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Effects of Folate Deficiency on the Metastatic Potential of Murine Melanoma Cells1'2

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Effects of Folate Deficiency on the Metastatic Potential of Murine Melanoma Cells1'2 [CANCER RESEARCH 48, 4529-4534, August 15. 1988| Effects of Folate Deficiency on the Metastatic Potential of Murine Melanoma Cells1'2 Richard F. Branda,2 John J. McCormack, Carol A. Perlmutter, Linda A. Mathews, and Steven H. Robison3 Departments of Medicine [R. F. B., C. A. P.], Pharmacology [J. J. M.], and Neurology [S. H. R.J. and the Vermont Regional Cancer Center [L. A. M.], University of Vermont, Burlington, Vermont 05405 ABSTRACT acid metabolism critically affects chromosome stability, and vitamin lack is associated with a variety of chromosomal ab Experiments were designed to measure the effect of folie acid defi normalities (6-9). Since tumor metastatic propensity appears ciency on a major determinant of cancer lethality, the propensity to form to correlate with chromosomal instability (10), we investigated métastases.Murine B16 melanoma cells (FIO strain) were grown in folate-deficient and -supplemented media. After 3 days, cells in the the effect of cellular folate deficiency on this important deter deficient medium had restricted proliferative capacity, low folate levels minant of tumor lethality. by bioassay, increased cell volume, abnormal deoxyuridine suppression tests, accumulation of cells in S phase by flow cytometry, and increased numbers of DNA strand breaks. These folate-deficient cells consistently MATERIALS AND METHODS initiated more pulmonary métastasesthancontrol cells when injected into Murine B16 melanoma cells (FIO strain) were obtained from the host mice. Cell size did not appear to be a major factor in pulmonary Tumor Repository of the Division of Cancer Treatment, National metastasis formation. In vitro growth rates and cloning efficiencies were Cancer Institute, Frederick Cancer Research Facility, Frederick, MD. comparable for cells in both types of medium as was subcutaneous growth The cells were grown in "folate-free" Dulbecco's modified Eagle's of tumors. We conclude that folate deficiency increases the metastatic medium (M. A. Bioproducts, Walkersville, MD) or the same medium potential of cultured melanoma cells. supplemented with 4 /ng/ml of folie acid (Sigma). To these media were added 10% dialyzed horse serum, 2% glutamine, and 1% penicillin- streptomycin (all obtained from Gibco Laboratories, Grand Island, INTRODUCTION NY). The final "low-folate" medium contained 0.26 ng/ml of folate Malnutrition is frequently observed and is often severe in activity by the Lactobacillus casei assay (11, 12). Cell suspensions in 15 ml of medium were placed in T75 flasks (Corning) and incubated at patients with malignant diseases (1). It is due to the combined 37°Cwith 5% COz. Cell counts were performed manually, and viability effects of decreased nutrient intake and increased utilization by was assessed by trypan blue exclusion. Cell cultures were divided by tumor metabolism. Losses of adipose tissue and muscle protein treating for 5 min with 2 ml of Versene (1:5000), washing with medium, are common, as is weight loss; the latter may adversely affect and inoculating a new flask with 1 x K)'1cells. In some experiments, survival and response to chemotherapy (1). Deficiencies of flasks were inoculated with 5 x IO5cells. micronutrients are also frequently encountered in cancer pa IMiraceliular folate levels were measured with a L. casei assay (13). tients. For example, some nutritional surveys have reported low Melanoma cells were treated with Versene and washed with cold saline. blood levels of folie acid in 60 to 85% of cases (2, 3). In the Then 1 x 10s cells were suspended in 2 ml of 0.1 M sodium acetate series reported by Magnus, 11 of 64 patients with metastatic buffer (pH 4.5) containing 0.1 % ascorbate and 0.2 ml of dialyzed horse cancer had serum levels of 0 to 0.9 ng/ml, and 19 others had serum. This suspending medium contains no measurable folate activity. Following sonication and incubation of the homogenate for 90 min at levels of 1 to 1.9 ng/ml; 53 of these 64 patients had serum 37°C,the protein was denatured by boiling for 5 min and removed by levels below the normal range (3.0 to 11.0 ng/ml) for his centrifugation. The supernatant was assayed as previously described laboratory (2). (11,12). Despite its frequency in patients with malignancies, the effect Deoxyuridine suppression tests were performed by modifications of of folie acid deficiency on the clinical course of neoplasia has our previously reported methods (12). After Versene treatment and not been studied in detail. Early reports by Farber and cowork- washing with medium, melanoma cells were resuspended in appropriate ers of an "acceleration phenomenon" in leukemic