Response of choline metabolites to docetaxel therapy is quantified in vivo by localized (31)P MRS of human breast cancer xenografts and in vitro by high-resolution (31)P NMR spectroscopy of cell extracts.
Choline-containing compounds (CCCs) are elevated in breast cancer, and detected in vivo by the (1)H MRS total choline (tCho) resonance (3.25 ppm) and the (31)P MRS phosphomonoester (PME) resonance (3.8 ppm). Both the tCho and PME resonances decrease early after initiation of successful therapy. The single major component of these composite resonances, phosphocholine (PCho), also responds to therapy by decreasing. The ability to resolve and quantify PCho in vivo would thus increase the sensitivity of this biomarker for early detection of therapeutic response. Herein, the in vivo resolution and quantification of PCho is reported in human mouse xenograft tumors of the human breast cancer cell lines MCF-7 and MDA-mb-231. Significant decreases in tumor PCho are observed within 2 to 4 d posttreatment with the antimicrotubule drug, docetaxel. To determine whether these decreases are a general tumor response or an intracellular metabolic response, high-resolution NMR spectroscopy was performed on extracts of cells treated with docetaxel. Significant decreases in intracellular PCho and increases in glycerophosphocholine (GPC) were observed. These decreases are coincident with other tumor and cellular responses such as tumor growth delay (TGD), cell-cycle arrest, and modes of cell death such as mitotic catastrophe, necrosis, and apoptosis, with mitotic catastrophe predominating.
Morse
David L
DL
The University of Arizona, BIO5 Institute, Arizona Cancer Center, Tucson, Arizona 85724, USA. dmorse@email.arizona.edu
Raghunand
Natarajan
N
Sadarangani
Pooja
P
Murthi
Shiva
S
Job
Constantin
C
Day
Sam
S
Howison
Christine
C
Gillies
Robert J
RJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004797:Enzyme-Linked Immunosorbent Assay; D005997:Glycerylphosphorylcholine / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D010759:Phosphorus Isotopes; D010767:Phosphorylcholine / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; D010759:Phosphorus Isotopes; D043823:Taxoids; D010767:Phosphorylcholine; D000077143:Docetaxel; D005997:Glycerylphosphorylcholine