Qimin He

Bio: Qimin He is an academic researcher from Karolinska University Hospital. The author has contributed to research in topics: Thymidine kinase 1 & Cancer. The author has an hindex of 3, co-authored 3 publications receiving 149 citations.

Thymidine kinase 1 in serum predicts increased risk of distant or loco-regional recurrence following surgery in patients with early breast cancer.

Abstract: Background The prognostic value of the concentration of serum thymidine kinase 1 (S-TK1) with regard to recurrence in low risk breast cancer patients, 3 months after surgery was evaluated. Patients and methods The concentration of S-TK1 in serum was determined in 120 breast cancer patients at the time of surgery and in 67 patients 3 months after surgery, by anti-TK1 chicken IgY antibody, using a dot-blot immuno-assay. The S-TK1 concentration was compared with the serological activity of thymidine kinase (STK) and of carbohydrate antigen (CA 15-3). Results A statistically significant trend (unadjusted) was found for recurrence (distant or loco-regional) in patients with a higher S-TK1 concentration, as compared with patients with a lower S-TK1 concentration. A multivariate analysis gave the same results. The hazard rate ratio for developing distant and/or loco-regional recurrence in patients with a higher S-TK1 concentration was about six to seven times higher than in patients with a lower S-TK1 concentration. Conclusion Our results indicate that the S-TK1 concentration is higher in patients developing distant and/or loco-regional recurrence 3 months post-surgery.

Concentration of thymidine kinase 1 in serum (S-TK1) is a more sensitive proliferation marker in human solid tumors than its activity.

Abstract: Activity of thymidine kinase 1 in serum (STK) is a useful marker for leukaemia and lymphoma, but not for solid tumors. We investigate thymidine kinase 1 concentration in serum (S-TK1) as a potential tumor marker. S-TK1 concentration and STK activity levels were determined in 9 human malignant diseases (breast, gastric, rectal, colorectal, lung, brain cancer, hepatoma, lymphoma, leukaemia) and in benign and non-cancerous diseases, representing 850 preoperative cases. Healthy volunteers (n=43) were used as positive controls. S-TK1 concentration was determined by ECL dot blot assay and STK activity levels by an RIA assay. S-TK1 concentrations and STK activity levels in preoperative malignant patients were significantly higher than in healthy individuals, in patients with benign tumors and in those with non-cancerous diseases. Significant correlations between concentration and activity level were only found in healthy individuals, in patients with benign tumors, and in some patients with malignancies, i.e. leukaemia, and breast and gastric cancers. About 90-95 percent of the malignant patients showed S-TK1 concentrations above those of the healthy controls. The corresponding value for STK activity was about 75 percent. When sera from malignant patients were diluted with sera from healthy individuals, S-TK1 concentrations and STK activity levels decreased more than expected. This indicates the presence of a compound (or compounds) in the serum of healthy individuals that destabilises S-TK1. We conclude that S-TK1 concentration is a more sensitive tumor marker in solid malignancies than is STK activity.

Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas.

Abstract: Thymidine kinase 1 (TK1), an enzyme involved in the synthesis of precursors for DNA, and thus proliferation dependent, has been suggested as a good tumour marker. We have recently developed poly/monoclonal antibodies against TK1, which proved useful for diagnostics in both serum and immunohistochemistry of cancer patients. The anti-TK1 monoclonal antibodies (mAbs) 1D11 and 1E3 were characterized by Western blot, immunoprecipitation and flow cytometry. TK1 mAbs and Ki-67 mAb were then used for immunohistochemistry staining of tumour sections from 54 patients with ductal infiltrated breast carcinoma. Results showed the relative number of patients with positively stained tumours for TK1 (mAb 1D11) and for Ki-67 (mAb MIB-1) were 47 and 41%, respectively, significantly related (p=0.007). Combination of TK1 mAbs 1D11 and 1E3 increased this number to 56%, due to detection of a significantly higher number of patients with grade 2 tumours. Patients with stage II and grade 2 tumours showed significantly higher TK1 staining when compared to stage I and grade 1. Ki-67 staining was significantly higher in stage III and grade 3. The tumours only stained for TK1 represented higher stages and grades, while tumours staining only for Ki-67 were of lower stages and grades. Combining TK1 and Ki-67 increased the number of patients with positively stained tumours to 69%. In conclusion, TK1 is a reliable marker for identification of patients with grade 2 tumours. The highest number of patients with positively stained tumours were obtained when both TK1 and Ki-67 markers were used.

Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods.

