Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an Index of Cell Proliferation after Pharmacological Ascorbate-Based Therapy

• Published in: Radiation research Vol. 185; no. 1; pp. 31 - 38
• Main Authors: Cieslak, John A., Sibenaller, Zita A., Walsh, Susan A., Ponto, Laura L. Boles, Du, Juan, Sunderland, John J., Cullen, Joseph J.
• Format: Journal Article
• Language: English
• Published: United States The Radiation Research Society 01.01.2016; Radiation Research Society; Allen Press Inc
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Ascorbic Acid - administration & dosage; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Chemoradiotherapy - methods; Cytotoxicity; Dideoxynucleosides - pharmacokinetics; Drug Monitoring - methods; Emissions; Humans; Imaging; Ionizing radiation; Isotope Labeling; Metabolic Clearance Rate; Mice; Mice, Nude; Oxidative stress; Pancreatic cancer; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - therapy; Pharmacology; Positron emission; Positron-Emission Tomography - methods; Radiation-Sensitizing Agents - administration & dosage; Radiopharmaceuticals - pharmacokinetics; Radiotherapy Dosage; REGULAR ARTICLES; Therapy; Tomography; Treatment Outcome; Tumors; Uptakes
• ISSN: 0033-7587; 1938-5404
• DOI: 10.1667/RR14203.1

Pharmacological ascorbate (AscH−) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells compared with normal cells. Positron emission tomography (PET) with the thymidine analog 3′-deoxy-3′-(18F) fluorothymidine (FLT) enables noninvasive imaging and quantification of the proliferation fraction of tumors. We hypothesized that the rate of tumor proliferation determined by FLT-PET imaging, would be inversely proportional to tumor susceptibility to pharmacological AscH−-based treatments. Indeed, there was decreased FLT uptake in human pancreatic cancer cells treated with AscH−in vitro, and this effect was abrogated by co-treatment with catalase. In separate experiments, cells were treated with AscH−, ionizing radiation or a combination of both. These studies demonstrated that combined AscH− and radiation treatment resulted in a significant decrease in FLT uptake that directly correlated with decreased clonogenic survival. MicroPET 18F-FLT scans of mice with pre-established tumors demonstrated that AscH− treatment induced radiosensitization compared to radiation treatment alone. These data support testing of pharmacological ascorbate as a radiosensitizer in pancreatic cancer as well as the use of FLT-PET to monitor response to therapy.