What is Thymidine Kinase 1?

Thymidine kinase 1 (TK1) is an essential enzyme in the DNA salvage pathway, and it is responsible for restoring thymidine activities for DNA synthesis and repair³. Thymidine is brought into the cell from the extracellular environment through assisted diffusion.

Once inside, TK1 transforms it into its monophosphate form (dTMP) in the cytosol. Deoxythymidine triphosphate (dTTP), necessary for DNA replication, is produced by additional cytosolic enzymes after converting dTMP. As an aid in DNA synthesis and transcription, nuclear pore complexes passively transfer these nucleotides, which include dTT, into the nucleus⁴.

Although the de novo pathway also plays a role in nucleotide regeneration, its anabolic nature and higher energy requirements make it less preferred. On the other hand, the salvage pathway, which TK1 mainly mediates, is energetically more efficient and is usually the cell’s favored method of producing dTTP.

Nevertheless, it is crucial to note that while TK1 is essential to this function, cells can produce dTTP through other mechanisms, so its presence is not necessary for cell viability⁵.

Thymidine kinase 1 (TK1) is necessary for DNA replication to proceed during the S phase of the cell cycle. In the cell cycle, there are four primary stages⁶:

• G1 Phase: This is the first growth phase, during which the cell increases in size, synthesizes proteins, and prepares for DNA replication.
• S Phase: In this synthesis phase, DNA replication occurs, which results in the duplication of the genetic material.
• G2 Phase: Following DNA replication, the cell grows further and prepares for cell division.
• M Phase: The mitotic phase where the cell divides into two daughter cells, each containing an identical set of chromosomes.

TK1 activities significantly increase to facilitate the synthesis of new DNA strands during the S phase, when DNA replication is at its highest³. Deoxythymidine triphosphate (dTTP), an essential building block for DNA molecules, can be produced quickly because of this increase in TK1 activity. Rapid cell proliferation is made possible by high amounts of TK1, which promotes effective DNA replication.

TK1 activities are, therefore, correlated with the rate of cell division and growth, making it a valuable marker for cell proliferation. Comprehending the function of TK1 in the cell cycle offers a significant understanding of the processes that propel cell growth and has consequences for numerous physiological and pathological phenomena, such as the emergence of cancer.

Thymidine Kinase 1 (TK1) has emerged as a promising biomarker for a list of solid tumors, including breast cancer, due to its association with cell proliferation and differential expression in cancerous tissues compared to healthy ones. A blood-based biomarker, enzyme activity, or level testing can be done with a small sample of blood drawn from patients, proving to be relatively non-invasive.

Research has repeatedly demonstrated that tissue and blood samples from breast cancer patients had higher activities of TK1 than samples from healthy people. This heightened expression reflects the increased demand for DNA synthesis and replication in rapidly dividing cancer cells⁷.

In the context of diagnosis, TK1 is a valuable tool for distinguishing between cancerous and non-cancerous conditions. Additionally, TK1 activities have demonstrated prognostic significance, with higher pre-treatment activities correlating with poorer prognosis and more aggressive disease progression³. This association underscores TK1’s potential as a predictive indicator, which aids clinicians in predicting patient outcomes and tailoring treatment strategies accordingly.

Elevated TK activities in serum or plasma have been linked to a poorer prognosis in several cancer types, including metastatic breast cancer. Studies have shown that higher TK activities correlate with more aggressive tumor behavior, increased risk of metastasis, and decreased survival rates among cancer patients⁸.

TK activities can also be a marker for treatment response and disease monitoring. In cancer therapy, a decrease in TK activities following treatment may indicate a positive response to therapy, while persistently elevated activities could signal treatment resistance.

Beyond breast cancer, Thymidine kinase 1 (TK1) exhibits implications in various other cancer types, which include leukemia, lymphoma, and lung cancer. Elevated TK1 activities have been observed in patients with leukemia and lymphoma, which reflects the increased rate of cell proliferation characteristic of these hematological malignancies. TK1 activities have also been linked to leukemia prognosis and disease severity; greater activities are linked to more aggressive types of illness and worse outcomes³.

Leukemia

Leukemia is a type of cancer that affects the body’s tissues that form blood, such as the lymphatic system and bone marrow. It is characterized by rapid growth of aberrant white blood cells⁹. It has been noted that TK1 overexpression occurs early in the development of leukemia. Serum TK1 activity monitoring can provide information about the course and prognosis of the condition³.

Lymphoma

Lymphoma is a class of blood and lymph malignancies known as lymphomas that arise from lymphocytes, a subset of white blood cells. They mainly affect the lymphatic system, which is essential to the body’s immune response¹⁰. TK1 has shown potential as a diagnostic and prognostic marker, with elevated activities detected in Hodgkin’s and non-Hodgkin’s lymphoma patients. Monitoring TK1 activities during treatment can provide valuable insights into treatment response and disease progression, which guides therapeutic decisions and optimizes patient care¹¹.

