Annual Meeting Program - Society of Toxicology

Society of Toxicology 2008
Program Description (Continued)
Abstract #
#1333 9:30 ETS AND GENDER EFFECTS ON ALLERGIC
ASTHMA. L. J. Gershwin 1 , V. L. Mitchell 1,2 and
L. S. Van Winkle 2 . 1 Pathology, Microbiology, &
Immunology, University of California, Davis, Davis,
CA and 2 Center for Health and the Environment,
University of California, Davis, CA.
#1334 9:55 PRENATAL EXPOSURE TO TOBACCO
SMOKE INDUCES ASTHMA-RELATED
RESPONSES IN NON-SENSITIZED FEMALE
OFFSPRING LATER IN LIFE. J. T. Zelikoff,
S. Doherty, C. Hoffman and E. Brush. School of
Medicine, Department Environment Med., New York
University, Tuxedo, NY.
#1335 10:20 ENVIRONMENTAL TOBACCO SMOKE
(ETS) AS A RISK FACTOR IN CHILDHOOD
BEHAVIORAL DISORDERS. M. Golub 1,2 .
1
California EPA, Sacramento, CA and 2 Department of
Environmental Toxicology, UC Davis, Davis, CA.
#1336 10:45 MATERNAL SMOKING AND FETAL LUNG
DEVELOPMENT. E. R. Spindel. Division of
Neuroscience, Oregon National Primate Research
Center, Oregon Health & Science University,
Beaverton, OR. Sponsor: L. Van Winkle.
#1337 11:10 SEX DIFFERENCES IN ADULT
SUSCEPTIBILITY TO TOXIC CHALLENGE:
ROLE OF NEONATAL ETS EXPOSURES. L. S.
Van Winkle 1 , K. Sutherland 1 , P. Edwards 1 , G. Baker 2 ,
M. Shultz 1 and D. Nguyen 1 . 1 UC Davis, Davis, CA
and 2 Battelle Toxicology Northwest, Richland, WA.
11:35 PANEL DISCUSSION.
Wednesday Morning, March 19
9:00 AM to 11:45 AM
Room 608
SYMPOSIUM SESSION: UNUSUAL MANIFESTATIONS OF
ON-TARGET AND OFF-TARGET TOXICITY: TOXICITY OF
KINASE INHIBITORS
Chairperson(s): Kyle Kolaja, Roche Palo Alto, Palo Alto, CA and Bruce
Car, Bristol-Myers Squibb Company, Princeton, NJ.
Endorsed by:
Drug Discovery Toxicology Specialty Section*
Abstract: In recent years, several relatively selective tyrosine and serinethreonine
kinase inhibitors have been discovered and developed for
therapeutic applications in oncology and immunology. In addition the
kinome is being explored for targeted inhibition in a much wider variety
of disease areas. Typically, small molecules or antibodies are used to
target a kinase proximal or otherwise key to a signal transduction cascade
leading to endpoints such as tissue inflammation or cell proliferation. In
addition to toxicity mediated by biotransformation to toxic intermediates
(e.g. hepatic and renal toxicity), a particularly broad and novel variety of
adverse behavioral or tissue-based changes are noted with kinase inhibitors
from memory loss (MEK), and extreme neuropathic pain (Ret), to failure of
growth plate closure (VEGFR2), clastogenicity (many kinase inhibitors),
cardiotoxicity, hematopoetic toxicity, and teratologic outcomes (Wnt kinases
and many others). These effects may be mediated either by inhibition of
targeted kinases, closely related kinases or ostensibly nonhomologous
kinases to those targeted or a combination of on- and off-target effects. As
more data are collected, an emerging trend is that the inhibition of kinases
by parent molecules and their metabolites is the causative factor leading
to the panoply of untoward toxicity. Substantial efforts requiring novel
approaches in predictive toxicology, risk assessment and monitoring have
been employed to adequately avoid, understand, and manage the outcomes
of kinase inhibition. This Symposium summarizes the different experiences
of several pharmaceutical companies in managing a challenging new area of
the toxicology of pharmaceutical agents.
