Abstract
As the incidence of pancreatic ductal adenocarcinoma (PDAC) continues to grow, so does the need for new strategies for treatment. One such area being evaluated is cryoablation. While promising, studies remain limited and questions surrounding basic dosing (minimal lethal temperature) coupled with technological issues associated with accessing PDAC tumors and tumor proximity to vasculature and bile ducts, among others, have limited the use of cryoablation. Additionally, as chemotherapy remains the first-line of attack for PDAC, there is limited information on the impact of combining freezing with chemotherapy. As such, this study investigated the in vitro response of a PDAC cell line to freezing, chemotherapy, and the combination of chemotherapy pre-treatment and freezing. PANC-1 cells and PANC-1 tumor models were exposed to cryoablation (freezing insult) and compared to non-frozen controls. Additionally, PANC-1 cells were exposed to varying sub-clinical doses of gemcitabine or oxaliplatin alone and in combination with freezing. The results show that freezing to −10 °C did not affect viability, whereas −15 °C and −20 °C resulted in a reduction in 1 day post-freeze viability to 85% and 20%, respectively, though both recovered to controls by day 7. A complete cell loss was found following a single freeze below −25 °C. The combination of 100 nM gemcitabine (1.1 mg/m2) pre-treatment and a single freeze at −15 °C resulted in near-complete cell death (<5% survival) over the 7-day assessment interval. The combination of 8.8 µM oxaliplatin (130 mg/m2) pre-treatment and a single −15 °C freeze resulted in a similar trend of increased PANC-1 cell death. In summary, these in vitro results suggest that freezing alone to temperatures in the range of −25 °C results in a high degree of PDAC destruction. Further, the data support a potential combinatorial chemo/cryo-therapeutic strategy for the treatment of PDAC. These results suggest that a reduction in chemotherapeutic dose may be possible when offered in combination with freezing for the treatment of PDAC.
Highlights
An estimated 60,430 new cases of pancreatic cancer (PaCa) will be diagnosed in 2021 in the US alone [1]
We investigated the use of approach, gemcitacomplete cell death can be obtained following with subclinical chemotherapy doses [41,48,52,64,86]
Given the observed high level of PANC-1 viability and subsequent recovery following exposure to −15 ◦ C as well as varying responses to 10, 50, and 100 nM gemcitabine, we explored the impact of combining gemcitabine pretreatment at these concentrations followed by freezing on cell survival (Figure 4)
Summary
An estimated 60,430 new cases of pancreatic cancer (PaCa) will be diagnosed in 2021 in the US alone [1]. Resectable cancers are typically stage 1, limited to the pancreas only and divided into stage 1A (2 cm or smaller) and stage 1B (between 2 and 4 cm). Treatment depends on staging, with resectable tumors typically surgically excised after the patient is treated for 6 months with neoadjuvant chemotherapy. In cases where surgical resection is not possible or is high risk due to tumor size, proximity to blood vessels, or other factors (non-resectable tumors), chemotherapy is the typical treatment, and sometimes radiation, small molecules, or immunotherapy are added. Thermal ablation techniques, such as radiofrequency (RFA)
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