Lung cancer

With 2.5 million new cases globally in 2022, lung cancer is the most common type of cancer and accounts for 12.4% of all cancer cases worldwide¹². Thymidine kinase (TK) has been identified as a noteworthy prospect among the biomarkers suggested as new diagnostic instruments for lung cancer¹³. While TK1’s role in lung cancer is still being explored, recent advances suggest it could serve as a diagnostic tool and prognostic factor. Further research is needed to fully understand its implications for lung cancer¹⁴.

Ovarian cancer

Ovarian cancer is characterized by the growth of cancer cells that form in the ovaries within the female reproductive system¹⁵. Thymidine kinase (TK) has been explored as a potential biomarker for ovarian cancer. Elevated activities of TK1 have been found in ovarian cancer tissues and serum samples. Studies have suggested that TK1 expression correlates with tumor stage, grade, and overall survival in ovarian cancer patients. Moreover, TK1 activities may have predictive value for chemotherapy response and disease recurrence in ovarian cancer¹⁶.

Overall, TK1’s unique ability to accurately reflect DNA synthesis rates during the S phase makes it a promising candidate for assessing cancer recurrence, treatment monitoring, and survival. As researchers delve deeper into its regulation and connections, TK1 remains a valuable biomarker.

Thymidine kinase 1 (TK1) is an important biomarker in breast cancer management, reflecting the proliferation rate of cancer cells. TK is primarily active in the G1/S-phase of the cell cycle, and it diffuses from proliferating tumor cells to the bloodstream. Increased cell proliferation is a hallmark of neoplasia, and serum TK-activity (TKa) measurements have shown changes in levels during progression and treatment of HR+ metastatic breast cancer.

Monitoring TKa can thus provide valuable insights into the disease’s progression and patient treatment response, which enables healthcare providers to tailor therapies to individual patients’ needs. By undergoing TK1 testing alongside other methods, patients with breast cancer can potentially benefit from personalized treatment plans guided by their unique TK1 activities¹⁷.

TKa can be measured by the DiviTum® TKa test, a monitoring tool designed to measure TK activity in blood samples. This produces a DiviTum TK activity score, which can be compared to a fixed cut-off value. While the test is not indicated as a standalone test to determine disease outcome, nor to suggest or infer patient prognosis, it can provide valuable information regarding the disease proliferative status in mBC patients who are hormone receptor-positive and postmenopausal¹⁸.

The test is intended for professional use by laboratory technologists and the results should be interpreted by a qualified physician. By tracking TKa over time along with the appropriate monitoring methods, doctors can evaluate treatment efficacy and make well-informed judgments about therapy modifications for personalized medical plans. This can result in targeted treatment strategies, potentially improving patient outcomes and quality of life.

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2. Bergqvist, Mattias, et al. “Thymidine kinase activity levels in serum can identify HR+ metastatic breast cancer patients with a low risk of early progression (SWOG S0226).” Biomarkers. Volume 28, 3, pp. 313-322. Published online 29 January 2023. https://www.tandfonline.com/doi/full/10.1080/1354750X.2023.2168063
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6. Hartwell, Leland H, Tim Hunt, Paul Nurse. “Cell cycle.” Britannica. Updated 28 March 2024. https://www.britannica.com/science/cell-cycle
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8. Larsson, Anna-Maria. “Serial evaluation of serum thymidine kinase activity is prognostic in women with newly diagnosed metastatic breast cancer.” Sci Rep. Volume 10: 4484. Published online 11 March 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066186/
9. “What is leukemia?” UPMC Hillman Cancer Center. https://hillman.upmc.com/cancer-care/blood/types/leukemia
10. Ansell, Stephen, MD. “Lymphoma.” Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/lymphoma/symptoms-causes/syc-20352638
11. Kiran Kumar, J., et al. “A clinical evaluation of the TK 210 ELISA in sera from breast cancer patients demonstrates high sensitivity and specificity in all stages of disease.” Tumor Biology. Volume 37, pp. 11937-11945. Published 14 April 2016. https://link.springer.com/article/10.1007/s13277-016-5024-z
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13. Holdenrieder, Stefan, et al. “Clinical Relevance of Thymidine Kinase for the Diagnosis, Therapy Monitoring and Prognosis of Non-Operable Lung Cancer.” Anticancer Research. Volume 30, 5. 2010, p. 1855, http://ar.iiarjournals.org/content/30/5/1855.abstract
14. Malvi, Parmanand, et al. “Loss of Thymidine Kinase 1 Inhibits Lung Cancer Growth and Metastatic Attributes by Reducing GDF15 Expression.” PLoS Genetics. Volume Published 7 October 2019. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008439
15. “Ovarian cancer.” Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/ovarian-cancer/symptoms-causes/syc-20375941
16. Wang, Jianjun, et al. “Thymidine kinase 1 expression in ovarian serous adenocarcinoma is superior to Ki-67: A new prognostic biomarker. “Tumour Biology. Volume 39, 6. June 2017. https://pubmed.ncbi.nlm.nih.gov/28651488/
17. “Instructions for Use DiviTum® TKa U.S.” Biovica International AB. Data on file.
18. “Clinical Benefits (EU) – DiviTum® TKa.” DiviTum® TKa. 30 June 2023. https://divitum.com/about-the-test/clinical-benefits-eu/