Cobalamin and folate binding proteins in human tumour tissue.

Sheppard, K; Bradbury, Dawn A.; Davies, J. M.; Ryrie, D R

doi:10.1136/jcp.37.12.1336

Cited by 11 publications

(7 citation statements)

References 19 publications

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“…Collins et al described an increased tumor uptake with optimized visualization for patients with high blood-pool levels of cobalamin before injection of 111 In-DAC and suggested that the saturation of blood-pool transport protein could increase the tumor uptake (20). Our first 2 patients investigated without cobalamin predose confirmed a high blood-pool activity over 24 h, most likely due to tracer binding to apo-haptocorrin, which amounts to about 22 mg of blood per liter (0.3 nmol/L) in a normal healthy individual (21). Considering the small amount of PAMA-cobalamin injected per patient (;0.1-0.2 nmol), it is not surprising that most of the radiotracer bound to circulating haptocorrin.…”

Section: Discussionmentioning

confidence: 89%

Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative

et al. 2013

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Targeting cancer cells with vitamin B12 (cobalamin) is hampered by unwanted physiologic tissue uptake mediated by transcobalamin. Adhering to good manufacturing practice, we have developed a new 99m Tc-cobalamin derivative ( 99m Tc(CO) 3 -[(4-amido-butyl)-pyridin-2-yl-methyl-amino-acetato] cobalamin, 99m Tc-PAMAcobalamin). The derivative shows no binding to transcobalamin but is recognized by haptocorrin, a protein present in the circulation and notably expressed in many tumor cells. In this prospective study, we investigated cancer-specific uptake of 99m Tc-PAMAcobalamin in 10 patients with various metastatic tumors. Methods: Ten patients with biopsy-proven metastatic cancer were included. Dynamic imaging was started immediately after injection of 300-500 MBq of 99m Tc-PAMA-cobalamin, and whole-body scintigrams were obtained at 10, 30, 60, 120, and 240 min and after 24 h. The relative tumor activity using SPECT/CT over the tumor region after 4 h was measured in comparison to disease-free lung parenchyma. Patients 3-10 received between 20 and 1,000 mg of cobalamin intravenously before injection of 99m Tc-PAMA-cobalamin. The study population comprised 4 patients with adenocarcinomas of the lung, 3 with squamous cell carcinomas of the hypopharyngeal region, 1 with prostate adenocarcinoma, 1 with breast, and 1 with colon adenocarcinoma. Results: The median age of the study group was 61 6 11 y. Six of 10 patients showed positive tumor uptake on 99m Tc-PAMA-cobalamin whole-body scintigraphy. The scan was positive in 1 patient with colon adenocarcinoma, in 3 of 4 lung adenocarcinomas, in 1 of 3 hypopharyngeal squamous cell carcinomas, and in 1 breast adenocarcinoma. Renal uptake was between 1% and 3% for the left kidney. Predosing with cobalamin increased the tumor uptake and improved blood-pool clearance. The best image quality was achieved with a predose of 20-100 ug of cold cobalamin. The mean patient dose was 2.7 6 0.9 mSv/patient. Conclusion: To our knowledge, we report for the first time on 99m Tc-PAMA-cobalamin imaging in patients with metastatic cancer disease and show that tumor targeting is feasible.

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Section: Discussionmentioning

confidence: 89%

Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative

et al. 2013

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“…TCN1 participates in vitamin B12 homeostasis together with another two vitamin B12 binding proteins (intrinsic factor and TCN2) 38. Elevated serum levels of vitamin B12 and TCN1 have been reported in patients with cancers 18, 21, 39. Furthermore, it has been well elucidated the associations between high serum levels of vitamin B12 and malignant hematological diseases such as chronic myeloid leukemia and acute leukemia and the pathogenesis involves release of TCN1 by proliferating granulocytes 36, 37, 40.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms implicated in the genesis of elevated serum vitamin B12, as addressed above, might be due to a decrease in hepatic clearance or an increase in TCN1 production 36 , 40 . Monitoring of serum vitamin B12 and TCN1 may be of specific clinical value in both the initial and subsequent evaluation of response to treatment in patients associated with increased vitamin B12-binding protein synthesis 21 . In addition, rapidly dividing cells such as cancer cells need certain vitamins including vitamin B12, folic acid, biotin and riboflavin for tumor growth and survival 48 , 49 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Transcobalamin 1 is an Independent Negative Prognosticator in Rectal Cancers Receiving Concurrent Chemoradiotherapy

