Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 1: 60 - 68

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.01.007

Clinical research

[18F]F-FMISO and [18F]F-FLT PET/CT dual-nuclide imaging for in vivo prediction of drug resistance in pancreatic cancer

  • SUN Chenwei ,
  • HAI Wangxi ,
  • QU Qian ,
  • XI Yun
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  • Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
XI Yun, E-mail: cloudylanhuit@163.com.

Received date: 2024-06-18

  Accepted date: 2024-08-27

  Online published: 2025-01-28

Supported by

National Natural Science Foundation of China(81801728)

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Abstract

Objective ·[18F]F-FMISO and [18F]F-FLT are specific PET imaging agents for detecting the hypoxia microenvironment and cell proliferation, respectively. This study aims to visualize and monitor the impact of drug resistance in pancreatic cancer on the hypoxia microenvironment and cell proliferation through [18F]F-FMISO and [18F]F-FLT PET/CT dual-nuclide imaging, with the goal of providing a theoretical basis for clinical application. Methods ·The CCK-8 assay was conducted to assess drug resistance in the PANC-1/R (PR) pancreatic cancer cell line compared to the parental PANC-1 (P) cell line. Subcutaneous xenograft models of pancreatic cancer were established by injecting male BALB/c nude mice with pancreatic cancer cells into the left axillary subcutaneous region. Subgroups were treated with gemcitabine (GEM) chemotherapy starting on day 18 (18D-G group) or day 12 (12D-G group) after inoculation of tumor cells. [18F] F-FMISO and [18F] F-FLT PET/CT imaging were performed before and after treatment to obtain semi-quantitative parameters (maximum standardized uptake value, SUVmax). ΔSUVmax was calculated by using the following equation: ΔSUVmax=(SUVmax of second imaging-SUVmax of first imaging)/ SUVmax of first imaging. Receiver operating characteristic (ROC) curves were used to determine the optimal threshold for the semi-quantitative parameters to assess pancreatic cancer drug resistance. Results ·The CCK-8 assay confirmed that the PR cells exhibited high resistance to GEM, with a resistance index of 4.24 (n=5). In vivo experiments showed that GEM chemotherapy significantly inhibited tumor growth and prolonged survival in the parental pancreatic cancer group (12D-G group, P=0.025), whereas GEM chemotherapy accelerated tumor growth and shortened survival (18D-G and 12D-G, P=0.025) in the drug-resistant pancreatic cancer group. In addition, in the non-chemotherapy group, ΔSUVmax-FLT might be negatively correlated with survival time, while in the chemotherapy group, both ΔSUVmax-FMISO and ΔSUVmax-FLT were negatively correlated with survival time (P=0.050, P=0.006). In the 18D-G and chemotherapy group, the second imaging showed significantly lower ΔSUVmax-FMISO and ΔSUVmax-FLT in P tumors compared to PR tumors (P=0.045, P=0.050). In the 12D-G and chemotherapy group, the second imaging showed slightly lower ΔSUVmax-FLT in P tumors compared to PR tumors (P=0.051). ROC analysis identified the optimal threshold for assessing pancreatic cancer drug resistance: when ΔSUVmax-FLT=0.45 in the non-chemotherapy group, the sensitivity and specificity were 100.00% and 50.00%, respectively; when ΔSUVmax-FMISO=0.37 and ΔSUVmax-FLT=0.36 in the chemotherapy group, the sensitivity and specificity were 100.00% and 83.33%, respectively. Conclusion ·[18F]F-FMISO and [18F]F-FLT PET/CT dual-nuclide imaging can be used to assess drug resistance in pancreatic cancer. The comparison of [18F]F-FMISO and [18F]F-FLT PET differences before and after chemotherapy provides the most accurate prediction of drug resistance and survival time.

