TY - JOUR
AU - Fong, Y
AB - Abstract Background Studies using phosphorus magnetic resonance spectroscopy (MRS) have pointed to the significance of phospholipid metabolite alterations as biochemical markers for tumour progression or therapy response. Methods Spectroscopic imaging was performed in colorectal flank tumours in nude mice. In vivo tumour doubling times for each cell line were measured. In vivo sensitivity of each tumour line to treatment with G207 and NV1020 oncolytic viruses was assessed. Correlations between viral sensitivity and tumour doubling time and phosphorus MRS were estimated. Results For G207 virus, in vitro cytotoxicity tests showed cell viability at multiplicities of infection (ratio of viral particles per tumour cell) of 0·1 on day 6 as follows: C85, less than 1 per cent; HCT8, 1 per cent; LS174T, 9 per cent; HT29, 18 per cent; and C18, 92 per cent. Respective values for NV1020 were 1, 18, 4, 18 and 86 per cent. The phosphoethanolamine to phosphocholine ratio was significantly lower in virus-sensitive than -insensitive cells, and was dependent on tumour doubling time. Conclusion Alterations in membrane phospholipid metabolites that relate to proliferation of cancer cells affect the efficacy of oncolytic viral therapy. MRS proved a highly sensitive non-invasive tool for predicting the efficacy of viruses. Introduction Although surgical resection may be curative for patients diagnosed with early-stage colorectal cancer, more than 60 per cent of patients are diagnosed with regional or distant metastases, most commonly to the liver1. Hepatic metastases determine the prognosis2. Complete surgical resection of such metastases results in 5-year survival rates of around 35 per cent3, but fewer than 10 per cent of patients are candidates for liver resection and most require other regional or systemic treatment4. Oncolytic viral therapy may offer an alternative or additional treatment option5–7. Viral oncolytics exploit the natural cytotoxicity of viruses towards tumour cells8. Preclinical studies demonstrating the intricate interaction between oncolytic viruses, their targeted tumours and their hosts have resulted in new strategies to maximize oncolytic viral efficacy while ensuring safety9. Novel viruses that can selectively target, preferentially replicate in and destroy cancer cells have been designed10–12. The efficacy of oncolytic viral therapy depends on specific cell characteristics. Several parameters, such as cell doubling time and S-phase fraction, may be responsible for differences between tumours13. A screening method for patient selection in targeting oncolytic viral therapy would be beneficial in predicting the effectiveness of this treatment. Several clinical and experimental studies using magnetic resonance spectroscopy (MRS) have pointed to the significance of signals derived from phospholipid precursors and catabolites as biochemical markers for tumour progression or therapeutic response14,15. Numerous in vivo and in vitro31P MRS studies have detected high levels of phosphocholine (PC) and/or phosphoethanolamine (PE) in several cancers, whereas low levels of these metabolites were found in normal tissues16. PC is a precursor and a product of phosphatidylcholine, the most abundant phospholipid in biological membranes17. Products of choline phospholipid metabolism are essential messengers for the mitotic activity of growth factors18. The altered choline phospholipid metabolism observed in cancer cells impacts on several phenotypic characteristics of solid tumours19. A significant decrease in PE/PC ratio in malignant compared with benign tumour cells has been reported20. The PE/PC ratio depends on factors related to cell proliferation14,21. Furthermore, alterations in PE/PC ratios after chemotherapy or radiation therapy have been reported22. 31P MRS showed a significant increase in the PE peak relative to the PC peak after irradiation23,24. MRS allows non-invasive imaging of differences between benign and malignant cells, and alterations in cancer cell metabolism after treatment. The aim of this study was to correlate the effects of oncolytic viral therapy with phospholipid metabolism in cancer cells. A further objective was to determine whether this technique could predict the effectiveness of oncolytic viral therapy in human colonic cancer xenografts. Methods Male athymic mice (National Cancer Institute, Bethesda, Maryland, USA) were used in all animal studies. All experiments were performed under guidelines approved by the Memorial Sloan-Kettering Cancer Center (MSKCC) Institutional Animal Care and Use Committee. Five colorectal carcinoma cell lines were used. HCT8, HT29 and LS174T were obtained from the American Type Culture Collection (Rockville, Maryland, USA). C85 and C18 were isolated at MSKCC as reported previously13. C85, C18 and HCT8 cells were cultured in Roswell Park Memorial Institute (RPMI) medium with 10 per cent fetal calf serum (FCS) supplemented