Abstract #
#1338 9:00 UNUSUAL MANIFESTATIONS OF
ON-TARGET AND OFF-TARGET TOXICITY:
TOXICITY OF KINASE INHIBITORS. B. Car 2
and K. L. Kolaja 1 . 1 Discovery and Investigative
Safety, Roche, Palo Alto, CA and 2 Discovery
Toxicology, BMS, Princeton, NJ.
#1339 9:15 INCREASED ORGAN CHEMICAL BURDEN
AS A CONTRIBUTOR TO THE TOXICITY
MECHANISM OF A RECEPTOR TYROSINE
KINASE INHIBITOR IN RATS. H. Hamadeh.
Toxicology, Amgen Inc, Thousand Oaks, CA.
#1340 9:45 KINASES OF TOXICOLOGICAL CONCERN:
DEVELOPMENT OF IN VITRO – IN VIVO
CORRELATIONS FOR KINASE INHIBITION
AND TOXICITY. K. L. Kolaja. Discovery and
Investigative Safety, Roche, Palo Alto, CA.
#1341 10:15 DISCOVERY AND IN VIVO APPROACHES
TO EVALUATION OF DIVERSE KINASE
INHIBITOR TOXICITIES. B. D. Car, B.
Gemzik, A. K. Gupta, P. C. Levesque, D. Li and R.
A. Westhouse. Bristol-Myers Squibb Company,
Princeton, NJ.
#1342 10:45 EVALUATING MECHANISM- AND NON-
MECHANISM-BASED TOXICITY OF
KINASE INHIBITORS: P38 MAP KINASE
INHIBITORS AS A CASE STUDY. D. Morris.
Drug Safety R&D, Pfizer Global Research &
Development, Chesterfield, MO.
#1343 11:15 SPECIES-SPECIFIC TOXICITIES
OBSERVED WITH KINASE INHIBITORS:
IMPACT ON THE PRECLINICAL SAFETY
PLAN AND REGULATORY STRATEGY. J. W.
Davis. DSRD, PGRD, Chesterfield, MO.
Wednesday Morning, March 19
9:00 AM to 11:45 AM
Room 6B
WORKSHOP SESSION: NATURAL KILLER CELLS AS
TARGETS OF DRUGS, TOXICANTS, AND BIOLOGICALS
Chairperson(s): Jeanine Bussiere, Amgen, Inc., Thousand Oaks, CA and
Stephen Pruett, Louisiana State University, Shreveport, LA.
Endorsed by:
Immunotoxicology Specialty Section*
Risk Assessment Specialty Section
NK (natural killer) and NK-T cells are immunologically important cells
involved at the interphase of innate and adaptive immunity and respond to
physiopathological processes. They may even be more sensitive than some
of the other commonly used immunotoxicity tests. Suppression of NK
cell activity by environmental contaminants is well known e.g., organotins.
NK cell activity is one of the initial screening study end points for
immunotoxicity testing under European drug regulatory guidelines. The
pharmacological activation of NK cells in anti-viral and anti-tumor therapies
has been emerging for approved therapeutics and those under clinical trial.
Imiquimod, a TLR7/8 ligand that induces NK-activating cytokines is an
approved agent for genital warts caused by papilloma virus. NK cell modulations
are known during Herpes virus and Cytomegalovirus infections.
Studies showing NK or NK-T cells being recruited into the liver after viral
infection, NK cells moving into the lymph nodes in response to immunization
or tumors, participation of NK / NK-T cells in inflammatory responses
in liver and lungs are noteworthy. The therapeutic activity of monoclonal
antibodies against human cancer cells may involve antibody-mediated cellmediated
cytotoxicity, one of NK cells’ known functions. Several natural
product extracts modulate NK cells. Thus, the effects of immunotoxicants,
immunotherapeutics or small molecules on NK cells, the modulations of NK
cells in anti-infectives / vaccine development are of interest to toxicologists
Wednesday
up-to-date information at www.toxicology.org 207