Key words： pancreatic cancer; drug resistance; [18F]F-FMISO; hypoxia microenvironment; [18F]F-FLT; cell proliferation

Cite this article

SUN Chenwei , HAI Wangxi , QU Qian , XI Yun . [18F]F-FMISO and [18F]F-FLT PET/CT dual-nuclide imaging for in vivo prediction of drug resistance in pancreatic cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025 , 45(1) : 60 -68 . DOI: 10.3969/j.issn.1674-8115.2025.01.007

References

1 LATENSTEIN A E J, van der GEEST L G M, BONSING B A, et al. Nationwide trends in incidence, treatmentand survival of pancreatic ductal adenocarcinoma[J]. Eur J Cancer, 2020, 125: 83-93.
2 XI Y, YUAN P, LI T, et al. hENT1 reverses chemoresistance by regulating glycolysis in pancreatic cancer[J]. Cancer Lett, 2020, 479: 112-122.
3 XI Y, GUO R, HU J J, et al. 18F-fluoro-2-deoxy-D-glucose retention index as a prognostic parameter in patients with pancreatic cancer[J]. Nucl Med Commun, 2014, 35(11): 1112-1118.
4 TOYONAGA T, HIRATA K, SHIGA T, et al. Players of ‘hypoxia orchestra’: what is the role of FMISO?[J]. Eur J Nucl Med Mol Imaging, 2017, 44(10): 1679-1681.
5 YAMANE T, AIKAWA M, YASUDA M, et al. [18F]FMISO PET/CT as a preoperative prognostic factor in patients with pancreatic cancer[J]. EJNMMI Res, 2019, 9(1): 39.
6 DOLEZEL M, SLAVIK M, BLAZEK T, et al. FMISO-based adaptive radiotherapy in head and neck cancer[J]. J Pers Med, 2022, 12(8): 1245.
7 GOUEL P, DECAZES P, VERA P, et al. Advances in PET and MRI imaging of tumor hypoxia[J]. Front Med, 2023, 10: 1055062.
8 LAMARCA A, ASSELIN M C, MANOHARAN P, et al. 18F-FLT PET imaging of cellular proliferation in pancreatic cancer[J]. Crit Rev Oncol Hematol, 2016, 99: 158-169.
9 BERGMAN A M, PINEDO H M, PETERS G J. Determinants of resistance to 2′, 2′-difluorodeoxycytidine (gemcitabine)[J]. Drug Resist Updat, 2002, 5(1): 19-33.
10 HONEYWELL R J, RUIZ van HAPEREN V W, VEERMAN G, et al. Inhibition of thymidylate synthase by 2′, 2′-difluoro-2′- deoxycytidine (gemcitabine) and its metabolite 2′, 2′-difluoro-2′- deoxyuridine[J]. Int J Biochem Cell Biol, 2015, 60: 73-81.
11 XI Y, CHEN H, XI Y, et al. Visualization research on ENT1/NIS dual-function gene therapy to reverse drug resistance mediated by MUC1 in GEM-resistant pancreatic cancer[J]. Nucl Med Biol, 2023, 120/121: 108350.
12 CARVALHO T M A, AUDERO M M, GRECO M R, et al. Tumor microenvironment modulates invadopodia activity of non-selected and acid-selected pancreatic cancer cells and its sensitivity to gemcitabine and C18-gemcitabine[J]. Cells, 2024, 13(9): 730.
13 KOHAN H G, BOROUJERDI M. Time and concentration dependency of P-gp, MRP1 and MRP5 induction in response to gemcitabine uptake in Capan-2 pancreatic cancer cells[J]. Xenobiotica, 2015, 45(7): 642-652.
14 EVANGELISTA L, ZUCCHETTA P, MOLETTA L, et al. The role of FDG PET/CT or PET/MRI in assessing response to neoadjuvant therapy for patients with borderline or resectable pancreatic cancer: a systematic literature review[J]. Ann Nucl Med, 2021, 35(7): 767-776.
15 GHIDINI M, VUOZZO M, GALASSI B, et al. The role of positron emission tomography/computed tomography (PET/CT) for staging and disease response assessment in localized and locally advanced pancreatic cancer[J]. Cancers, 2021, 13(16): 4155.
16 LEE J W, KANG C M, CHOI H J, et al. Prognostic value of metabolic tumor volume and total lesion glycolysis on preoperative 18F-FDG PET/CT in patients with pancreatic cancer[J]. J Nucl Med, 2014, 55(6): 898-904.