with 5 mmol/l l-glutamine. LS174T cells were cultured in RPMI with 10 per cent FCS, non-essential amino acids and 5 mmol/l l-glutamine. HT29 cells were cultured in McCoy's 5A medium with 10 per cent FCS. Cells were maintained in a 5 per cent carbon dioxide humidified environment at 37 °C. Two viruses were employed. G207, a gift from S. D. Rabkin, was constructed as described previously, with deletion of both copies of the γ134.5 gene and insertion of the Escherichia coli lacZ gene into the UL39 sequence of the R3616 mutant25. NV1020 is a non-selected clonal derivative of R7020, an attenuated, replication-competent virus based on herpes simplex virus (HSV) 1 strain F, originally obtained from B. Roizman26. It has a 15-kB deletion over the joint region of the HSV-1 genome and one copy of the neurovirulence gene (γ134.5)27. Viral sensitivity In vitro Cancer cells were plated at 4 × 104 cells per well in 12-well plates in 1 ml medium. After incubation for 6 h, NV1020 or G207 (100 µl) was added to each well at multiplicities of infection (MOI; the ratio of viral particles per tumour cell) of 0, 0·01, 0·1 or 1. Viral cytotoxicity was measured at 24-h intervals. Cells were washed with phosphate-buffered saline (PBS) and lysed with 1·5 per cent Triton X to release intracellular lactate dehydrogenase (LDH), which was quantified with a CytoTox® 96 kit (Promega, Madison, Wisconsin, USA) by spectrophotometry at 490 nm. Results were expressed as the ratio of surviving cells determined by comparing the measured LDH in each infected sample relative to that in control untreated samples that were considered 100 per cent viable. All samples were analysed in triplicate. In vivo In vivo tumour doubling times for each cell line were measured. In addition, the in vivo sensitivity of each tumour line to NV1020 treatment was assessed. Ten million cells were implanted subcutaneously in the flanks of nude mice (ten mice per cell line). Palpable tumours, 5–7 mm in diameter for each cell line, were treated with 5 × 106 plaque-forming units of NV1020 or PBS (five mice per group) by intratumoral injection. Tumour volumes were followed for 7 days and the resistance of each tumour type to NV1020 was expressed as the mean tumour remaining as a percentage of the baseline control value. Animal models and imaging Ten million cells of each tumour model were implanted subcutaneously in the flanks of 25 nude mice (five per cell line). When the tumours reached 300–500 mm3, spectroscopic imaging was performed on a 33- or 40-cm bore, 4·7-T horizontal bore Bruker-CSI magnetic resonance spectrometer (Bruker Biospin, Billerica, Massachusetts, USA). Animals were immobilized with the flank submerged in a 37 °C water bath, with the tumour protruding into a four-turn solenoid coil tuned to the resonance frequency of 31P (121·5 MHz) (Fig. 1). The bath was surrounded by a proton-tuned Helmholtz imaging coil whose field was orthogonal to the 31P coil. The study consisted of T1-weighted proton imaging for tumour localization, followed by one-dimensional 31P MRS imaging (16 phase encode steps, repetition time 1·8 s, 45° hard pulse 6 µs, 64 averages, spectral width 10 000, 2048 points, field of view 80, 88 or 96 mm depending on tumour size). Because the tumour protruded laterally from the flank, a tumour spectrum could be isolated in a single slab from the one-dimensional chemical shift imaging data set using retrospective voxel shifting to minimize contamination from adjacent muscle. A single free induction decay from the tumour was extracted using SAGE/IDL (GE Medical Systems, Milwaukee, Wisconsin, USA; RSI, Boulder, Colorado, USA) and the peaks were fitted in the time domain using MRUI-AMARES28. Assignments of peaks in the 31P NMR spectrum were based on comparison with in vivo and in vitro NMR studies performed in HT29 tumours29. Peak area ratios were calculated for quantitative comparisons between cell lines. Fig. 1 Open in new tabDownload slide Spectroscopic image of a flank tumour. The phase-encoded slice containing tumour is indicated by white lines Statistical analysis The correlation between PE/PC ratios and resistivity and doubling time were estimated separately. Confidence intervals and P values were calculated using Fisher's z transform and the Pearson product moment correlation coefficient. Results In vitro studies Cytotoxicity experiments demonstrated that both viruses showed similar efficacy against the colorectal cancer cell lines in vitro. Analyses were performed after day 6 of viral infection at a MOI of 0·1. C85, HCT8, LS174T and HT29 showed excellent sensitivity to G207 and NV1020 (Fig. 2). With the G207 virus, C85 and HCT8 cells were nearly completely killed after 6 days (less than 1 per cent and 1 per cent cell viability respectively). LS174T and HT29 showed 9 and 18 per cent cell viability respectively. HCT8 cells were less sensitive to the NV1020 virus (18 per cent cell viability) than the G207 virus. In contrast, C18 showed