Lee¹,

Wei²,

Tian³

et al. 2017

J. Cancer

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Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) is an increasingly common therapeutic strategy for locally advanced rectal cancer, but stratification of risk and final outcomes remain a major challenge. Transcobalamin 1 (TCN1), a vitamin B12 (cobalamin)-binding protein, regulates cobalamin homeostasis. High expression of TCN1 have been reported in neoplasms such as breast cancer and hepatocellular carcinoma. However, little is known about the relevance of TCN1 to rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of TCN1 expression in patients with rectal cancer following neoadjuvant CCRT.Methods: Through data mining from a published transcriptome of rectal cancers (GSE35452), we identified upregulation of TCN1 gene as the most significantly predicted poor response to CCRT among ion transport-related genes (GO:0006811). We evaluated TCN1 immunohistochemistry and performed an H-score analysis on endoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery. Expression levels of TCN1 were further correlated with clinicopathologic features, therapeutic response, tumor regression grade (TRG) and survivals including metastasis-free survival (MeFS), disease-specific survival (DSS) and recurrent-free survival (LRFS).Results: TCN1 overexpression was significantly related to advanced post-treatment tumor (T3, T4; p<0.001) and nodal status (N1, N2; p<0.001), vascular invasion (p=0.003) and inferior tumor regression grade (p < 0.001). In survival analyses, TCN1 overexpression was significantly associated with shorter DSS (p<0.0001), MeFS (p=0.0002) and LRFS (p=0.0001). Furthermore, it remained an independent prognosticator of worse DSS (p=0.002, hazard ratio=3.344), MeFS (p=0.021, hazard ratio=3.015) and LRFS (p=0.037, hazard ratio=3.037) in the multivariate comparison.Conclusion: Overexpression of TCN1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT, justifying the potential prognostic value of TCN1 in rectal cancer receiving CCRT.

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“…High expression of TCI on the tumor would help to satisfy the increased demand for cobalamin. High levels of the cobalamin-binding protein TCI have been described in malignancies such as cancer of the breast, colon, pancreas, lung, liver, kidney, salivary gland, stomach, and endometrial adenocarcinoma (35)(36)(37)(38)(39)(40). It has been suggested that tumors are capable of producing TCI (41, 42) themselves.…”

Section: Discussionmentioning

confidence: 99%

New Derivatives of Vitamin B12 Show Preferential Targeting of Tumors

Treichler²,

et al. 2008

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Rapidly growing cells show an increased demand for nutrients and vitamins. The objective of our work is to exploit the supply route of vitamin B12 to deliver new derivatives of this vital vitamin to hyperproliferative cells. To date, radiolabeled ( 57 Co and 111 In) vitamin B12 derivatives showed labeling of tumor tissue but also undesired high accumulation of radioactivity in normal tissue. By abolishing the interaction of a tailored vitamin B12 derivative to its transport protein transcobalamin II and therefore interrupting transcobalamin II receptor and megalin mediated uptake in normal tissue, preferential accumulation of a radiolabeled vitamin in cancer tissue could be accomplished. We identified transcobalamin I on tumors as a possible new receptor for this preferential accumulation of vitamin-mediated targeting. The low systemic distribution of radioactivity and the high tumor to blood ratio opens the possibility of a more successful clinical application of vitamin B12 for imaging or therapy.

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Cobalamin and folate binding proteins in human tumour tissue.

Cited by 11 publications

References 19 publications

Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative

Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative

Overexpression of Transcobalamin 1 is an Independent Negative Prognosticator in Rectal Cancers Receiving Concurrent Chemoradiotherapy

New Derivatives of Vitamin B12 Show Preferential Targeting of Tumors

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Cobalamin and folate binding proteins in human tumour tissue.

Cited by 11 publications

References 19 publications

Tumor Imaging in Patients with Advanced Tumors Using a New 99mTc-Radiolabeled Vitamin B12 Derivative

Tumor Imaging in Patients with Advanced Tumors Using a New 99mTc-Radiolabeled Vitamin B12 Derivative

Overexpression of Transcobalamin 1 is an Independent Negative Prognosticator in Rectal Cancers Receiving Concurrent Chemoradiotherapy

New Derivatives of Vitamin B12 Show Preferential Targeting of Tumors

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Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative

Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative