Kerry T. Holmes

Proteolipid identified by magnetic resonance spectroscopy in plasma of a patient with borderline ovarian tumour

Magnetic resonance spectroscopy (MRS) can identify abnormal lipoproteins in the plasma of patients with premalignant and malignant tumours. Proteolipid complexes, 8-11 nm and 25-28 nm in size, were isolated from the plasma of a patient with a borderline ovarian tumour. These complexes, which generated a characteristically long MRS T2 relaxation value (greater than 400 ms), were disrupted by ribonuclease. None of the conventional lipoproteins had a T2 value above 160 ms. Chemical analysis of the proteolipid complexes showed a 20% glycolipid component, and MRS identified a fucosylated molecule as the origin of the long T2 value. 9 months after resection of all tumour, a visible lipoprotein band, possibly lipoprotein (a), persisted in the plasma but neither the long T2 relaxation value nor the 8-11 nm or 25-28 nm particles were present. The long T2 relaxation value in the MRS profile, found in isolated proteolipid and unfractionated plasma and serum of other patients with carcinoma of the ovary and colon, provides a non-invasive method of assaying for cancer.

Lipid domain in cancer cell plasma membrane shown by 1H NMR to be similar to a lipoprotein

Human blood lipoproteins have been characterised by 1H NMR methods and chemical analysis, and comparisons made with the properties of the triglyceride‐rich plasma membrane domain found in cancer cells. By means of selective and non‐selective T 1 experiments, the lipids in HDL and LDL are shown to be in diffusive exchange. In contrast, the lipids ofchylomicra and VLDL do not exhibit lipid diffusion, and therefore resemble the neutral lipids of cancer cell plasma membranes. 2D scalar correlated NMR (COSY) spectra of cancer cells or solid tumours are similar to those obtained from VLDL and LDL. The long T 2 relaxation value observed for neutral lipid methylenes in metastatic cancer cells (>00 ms) was not observed for any of the 4 lipoproteins studied. None of the lipoprotein classes gave a T 2 longer than 250 ms.

Magnetic resonance studies of murine macrophages. Proliferation is not a prerequisite for acquisition of an 'activated' high resolution spectrum.

Proton magnetic resonance spectroscopy (1H-MRS) was used to investigate the membranes of macrophages activated by γ-interferon in vitro and by Listeria monocytogenes in vivo. We report the appearance with activation, of a high resolution spectrum indistinguishable from that found in activated T and B cells and embryonic and malignant cell types previously studied. We furthermore show that proliferation is not a prerequisite for the appearance of this activated spectrum. This supports the idea that membrane ‘activation’ in all cells, irrespective of origin, may be accompanied by similar architectural changes, and suggests that a common pathway exists for the activation of cell membranes of the immune system, possibly important in the acquisition of increased motility. The use of 1H-MRS as a non-invasive tool for analysis of activation is discussed.Proton magnetic resonance spectroscopy (1H‐MRS) was used to investigate the membranes of macrophages activated by γ‐interferon in vitro and by Listeria monocytogenes in vivo. We report the appearance with activation, of a high resolution spectrum indistinguishable from that found in activated T and B cells and embryonic and malignant cell types previously studied. We furthermore show that proliferation is not a prerequisite for the appearance of this activated spectrum. This supports the idea that membrane ‘activation’ in all cells, irrespective of origin, may be accompanied by similar architectural changes, and suggests that a common pathway exists for the activation of cell membranes of the immune system, possibly important in the acquisition of increased motility. The use of 1H‐MRS as a non‐invasive tool for analysis of activation is discussed.

NMR Analysis of Cancer Cells

Nuclear magnetic resonance has been used to study cancer cells for almost two decades. Much confusion has been generated in the past due to heterogeneity of cell populations and to differences in sample preparation. Improved instrumentation and a better understanding of the complex growth patterns of cancer cells has led to more accurate measurements and to better control of samples. A brief overview of the NMR method is presented.