little oncolytic effect when exposed to G207 or NV1020 (92 and 86 per cent cell survival rate respectively). Fig. 2 Open in new tabDownload slide Survival of five human colorectal cancer cell lines in vitro after incubation for 6 days with oncolytic herpes viruses a G207 and b NV1020 added at a multiplicity of infection of 0·1. Results are expressed as the mean(s.d.) ratio of surviving cells determined by comparing the measured lactate dehydrogenase of each infected sample relative to control untreated samples that were considered 100 per cent viable Comparison of in vivo and in vitro sensitivity to NV1020 virus In vivo sensitivity of C85, HCT8, HT29, LS174T and C18 tumours to the NV1020 virus was assessed by volumetric measurements. The cell lines that had a good in vitro response to viral treatment (HCT8, C85, HT29 and LS174T) all showed tumour shrinkage in vivo (Fig. 3). C18, the tumour line that was not sensitive to viral treatment in vitro, also showed a poor response to NV1020 virus in vivo. Fig. 3 Open in new tabDownload slide In vivo sensitivity to NV1020 treatment of five different colorectal cell lines Magnetic resonance spectroscopy Tumours were analysed by 31P MRS after reaching 300–500 mm3 in size. 31P spectral characteristics depended on the sensitivity of the cell line to oncolytic virus. The difference is shown qualitatively in Fig. 4; the sensitive HCT8 tumour demonstrated a PC peak that was larger than the PE peak (Fig. 4a), whereas the PE peak was larger in the resistant C18 tumour (Fig. 4b). Calculation of the average PE/PC ratio for each cell line showed that the ratio in the virus-sensitive cell lines was 0·59, 0·88, 1·22 and 1·39 for HCT8, HT29, LS174T and C85 respectively, compared with 2·59 for virus-insensitive C18 cells. Fig. 5 shows the relationship between PE/PC ratio and resistivity to the virus. The two parameters were correlated with a Pearson correlation coefficient of 0·96 (95 per cent confidence interval (c.i.) 0·52 to 1·00); P = 0·012). Inorganic phosphate and nucleoside triphosphate peaks did not correlate with virus sensitivity. Fig. 4 Open in new tabDownload slide 31P spectra from a virus-sensitive (HCT8) and b virus-resistant (C18) colonic cancer flank tumour. PE, phosphoethanolamine; PC, phosphocholine; Pi, inorganic phosphate; NTP, nucleoside triphosphate Fig. 5 Open in new tabDownload slide Mean(s.d.) phosphoethanolamine to phosphocholine (PE/PC) ratio plotted against resistivity of five human colorectal cancer cell lines to NV1020 virus in vivo. Dashed line indicates best fit. R2 = 0·921 C18 had a higher tumour doubling time (364 h) than the virus-sensitive cell lines (C85, 60 h; LS174, 64 h; HCT8, 103 h; HT29, 164 h) (Fig. 6). The Pearson correlation coefficient for PE/PC ratio and in vivo tumour doubling time was 0·85 (95 per cent c.i. −0·13 to 0·99); P = 0·071). Thus there was a trend toward higher doubling times in resistant tumours, although this was not statistically significant, possibly because of the limited sample size. Fig. 6 Open in new tabDownload slide Mean(s.d.) phosphoethanolamine to phosphocholine (PE/PC) ratio plotted against doubling time of five human colorectal cancer cell lines. Dashed line indicates best fit. R2 = 0·723 Discussion This study has shown a correlation between levels of membrane phospholipid metabolites, efficacy of oncolytic viral therapy and tumour doubling time. 31P MRS served as a highly sensitive non-invasive tool for predicting the efficacy of viruses in colorectal tumour xenografts based on PE and PC. Colorectal cancer was the third commonest malignant disease and the second most frequent cause of cancer-related death in the USA in 200530. Worldwide, it is the fourth most commonly diagnosed malignant disease31. Half of those affected will die from advanced or recurrent disease, despite aggressive treatment even with biological agents32,33. Thus, novel therapies for colorectal cancer are being investigated. Several viruses have been investigated for their oncolytic efficiency7. Oncolytic viral therapy with HSV-1 viral mutants G207 and NV1020 is an effective strategy in vitro and in experimental animal models9,13. The tumoricidal ability of these viruses is supposed to be dependent on the viral replication cycle, in which progeny virions infect neighbouring cells after cell lysis, rather than on the expression of particular viral genes34. The authors' laboratory has demonstrated the oncolytic effects of NV1020 and G207 on colorectal cell lines13,35. Few results evaluating the efficiency of NV1020 in killing colorectal cell lines are available in the literature. Cell lines tested by Gutermann and colleagues9 showed viral efficacy of NV1020 similar to that in the present experiments. The different response rates of cancer cell lines to oncolytic viruses seem to be dependent on rates of cell proliferation and the cell phase during infection13,36. Rapidly dividing cells, which presumably express higher levels of