17 FIORE M, TARALLI S, TRECCA P, et al. A bio-imaging signature as a predictor of clinical outcomes in locally advanced pancreatic cancer[J]. Cancers, 2020, 12(8): 2016.
18 MOHAMED E, NEEDHAM A, PSARELLI E, et al. Prognostic value of 18FDG PET/CT volumetric parameters in the survival prediction of patients with pancreatic cancer[J]. Eur J Surg Oncol, 2020, 46(8): 1532-1538.
19 TAMAKI N, HIRATA K. Tumor hypoxia: a new PET imaging biomarker in clinical oncology[J]. Int J Clin Oncol, 2016, 21(4): 619-625.
20 HIRATA K, YAMAGUCHI S, SHIGA T, et al. The roles of hypoxia imaging using 18F-fluoromisonidazole positron emission tomography in glioma treatment[J]. J Clin Med, 2019, 8(8): 1088.
21 HIRATA K, WATANABE S, KITAGAWA Y, et al. A review of hypoxia imaging using 18F-fluoromisonidazole positron emission tomography[J]. Methods Mol Biol, 2024, 2755: 133-140.
22 DENG K P, ZOU F, XU J, et al. Cancer-associated fibroblasts promote stemness maintenance and gemcitabine resistance via HIF-1α/miR-21 axis under hypoxic conditions in pancreatic cancer[J]. Mol Carcinog, 2024, 63(3): 524-537.
23 CHINTAMANENI P K, PINDIPROLU S K S S, SWAIN S S, et al. Conquering chemoresistance in pancreatic cancer: exploring novel drug therapies and delivery approaches amidst desmoplasia and hypoxia[J]. Cancer Lett, 2024, 588: 216782.
24 MATHUR S, CHEN S, REJNIAK K A. Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs[J]. NPJ Syst Biol Appl, 2024, 10: 1.
25 SADR-AZODI O, OSKARSSON V, DISCACCIATI A, et al. Pancreatic cancer following acute pancreatitis: a population-based matched cohort study[J]. Am J Gastroenterol, 2018, 113(11): 1711-1719.
26 COLBERT L E, FISHER S B, BALCI S, et al. High nuclear hypoxia-inducible factor 1 alpha expression is a predictor of distant recurrence in patients with resected pancreatic adenocarcinoma[J]. Int J Radiat Oncol Biol Phys, 2015, 91(3): 631-639.
27 NORIKANE T, YAMAMOTO Y, MAEDA Y, et al. Correlation of 18F-fluoromisonidazole PET findings with HIF-1α and p53 expressions in head and neck cancer: comparison with 18F-FDG PET[J]. Nucl Med Commun, 2014, 35(1): 30-35.
28 KAWAI N, LIN W, CAO W D, et al. Correlation between 18F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas[J]. Eur J Nucl Med Mol Imaging, 2014, 41(10): 1870-1878.
29 LJUNGKVIST A S, BUSSINK J, KAANDERS J H, et al. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers[J]. Radiat Res, 2007, 167(2): 127-145.
30 SWARTZ J E, POTHEN A J, STEGEMAN I, et al. Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: a systematic review[J]. Cancer Med, 2015, 4(7): 1101-1116.
31 BASHIR A, BINDERUP T, VESTERGAARD M B, et al. In vivo imaging of y in meningioma using 3′-deoxy-3′-[18F]fluorothymidine PET/MRI[J]. Eur J Nucl Med Mol Imaging, 2020, 47(6): 1496-1509.
32 NAKAJO M, KAJIYA Y, TANI A, et al. A pilot study of the diagnostic and prognostic values of FLT-PET/CT for pancreatic cancer: comparison with FDG-PET/CT[J]. Abdom Radiol, 2017, 42(4): 1210-1221.
33 PRETZ J L, BLAKE M A, KILLORAN J H, et al. Pilot study on the impact of F18-labeled thymidine PET/CT on gross tumor volume identification and definition for pancreatic cancer[J]. Pract Radiat Oncol, 2018, 8(3): 179-184.
34 KAFKALETOS A, MIX M, SACHPAZIDIS I, et al. The significance of partial volume effect on the estimation of hypoxic tumour volume with[18F]FMISO PET/CT[J]. EJNMMI Phys, 2024, 11(1): 43.
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