X‐irradiation effects on thymidine kinase (TK): I. TK1 and 2 in normal and malignant cells

Abstract

The effect of radiation on TK is more complicated than would be expected from earlier results on bone marrow cells (Feinendegen et al. 1984, Int. J. Radiat. Biol. 45, 205). TK activity increased at 0.01 Gy and then decreased up to 1 Gy in mouse spleen. In contrast to the results for the spleen, an increase in activity at 0.1 Gy was seen in mouse thymus. The activity of dephosphorylated TK1 (TK1a) in both spleen and thymus was reduced to 50% after irradiation at 0.5-1 Gy. The degree of phosphorylation (TK1b/TK1a ratio) changed in spleen, but not in thymus. The activity of TK2 in mouse liver increased at 3 h after 5 Gy by about 60%. In mouse ascites tumour, a dose-independent (1-5 Gy) oscillating TK1 activity was found up to 24 h, especially for TK1a and TK1b. The amount of TK1 was unchanged up to 12 h, but decreased at 24 h. This suggests that the differences in the changes in the degree of phosphorylation of TK1 after irradiation among spleen, thymus and ascites tumour further underline the complexity of the response of TK1 activity to irradiation. The dramatic change in the activities of TK1a and TK1b may illustrate that both of them are more radiosensitive than TK-h, a variant with mixed TK1 and TK2 properties.

Monitoring tumor proliferative response to radiotherapy using 18F-fluorothymidine in human head and neck cancer xenograft in comparison with Ki-67

“…As FLT is a substrate of TK and FLT uptake positively correlates with cell growth and TK1 activity, the rapid decrease in 15 FLT uptake level observed may be due to a rapid decrease in TK1 activity after radiation treatment [15,19,24]. Fowler et al suggested that as soon as a proportion of cells have been killed after radiotherapy, the size of the tumor cord shrinks, indicating that enhanced nutrition is available to all surviving cells, which leads to the reproliferation of surviving cells [25].…”

“…18 F-fluorothymidine (FLT) PET which reflects thymidine kinase 1 (TK1) activity is one of the noninvasive methods of detecting tumor proliferation [14][15][16][17][18]. TK1 activity is extremely sensitive to ionizing radiation, and the changes in FLT uptake level directly reflect the biological effect of radiation therapy [19,20]. Several studies have shown that tumor proliferation level decreases after radiotherapy, as detected by FLT PET [11,15,18,21].…”

Investigation of the pharmacokinetics of 3′-deoxy-3′-[18F]fluorothymidine uptake in the bone marrow before and early after initiation of chemoradiation therapy in head and neck cancer

“…Thymidine kinase (TK 1 ) phosphorylates FLT and should therefore determine k 3 . Radiation exposure in the range of 0.1 Gy to 4 Gy has been reported to decrease thymidine kinase activity in spleen and tumor cells[18]. TK mRNA levels are also decreased following irradiation [19].…”

Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008

“…Radiation can quickly cause upregulation of thymidine kinase (Tk), involved in DNA repair. Inhibition of Tk by 5FU or gemcitabine is probably an important aspect of their interaction with radiation (83). Since even sublethal doses of 5FU are powerful radiosensitizers, dose de-escalation of either radiation or drug may be possible, and warrant study.…”