PRECLINICAL MODELS OF CANCER:

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PRECLINICAL MODELS OF CANCER ROLE IN DEFINING
PAIN MECHANISMS AND THEIR THERAPY Looking for
collaborations on Using Transgenic/Knockout Mice
to Identify Potential Target Genes That May Play
a Role in Cancer Pain Different Rat/Mouse Cancer
Pain Models Z. David Luo Department of
Anesthesiology UCSD
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• Late stage cancer often presents difficult pain
• management problems
• Primary/Metastasized Ca severe pain
  states
• Bone cancer
• Primary
• Metastases from breast, prostate, lung cancer
• Distinct Mechanisms underlying Ca pain
• Distinct biochemical changes in sensory neurons
  and
• spinal cord
• Different pharmacological profiles of pain
  therapies

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• MOUSE OSTEOSARCOMA
• Femoral injection of murine osteolytic sarcoma
  cell line (NCTC2472).
• Over 17 days
• .decalcification of femur (left)
• extensive bone destruction (arrows)
• Pain/Hyperalgesia
• (Luger, et al 2002)

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TIME DEPENDENT ONSET OF PAIN STATE AFTER
UNILATERAL FEMORAL SARCOMA INJECTION.
(LUGER, ET AL, 2002)
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Mouse osteosarcoma-induced hyperalgesia
correlates with biochemical changes in spinal
cord/DRG that are distinct from those observed
with nerve injury or inflammation
EXAMPLE Time dependent increase in spinal
astrocyte activation after unilateral femoral
osteosarcoma
GFAP (glial fibrillary acidic protein)
(Schwei, et al , 1999)
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Analgesic efficacy of morphine in
osteosarcoma- vs complete Freunds adjuvant
Inflammation- induced pain in mice
INJURY PAIN STATE
Morphine dose (mg/kg)
Allodynia Guarding
CFA Inflammation 3 1 Osteosarcoma (OS)
10 gt30

• Baseline pain states CFA OS
• Analgesic Morphine dose OS gt CFA

(Luger, et al., 2002)
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Research interest Approaches
Identifying potential target genes that may play
a role in cancer pain states
Mouse bone cancer model (supported by UCSD
Cancer Center) Other cancer pain models, pain
effects of other tumor cell lines Pain
behavioral testing Immunohistochemical
identification of potential target genes in
DRG and spinal cord Functional correlation
between gene expression and pain Pharmacological
agents Antibody/antisense oligonucleotides Trans
genic/knockout mice
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Potential target genes important in pain
transduction
Calcium channel subunits Sodium channel
subunits Potassium channel subunits Membrane
receptors glutamate, NK-1, ATP, etc. COX-1,
COX-2 TNF-a, TNF R1/R2 Factors signaling
pathways transcription factors synaptogenesis n
eurotransmission
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And there are linkages that promise yet greater
surprises
PNAS (2000) vol 97(11)6132-6137