Abstract: There is an unmet need to develop imaging methods for the early and objective assessment of breast tumors to therapy. 3′-Deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]FLT)–positron emission tomography represents a new approach to imaging thymidine kinase activity, and hence, cellular proliferation. We compared graphical, spectral, and semiquantitative analytic methodologies for quantifying [ 18 F]FLT kinetics in tumor and normal tissue of patients with locally advanced and metastatic breast cancer. The resultant kinetic parameters were correlated with the Ki-67 labeling index from tumor biopsies. [ 18 F]FLT accumulation was detected in primary tumor, nodal disease, and lung metastasis. In large tumors, there was substantial heterogeneity in regional radiotracer uptake, reflecting heterogeneity in cellular proliferation; radiotracer uptake in primary tumors also differed from that of metastases. [ 18 F]FLT was metabolized in patients to a single metabolite [ 18 F]FLT-glucuronide. Unmetabolized [ 18 F]FLT accounted for 71.54 ± 1.50% of plasma radioactivity by 90 minutes. The rate constant for the metabolite-corrected net irreversible uptake of [ 18 F]FLT (K i ) ranged from 0.6 to 10.4 × 10 −4 and from 0 to 0.6 × 10 −4 mL plasma cleared/s/mL tissue in tumor (29 regions, 15 patients) and normal tissues, respectively. Tumor K i and fractional retention of radiotracer determined by spectral analysis correlated with Ki-67 labeling index ( r = 0.92, P r = 0.92, P 18 F]FLT-positron emission tomography is a promising clinical tool for imaging cellular proliferation in breast cancer, and is most predictive when analyzed by graphical and spectral methods.

Thymidine kinase 1 in serum predicts increased risk of distant or loco-regional recurrence following surgery in patients with early breast cancer.

Abstract: Background The prognostic value of the concentration of serum thymidine kinase 1 (S-TK1) with regard to recurrence in low risk breast cancer patients, 3 months after surgery was evaluated. Patients and methods The concentration of S-TK1 in serum was determined in 120 breast cancer patients at the time of surgery and in 67 patients 3 months after surgery, by anti-TK1 chicken IgY antibody, using a dot-blot immuno-assay. The S-TK1 concentration was compared with the serological activity of thymidine kinase (STK) and of carbohydrate antigen (CA 15-3). Results A statistically significant trend (unadjusted) was found for recurrence (distant or loco-regional) in patients with a higher S-TK1 concentration, as compared with patients with a lower S-TK1 concentration. A multivariate analysis gave the same results. The hazard rate ratio for developing distant and/or loco-regional recurrence in patients with a higher S-TK1 concentration was about six to seven times higher than in patients with a lower S-TK1 concentration. Conclusion Our results indicate that the S-TK1 concentration is higher in patients developing distant and/or loco-regional recurrence 3 months post-surgery.

The role of thymidine kinase in cancer diseases.

Abstract: Thymidine kinase 1 (TK 1-fetal) is a cell cycle-dependent marker that increases dramatically during the S-phase of the cell cycle. In this review, the authors discuss serum levels of thymidine kinase in a variety of neoplasias. Determination of thymidine kinase helps to monitor the follow-up of solid tumours and haematological malignancies as well as indicating the efficacy of adjuvant and palliative chemotherapy. Elevated levels of thymidine kinase must always be interpreted together with a detailed knowledge of the patient's condition because nonspecific elevations of serum levels (inflammatory and autoimmune diseases) must be excluded.

In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography.

Abstract: Histone deacetylase inhibitors (HDACI) are emerging as growth inhibitory compounds that modulate gene expression and inhibit tumor cell proliferation. We assessed whether 3′-deoxy-3′-[ 18 F]fluorothymidine–positron emission tomography ([ 18 F]FLT-PET) could be used to noninvasively measure the biological activity of a novel HDACI LAQ824 in vivo . We initially showed that thymidine kinase 1 (TK1; EC2.7.1.21), the enzyme responsible for [ 18 F]FLT retention in cells, was regulated by LAQ824 in a drug concentration–dependent manner in vitro . In HCT116 colon carcinoma xenograft–bearing mice, LAQ824 significantly decreased tumor [ 18 F]FLT uptake in a dose-dependent manner. At day 4 of treatment, [ 18 F]FLT tumor-to-heart ratios at 60 minutes (NUV60) were 2.16 ± 0.15, 1.86 ± 0.13, and 1.45 ± 0.20 in vehicle, and 5 and 25 mg/kg LAQ824 treatment groups, respectively ( P ≤ 0.05). LAQ825 at 5 mg/kg also significantly reduced both TK1 levels and [ 18 F]FLT uptake at day 10 but not at day 2 ( P ≤ 0.05). [ 18 F]FLT NUV60 correlated significantly with cellular proliferation ( r = 0.68; P = 0.0019) and was associated with drug-induced histone H4 hyperacetylation. Of interest to [ 18 F]FLT-PET imaging, both TK1 mRNA copy numbers and protein levels decreased in the order vehicle >5 mg/kg LAQ824 > 25 mg/kg LAQ824, providing a rationale for the use of [ 18 F]FLT-PET in this setting. We also observed increases in Rb hypophosphorylation and p21 levels, factors that could have contributed to the alteration in TK1 transcription in vivo . In conclusion, we have shown the utility of [ 18 F]FLT-PET for monitoring the biological activity of the HDACI, LAQ824. Drug-induced changes in tumor [ 18 F]FLT uptake were due, at least in part, to reductions in TK1 transcription and translation. (Cancer Res 2006; 66(15): 7621-9)