Painful neuropathy is the principal dose-limiting factor requiring discontinuation of chemotherapy with vincristine, taxol and cisplatin, the frontline chemotherapeutic drugs used for a multitude of tumors, including leukemia, lung, and breast cancers, those most common in Americans. Moreover, this pain is refractory to treatment and often persists in cancer survivors. The long-term goal of this project is to determine the mechanism of chemotherapy-induced pain and identify potential therapeutic interventions for its relief and prevention. Three hypotheses related to this goal will be tested in three specific aims that are composed of complementary studies in humans who have received or are undergoing chemotherapy with vincristine, taxol or cisplatin and in animals treated with the same compounds. Hypothesis 1: Vincristine, taxol and cisplatin have shared effects on primary afferent fiber function that contribute to neuropathic pain. This hypothesis will be tested in humans alone.
Specific Aim 1. 1: Primary afferent function will be tracked by quantitative sensory testing over time during chemotherapy in cancer patients. The results in patients who develop pain will be contrasted with those in normal volunteers and with data from patients who do not develop pain. Hypothesis 2: Vincristine, taxol and cisplatin have shared effects on pro-inflammatory cytokines that contribute to neuropathic pain. This hypothesis will be tested in humans and animals.
Specific Aim 2. 1: Blood serum levels of cytokines, quantitative sensory function and symptom assessments will be tracked over time in patients as they undergo chemotherapy. The results in patients who develop pain will be contrasted to normative controls and to patients who do not develop pain.
Specific Aim 2. 2: In animals, the expression of cytokines in blood serum, spinal cord, dorsal root ganglia, and plantar skin will be measured over time with chemotherapy. Hypothesis 3: Chemotherapy-induced neuropathy is produced by the action of proinflammatory cytokines in specific body compartments. This will be tested in animals alone.
Specific Aim 3. 1: Individual cytokines shown to be elevated by chemotherapy will be infused onto spinal cord, dorsal root ganglia and around nerve endings in skin to reproduce the behavioral signs of chemo-neuropathy.
Specific Aim 3. 2: Cytokine antagonists will be administered systemically and into local body compartments in parallel with the chemotherapeutic drugs to prevent the onset of chemo-neuropathy. In summary this project will define mechanisms of chemotherapy-induced pain, identify novel near-term treatment candidates, and establish the key databases needed to design and justify follow-up clinical trials. This project will therefore improve the quality of life, survival and return to productivity of hundreds of thousands of patients that are affected by this neuropathy each year. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS046606-01A2
Application #
7213577
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2007-02-15
Project End
2012-01-31
Budget Start
2007-02-15
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$364,379
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Trahan, Lisa H; Cox-Martin, Emily; Johnson, Carrie E et al. (2017) Psychometric Study of the Pain Drawing. J Appl Biobehav Res 22:
Cox-Martin, Emily; Trahan, Lisa H; Cox, Matthew G et al. (2017) Disease burden and pain in obese cancer patients with chemotherapy-induced peripheral neuropathy. Support Care Cancer 25:1873-1879
Li, Yan; Tatsui, Claudio Esteves; Rhines, Laurence D et al. (2017) Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy. Pain 158:417-429
Zhang, Hongmei; Li, Yan; de Carvalho-Barbosa, Marianna et al. (2016) Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. J Pain 17:775-86
Shah, Nina; Shi, Qiuling; Williams, Loretta A et al. (2016) Higher Stem Cell Dose Infusion after Intensive Chemotherapy Does Not Improve Symptom Burden in Older Patients with Multiple Myeloma and Amyloidosis. Biol Blood Marrow Transplant 22:226-231
Dougherty, Patrick M (2016) Is Chemotherapy-induced Peripheral Neuropathy More Than Just a Peripheral Nervous System Disorder? Anesthesiology 124:992-3
Boyette-Davis, Jessica A; Walters, Edgar T; Dougherty, Patrick M (2015) Mechanisms involved in the development of chemotherapy-induced neuropathy. Pain Manag 5:285-96
Li, Yan; Zhang, Hongmei; Kosturakis, Alyssa K et al. (2015) MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy. Brain Behav Immun 49:255-66
Li, Yan; Adamek, Pavel; Zhang, Haijun et al. (2015) The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4. J Neurosci 35:13487-500
Kim, Joyce H; Dougherty, Patrick M; Abdi, Salahadin (2015) Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy. Gynecol Oncol 136:453-9

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