Model Organisms in Drug Discovery

. Olfactory discrimination test (olfaction and social recognition)
. Trace and delay aversive conditioning
. Social interaction and social recognition tests
. Zero maze (anxiety)
Oncology
The targets of current oncology therapeutics fall into three major categories:
cytotoxic agents such as DNA damaging agents or inhibitors of tubulin or
topoisomerase, tissue-specific growth regulators such as estrogen receptor
blockers and leutinizing hormone blockers, and disease-specific antitumor
agents such as Gleevec, Herceptin and Rituxan. The oncology Level 1 screen
is based on the hypothesis that targets for the next generation of cancer drugs
are likely to fall into the same categories operating through control points in
mammalian cell cycle, apoptosis or response to DNA damage.
Level 1 tests
Embyronic lethality and reduced viability
Targets for future cytotoxic agents are likely to be identified first by embryonic
lethality or reduced viability. These phenotypes are examined further to
detemine effects on cell cycle, apoptosis and angiogensis.
Tissue-specific growth regulation
Targets affecting growth, differentiation and function of reproductive organs
are examined through histopathologic survey of males, virgin females and
lactating female mice.
Cell proliferation
HIGH-THROUGHPUT BIOLOGY 271
Oncogene targets that have a direct effect on cell cycle, DNA repair or
apoptosis can manifest their function through changes in adult skin fibroblast
proliferation. Punch biopsies are taken of skin samples from the backs of
mutant mice and cohort controls. These are developed into primary fibroblast
cultures and the fibroblast proliferation rates are measured in a strictly
controlled protocol. The ability of this assay to detect hyperproliferative and
hypoproliferative phenotypes has been demonstrated with p53 and Ku80
(unpublished results).