Background & Aims
Despite advances in cancer treatment, cancer survivors often suffer treatment-related adverse effects. One of the most disabling adverse effects of the highly effective chemotherapeutic, paclitaxel (PTX), is paclitaxel-induced peripheral neuropathy (PIPN) which often limits the duration of treatment.(1) Despite improvements in our understanding of PIPN, no effective preventative or therapeutic options are available. PTX is administered in 3-6 consecutive cycles over several months and the dosage and duration of therapy confer its effectiveness.(2,3) However, the intensity and duration of PIPN increase with each cycle of PTX.(4) Current rodent models administer just one cycle of PTX, which does not mirror the clinical schedule of PTX therapy.(4) The purpose of our study was to evaluate the rodent PIPN phenotype in a translation model that more closely mimics the clinical PTX regimen where we administer three consecutive cycles of PTX.
Methods
Adult female C57Bl/6J mice were given four doses of PTX (4 mg/kg) or vehicle every other day to mimic a single chemotherapy cycle.4 Following the resolution of mechanical sensitivity, mice received another cycle of PTX or vehicle according to their assigned group. This was repeated for a total of three cycles. Behavioral assessments were conducted to measure the peak and resolution of PIPN. Responses to stimulation with 0.6g (low force) and 1.4g (high force) von Frey monofilaments measured mechanical sensitivity [%PWF]. Time spent reacting in the minute after application of acetone to the hind paw measured cold sensitivity. PIPN peak was defined as the maximum mechanical and cold sensitivity for a cycle. PIPN resolution was defined as a return to baseline sensitivity and time to resolution as the interval between the first PTX dose of a cycle to resolution. The area under the curve is the area under the mean intensity of mechanical or cold sensitivity over time for a given cycle.
Results
The first PTX cycle produced mechanical and cold sensitivity as previously reported with peak occurring on days 7-10 following the first PTX dose and resolution of mechanical sensitivity occurring on day 29.4 The time to resolution of mechanical sensitivity following the third cycle of PTX was significantly longer than cycles 1 and 2 (58 versus 29 days, ?2 (3)=16.00, p=0.0081). Mechanical sensitivity associated with the third PTX cycle had a greater area under the curve for stimulation by the low-force (2041±1089 vs 1004±1765 vs 1124±1459, F(2,172) = 6.630, p<0.001) and high-force (3293±1870 vs 1465±1618 vs 1623±1175, F (2,172) = 20.29, p<0.0001) filaments compared to cycles 1 and 2. Cold sensitivity peaked on day 9 following the first PTX dose and did not fully resolve. The total area under the curve associated with cold sensitivity for the third PTX cycle was greater than that for the first or second cycle (499.0±79.37 vs 202.6±237.5 vs 258.0±202.5, F(2,125) = 21.12, p<0.0001).
Conclusions
A single cycle of PTX caused mechanical and cold sensitivity as expected. Administration of three consecutive PTX cycles resulted in an increased time to resolution of mechanical sensitivity following the third cycle of PTX; which mimics the clinical cases of worsening PIPN as PTX cumulative dose increases. The peak intensities of mechanical and cold sensitivity did not change between cycles with the administration of consecutive PTX cycles. Mechanical and cold sensitivity showed differences in resolution which suggests different mechanisms are involved in mechanical and cold sensitivity resolution in PIPN. Our findings support the use of multiple PTX cycles to provide a translational PIPN model in rodents where additional cycles confer an extended PIPN phenotype that more closely matches the clinical phenotype.
References
1.Kampan NC, Madondo MT, McNally OM, Quinn M, & Plebanski M (2015). Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer. BioMed Research International, 2015, 413076.
2.Tanabe Y, Hashimoto K, Shimizu C, Hirakawa A, Harano K, Yunokawa M, Yonemori K, Katsumata N, Tamura K, Ando M, Kinoshita T, & Fujiwara Y. (2013). Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer. International Journal of Clinical Oncology, 18(1), 132–138.
3.Chemotherapy for Breast Cancer | Breast Cancer Treatment. (n.d.). Retrieved December 14, 2023, from https://www.cancer.org/cancer/types/breast-cancer/treatment/chemotherapy-for-breast-cancer.html
4.Gadgil S, Ergün M, van den Heuvel SA, van der Wal SE, Scheffer GJ, & Hooijmans CR. (2019). A systematic summary and comparison of animal models for chemotherapy induced (peripheral) neuropathy (CIPN). PloS One, 14(8), e0221787.
Presenting Author
Laura R. Osborn
Poster Authors
Laura Osborn
BA
University of Arkansas for Medical Sciences
Lead Author
Mary Grace Bishop
BA
Arkansas Children's Research Institute, University of Arkansas for Medical Sciences
Lead Author
Kayleigh Rodriguez
University of Arkansas for Medical Sciences
Lead Author
Dakota Redling
BS
Arkansas Children's Research Institute, University of Arkansas for Medical Sciences
Lead Author
Kimberly Stephens
University of Arkansas for Medical Sciences
Lead Author
Topics
- Models: Chronic Pain - Neuropathic