Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models

MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (col...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006, Vol.66 (1), p.427-434
Main Authors: AL-SAFFAR, Nada M. S, TROY, Helen, CHUNG, Yuen-Li, RAMIREZ DE MOLINA, Ana, JACKSON, Laura E, MADHU, Basetti, GRIFFITHS, John R, LEACH, Martin O, WORKMAN, Paul, LACAL, Juan C, JUDSON, Ian R
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Biomarkers, Tumor - metabolism
Breast Neoplasms - drug therapy
Breast Neoplasms - enzymology
Breast Neoplasms - metabolism
Butanes - pharmacology
Carcinoma - drug therapy
Carcinoma - enzymology
Chemotherapy
Choline Kinase - antagonists & inhibitors
Colonic Neoplasms - drug therapy
Colonic Neoplasms - enzymology
Colonic Neoplasms - metabolism
Enzyme Inhibitors - pharmacology
Genital system. Mammary gland
HT29 Cells
Humans
Investigative techniques, diagnostic techniques (general aspects)
Medical sciences
Mice
Mice, Nude
Nuclear Magnetic Resonance, Biomolecular - methods
Pharmacology. Drug treatments
Phosphorus
Phosphorylcholine - metabolism
Protons
Pyridinium Compounds - pharmacology
Radiodiagnosis. Nmr imagery. Nmr spectrometry
Xenograft Model Antitumor Assays
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Summary:MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells were examined by proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment with MN58b both in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P < 0.05) was observed in vitro in both cell lines after MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDA-MB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58b treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels (measured by MRS) and choline kinase activities (r2 = 0.95, P = 0.0008) following MN58b treatment. Phosphomonoesters also decreased significantly (P < 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. 31P-MRS and 1H-MRS of tumor extracts showed a significant decrease in phosphocholine (P < or = 0.05). Inhibition of choline kinase by MN58b resulted in altered phospholipid metabolism both in cultured tumor cells and in vivo. Phosphocholine levels were found to correlate with choline kinase activities. The decrease in phosphocholine, total choline, and phosphomonoesters may have potential as noninvasive pharmacodynamic biomarkers for determining tumor response following treatment with choline kinase inhibitors.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-1338