patients medium at a concentration of 1 x 10' cells/ml. One ml of suspension receiving folie acid were followed by animal studies suggesting was placed in 12- x 75-mm tubes, to which was added deoxyuridine that tumor growth is retarded in folate-deficient hosts (4, 5). (Sigma) (final concentration, 0.1 or 1 ^M) in phosphate-buffered saline or buffer alone. After l h at 37°C,0.1 /¿Ciof[3H]thymidine (Research Subsequently clinicians have been reluctant to administer folie acid to deficient cancer patients on the chance that the vitamin Products International Corp., Mt. Prospect, IL) was added, and the mixture was incubated for an additional 3 h. Radioactivity was then might enhance the growth of the malignancy. Since the publi determined in the trichloroacetic acid precipitates. Results are ex cation of these studies 20 or more years ago, a great deal has pressed as thymidine incorporation in samples with deoxyuridine di been learned about folate metabolism. Consequently, we sought vided by incorporation by control cells in deoxyuridine-free cultures x to investigate the influence of this common vitamin deficiency 100. All determinations were done in triplicate. on tumor biology in the light of more recent information. Folk Cell cycle distribution was determined by flow cytometry and ana lyzed by a parametric method (14). Melanoma cells (1 x IO4) were Received 1/11/88; revised 5/12/88; accepted 5/19/88. stained with propidium iodide (50 ^g/ml in 10% horse serum containing The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in 1 mg/ml of RNase and 0.025% Nonidet P-40). Nuclear fluorescence accordance with 18 U.S.C. Section 1734 solely to indicate this fact. intensity was determined with an Ortho Cytofluorograf 50 H/H using 1This work was supported by grants from the Vermont Division of the 488 mn argon ion laser excitation. American Cancer Society, the National Cancer Institute (CA 24543, CA 41843, and IS 10 RRO 1510-01), and the American Institute for Cancer Research. DNA strand breaks were detected by alkaline elution as described by Presented in part at the national meeting of the American Society of Clinical Kohn with several minor modifications (15, 16). Cells were seeded at 1 Investigation, May 1985 (31). x 106/mlin 10 ml of medium containing 0.02 jiCi/ml of [14C]thymidine 2 Recipient of a Research Career Development Award from the NIH (CA- for 24 h. The cells were deposited on a polycarbonate filter (2-^m pore 00946). To whom requests for reprints should be addressed, at Hematology/ size) and lysed with a buffer containing 2% sodium dodecyl sulfate-20 Oncology Unit, 32 N. Prospect Street, University of Vermont, Burlington, VT 05405. IHMEDTA (pH 10.1). The filters were washed with 5 ml of 20 mM 3Supported by a grant from the Sandoz Foundation of America. EDTA (pH 10.1). Elution buffer [25 ml of 20 mM EDTA (free acid)- 4529 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1988 American Association for Cancer Research. FOLATE DEFICIENCY AND METASTATIC POTENTIAL 2% tetrapropyl ammonium hydroxide (pH 12.15)] was applied to the filter and pumped through at a rate of 0.035 ml/min. Fractions of 3 ml were collected at 90-min intervals. Afterward, the filter was dissolved in 1 ml of protosol and prepared for liquid scintillation counting. Elution fractions and a wash of the pump lines were suspended as a gel using Aquasol-2 containing 0.7% glacial acetic acid and assayed for radioactivity. Cloning efficiency was measured by growing cells for 3 days in standard or low folate medium and then plating at a density of 100 or 200 cells/plate in 60-mm culture dishes containing standard culture medium. After 1 wk, the plates were stained with crystal violet and colonies were counted. Mean channel volume was measured on a Model ZBI Coulter Coun ter and Model 256 channelyzer (Coulter Electronics, Inc., Hialeah, FL). The mean channel volume was converted into mean volume by calibrating the machine with microspheres of 9.77, 14.75, and 20.01 ^m in diameter (Epics Division of Coulter Corp., Hialeah, FL). ÛJ 2 Chromosome counts were performed on cells which were incubated U with Colcemid (0.02 ¿ig/ml)for 2 h prior to harvesting. Following Versene treatment, the suspended cells were treated with 0.075 M KCI for 15 min at 37°C,fixed with methanol:acetic acid, 3:1 by volume, for 10 min, spread on wet slides, and then air dried. Slides were stained with 2% Giemsa solution. Metastasis formation was determined by injecting murine melanoma cells into the tail veins of male C57BL/6 mice which were 6 to 8 wk old. The cell suspension contained 1 x 10' viable cells in 0.1 ml of medium. Cell viabilities were 95.7 ±3.4% (mean ±SD) for control cells and 95.4 ±3.0% for low folate cells in 13 experiments. DAY Fig. 1. Effect of incubation in folate-defïcient medium on melanoma cell RESULTS proliferation.
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