Cell surface involvement in cancer metastasis: an NMR study

NMR spectroscopy is one of the few techniques which has the sensitivity to detect subtle changes to the surface chemistry of cells. It has previously been demonstrated that high resolution 1H NMR methods can distinguish tumour cells with the capacity to metastasise and this information appears to arise from a type of proteolipid in or attached to the plasma membrane. Here we report that the 1H NMR signal, which we have used to identify metastatic cells in rat tumours, is significantly reduced in intensity after cultured cells are treated with trypsin/EDTA. The long T 2 relaxation value (⪢ 350 ms) observed in metastatic cells is absent after enzyme treatment. 2D scalar correlated NMR (COSY) spectra of these treated cells show that a cross peak normally associated with malignancy and metastatic disease is markedly reduced. These findings indicate that the plasma membrane lipid particle which generates the high resolution spectrum is directly affected by trypsin/EDTA. Alterations to the cell surface properties were also demonstrated in vivo since reduced numbers of metastases were observed in animals injected with enzyme‐treated cells. The correlation between the absence of a long T 2 relaxation value and the diminished numbers of metastases in animals suggests that the plasma membrane particle is involved in the metastatic process.

Research lettersMagnetic resonance studies of murine macrophages: Proliferation is not a prerequisite for acquisition of an ‘activated’ high resolution spectrum

Proton magnetic resonance spectroscopy (1H-MRS) was used to investigate the membranes of macrophages activated by γ-interferon in vitro and by Listeria monocytogenes in vivo. We report the appearance with activation, of a high resolution spectrum indistinguishable from that found in activated T and B cells and embryonic and malignant cell types previously studied. We furthermore show that proliferation is not a prerequisite for the appearance of this activated spectrum. This supports the idea that membrane ‘activation’ in all cells, irrespective of origin, may be accompanied by similar architectural changes, and suggests that a common pathway exists for the activation of cell membranes of the immune system, possibly important in the acquisition of increased motility. The use of 1H-MRS as a non-invasive tool for analysis of activation is discussed.Proton magnetic resonance spectroscopy (1H‐MRS) was used to investigate the membranes of macrophages activated by γ‐interferon in vitro and by Listeria monocytogenes in vivo. We report the appearance with activation, of a high resolution spectrum indistinguishable from that found in activated T and B cells and embryonic and malignant cell types previously studied. We furthermore show that proliferation is not a prerequisite for the appearance of this activated spectrum. This supports the idea that membrane ‘activation’ in all cells, irrespective of origin, may be accompanied by similar architectural changes, and suggests that a common pathway exists for the activation of cell membranes of the immune system, possibly important in the acquisition of increased motility. The use of 1H‐MRS as a non‐invasive tool for analysis of activation is discussed.

Vinblastine sensitivity of leukaemic lymphoblasts modulated by serum lipid

The high‐resolution proton magnetic resonance spectrum of leukaemic lymphoblasts is characteristic of neutral lipid in an isotropic environment. When such lymphoblasts are selected for resistance to the anticancer drug vinblastine, the intensity of this spectrum increases with increasing drug resistance. A reversal of this trend can be achieved by growing cells in delipidated serum, whereby lipid spectrum and drug resistance are diminished. However, both can be restored by subsequent regrowth in normal medium. Thus, although detectable genetic changes accompany the development of vinblastine resistance, the expression of these changes can be modulated by environmental lipid.

Metabolic control in diabetes mellitus, beta adrenoceptor blocking drugs, NMR analysis of cancer cells, immunoassay in the clinical laboratory, cyclosporine

Monitoring of Metabolic Control in Diabetes Mellitus: Methodological and Clinical Aspects.- Recent Chemical Developments in the Field of Beta Adrenoceptor Blocking Drugs.- NMR Analysis of Cancer Cells.- The Role of Immunoassay in the Clinical Laboratory.- Cyclosporine: Chemistry, Structure-Activity Relationships and Mode of Action.- Author Index Volumes 1-3.