ribonucleotide reductase, may serve as more suitable hosts for G207 replication37–40. The present study found a relationship between tumour doubling time and sensitivity to virus. For example, the virus-sensitive HCT8 cell line showed nearly one-third of the tumour doubling time in vivo compared with the insensitive C18 cell line. Differences in efficacy between NV1020 and G207 might be explained by differences in the construction of these two viruses. Compared with G207, the NV1020 virus maintains endogenous ribonucleotide reductase and one copy of the γ134.5 neurovirulence gene26. Viral growth of infected cell protein (ICP) 6 mutants occurs only in rapidly dividing cells that compensate for defects in viral ribonucleotide reductase38,41,42. The γ134.5 gene product is known to inhibit the protein kinase R (PKR) system, thereby preventing the shutdown of host protein synthesis and permitting viral replication43,44. Viruses deleted for ICP34.5 are attenuated in vivo because the PKR system remains active, blocking protein synthesis and viral replication45,46. Wild-type replication and virulence of ICP34.5 mutants can be restored if PKR is deleted47. These studies suggest that only cells defective for PKR can permit significant replication of ICP34.5 mutants such as G207, thereby restricting their oncolytic potential48. MRS studies have detected higher levels of PE and/or PC in tumours compared with normal tissues15,24,49,50. This provoked clinical interest in analysing the potential of magnetic resonance imaging and MRS to provide information on therapeutic response51,52. Radiation and chemotherapy affect PE/PC ratios. After tumour irradiation, a dose response was noted, with higher doses leading to greater increases in the PE/PC ratio23. In vivo studies of breast carcinoma, lymphoma, adenocarcinoma and musculoskeletal tumours have shown that a therapeutic response to chemotherapy was accompanied by decreases in PE and PE/PC51,53. The phosphomono ester/nucleoside triphosphate ratio in malignant breast lesions also decreased after treatment51,54. Based on the above findings, the potential of MRS to serve as a non-invasive tool for predicting the efficacy of oncolytic viruses was investigated. A positive correlation was observed between the PE/PC ratio and the resistivity of five colonic tumour lines to the NV1020 oncolytic virus. PE/PC ratios of 1 or less resulted in higher rates of tumour cell death whereas cells with PE/PC ratios of 2 and above showed low sensitivity to oncolytic viral therapy. The efficacy of oncolytic viruses was also dependent on tumour doubling time. Tumour cells with long doubling times showed higher PE/PC ratios than those with faster doubling times. It remains to be determined whether the PE/PC ratio simply predicts viral sensitivity by reflecting doubling time or whether a more complex relationship exists. Nonetheless, tumour doubling time cannot be assessed in a patient with cancer and non-invasive measurement of PE/PC ratio could provide valuable prognostic information. Alterations in the metabolism of membrane phospholipids have been investigated with respect to cell proliferation and cell cycle phase. PE and PC are precursors of the membrane phospholipids phosphatidylethanolamine and phosphatidylcholine respectively, and could be expected to change when cell membrane events occur. In perfused breast cancer cells increases in both PE and PC in log phase compared with confluency have been demonstrated55. In tumour cells grown in a bioreactor, the PC/PE ratio was consistently lower in stationary cultures than in proliferating cultures21. A negative correlation between PE/PC ratio and S-phase fraction has been reported in cell spheroids56. These findings appear to conflict with the positive correlation between PE/PC ratio and tumour doubling time found in the present study. However, there is a considerable difference in physiology between perfused cells and in vivo tumour xenografts. It should also be noted that fibroblasts present in tumour tissue can contribute to the PE and PC peaks57. This study has shown a correlation between levels of membrane phospholipid metabolites, efficacy of oncolytic viral therapy and tumour doubling time. Further studies at other tumour sites are now needed to determine the general applicability of this finding. Acknowledgements This work was supported by National Institutes of Health (NIH) P50 CA86438, NIH R24 CA83084, and NIH R01 CA75416. 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Published by John Wiley & Sons, Ltd. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
TI - Relationship between 31P metabolites and oncolytic viral therapy sensitivity in human colorectal cancer xenografts
JO - British Journal of Surgery
DO - 10.1002/bjs.6604
DA - 2009-06-15
UR - https://www.deepdyve.com/lp/oxford-university-press/relationship-between-31p-metabolites-and-oncolytic-viral-therapy-kZNBiKbz70
SP - 809
EP - 816
VL - 96
IS - 7
DP - DeepDyve
ER -