FOR 5 DAYS. Pavel L.
`Lomen, V. K. Vaitkevicius, and Michael K. Samson.
`Dept. of Oncology, Wayne State University, Detroit,
`Mich. 48201
`The biological and antitumor activity of
`5-azacytidine (5-azaCR) has been well demon-—
`strated in the past. The drug at present is
`thought by most to be primarily cell cycle phase
`specific. This study was designed to eliminate
`undesirable side effects occurring with a bolus
`dose and to confirm the recent findings of rela-
`tive stability of 5-azaCR's solution with pre-
`served biological and antitumor activity.
`In
`the study we determined that 150 ng/m2/day given
`as a 120 hr continuous intravenous infusion, re-
`peated at 28 day intervals produced safe, man-
`ageable, and reproducible toxicity.
`The drug
`was freshly prepared at 4 hr intervals. Eleven
`courses were administered to 6 patients at this
`dose level. No patient experienced nausea or
`vomiting, Leukopenia was the major toxicity.
`Mean nadir of WBC was 2.6 x 103 (range 0:7-6.1).
`Day 17 was the mean day to nadir with recovery
`occurring within 2-13 days.
`In only 3 courses
`was thrombocytopenia (7-92 x 10%) produced.
`In
`two patients multiple samples of plasma and
`urine were analyzed by microbiologic assay.
`There was no 5-azaCR detected in the plasma sam-
`ples.
`In 24 hr urine collections,
`there was
`0.89% and 0.74% of free azacytidine detected.
`Antitumor activity was demonstrated in one pa-
`tient with colon cancer and another with Ameri-
`can Burkitt's lymphoma. Analysis of this study
`confirmed our expectations and pointed out some
`new aspects of 5-azaCR metabolism.
`
`208 MECHANISM OF 5-FLUOROURIDINE TOXICITY IN
`NOVIKOFF HEPATOMA CELLS. David §.
`Wilkinson and Jeanne Crumley. University of
`South Florida, Tampa, Florida 33620.
`Several of the fluorinated pyrimidines
`have the ability to inhibit rRNA maturation.
`This effect appears to be a significant factor
`in the cytotoxicity of 5-fluorouridine (FUrd)
`in Novikoff hepatoma cells.
`The incorporation
`of labeled precursors into mature 18S and 28S
`rRNA is completely inhibited by the simulta-
`neous addition of 1xl074M FUrd, whereas the
`cells must be preincubated with this drug for
`2 hrs before comparable inhibition of DNA
`synthesis occurs. When cells are incubated
`with 1xl0-5M FUrd for one hr, washed, resus-
`pended in fresh medium for 1 hr and then
`exposed to [3H] guanosine for 90 min, one finds
`little or no incorporation of precursor into
`mature 18S or 28S rRNA. Under similar condi-
`tions,
`there is very little inhibition of DNA
`synthesis. Cells exposed to 1x10-5M FUrd for
`one hr and then allowed to incubate for one
`hr in analog-free media do not grow when sub-
`cultured into Standard media.
`The addition of
`1x1074M uridine (Urd) during analog exposure
`prevents most of the growth inhibition,
`whereas the addition of 1x10~4M thymidine (Thd)
`has little effect.
`Thd, which can prevent the
`inhibition of DNA synthesis by FUrd, does not
`prevent the inhibition of rRNA maturation.
`However, Urd, which blocks the growth inhibi-
`tory effects of FUrd, also blocks the inhibi-
`tion of rRNA maturation.
`(Supported by DRG-
`1220 and ACS F73FS-2).
`
`52
`
`PROCEEDINGS OF AACR AND ASCO
`
`