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Folate and Pterin Metabolism by Cancer Cells in Culture1

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Folate and Pterin Metabolism by Cancer Cells in Culture1 [CANCER RESEARCH 38, 2378-2384, August 1978) 0008-5472/78/0038-0000$02.00 Folate and Pterin Metabolism by Cancer Cells in Culture1 Baldassarre Stea, Peter S. Backlund, Jr., Phillip B. Berkey, Arthur K. Cho, Barbara C. Halpern, Richard M. Halpern, and Roberts A. Smith2 Departments of Chemistry (B. S., P. S. B., P. B. B., B. C. H.¡,Pharmacology ¡A.K. C.], Medicine, ¡Ft.M. H.]. and Chemistry [Ft. A. SJ and Molecular Biology Institute ¡R.M. H., R. A. S.], University of California, Los Angeles, California 90024 ABSTRACT cells, a significant peak of radioactivity was observed in the blue-fluorescent region. This peak of radioactivity was ab Malignant cells grown in culture excrete into their sent in chromatograms of growth media of normal cells growth medium a folate catabolite that can be seen as a grown under the same conditions. blue-fluorescent region on paper chromatograms of such We tentatively identified this blue-fluorescent compound media. This folate catabolite has now been identified by as Pt-6-CHO,3 primarily on the basis of its inhibitory power paper chromatography, thin-layer chromatography, and toward xanthine oxidase. However, we later found that Pt- combined gas chromatography-mass spectrometry as 6- 6-CH2OH also is a potent inhibitor of the same enzyme hydroxymethylpterin and not as pterin-6-carboxaldehyde system. This prompted us to identify by unequivocal means as previously reported. the fluorescent folate catabolite characteristic of cultured Moreover, when pterin-6-carboxaldehyde was added to malignant cells. the growth medium of logarithmically growing malignant Here we report the definitive identification of this blue- cells, it was primarily reduced to 6-hydroxymethylpterin. fluorescent compound isolated from growth media of KB In contrast pterin-6-carboxylate was the principal product cells as Pt-6-CH2OH.We also show that Pt-6-CHO, a putative formed from added pterin-6-carboxaldehyde by normal catabolite in the cancer cell-mediated cleavage of folie established cell lines in culture. These results have been acid, is reduced to Pt-6-CH2OH. interpreted as indicative of a possible mechanism of We believe that the elucidation of pterin and folate catab folate catabolism in malignant cells. Folie acid or another olism in malignant cells, as opposed to normal cells grown folate derivative is oxidatively cleaved at the C-9-N-10 in tissue culture, may be of great value in determining a bond to yield pterin-6-carboxaldehyde as one of the prod metabolic difference that could be exploited to differentially ucts. This derivative is subsequently reduced to 6-hydrox and specifically inhibit malignant growths. Moreover, as we ymethylpterin, which is excreted into the growth medium. have already suggested (12), monitoring for the levels of the highly fluorescent products of folate catabolism in body INTRODUCTION fluids may have a wide application as a diagnostic tool in the detection of malignant diseases. Controversial views exist in the literature as to whether active folate catabolism takes place in humans and other mammals. When [2-14C]folic acid was administered p.o. to MATERIALS AND METHODS rats (3), radioactivity in the urine could be identified only as Tissue Culture. Cells were usually grown in McCoy's folate metabolites in which the C-9-N-10 bond had re Modified Medium 5A (Grand Island Biological Co., Grand mained intact. No radioactive pterins were detected in the Island, N. Y.) containing Bacto-peptone (600 mg/liter), 15% first 24-hr urine samples following administration of the [2- undialyzed PCS, and gentamicin (50 /^g/ml). In some exper 14C]folic acid. However, a more recent study (19), in which rats received tracer doses of [3',5',9-3H]folic acid i.m., has iments, modifications and additions were made to this basic medium as specified in each case. All cultures were shown shown that after a period of equilibration of the tracer with to be concurrently pneumonia-like organism-negative by the folate pool the principal urinary catabolite is acetami- culture for 3 weeks in Grand Island Biological Co. broth dobenzoylglutamate. This finding suggests that active fol and pour plates. Of the cell lines used, the BALB/c3T3 ate catabolism takes place in vivo via cleavage of the C-9- fibroblasts and the SV40-transformed 3T3 cells (SV3T3) N-10bond. were kindly supplied by Dr. J. M. Jordan, UCLA; the We have previously shown (12) that malignant cells cata- benzo(a)pyrene-transformed 3T3 cells were a gift from Julie bolize folie acid yielding a compound visible as a blue- Baldwin, The Salk Institute, La Jolla, Calif. fluorescent region on paper chromatograms of their growth Determination of Cell Growth. Growth rates were esti media. At the limit of detection of paper chromatography, mated either by cell counts or by the following procedure. we could not see the same blue-fluorescent region in The cells left in the flasks after the medium had been chromatograms of growth media of normal cells. When [2- removed were carefully rinsed 4 times with cold 0.9% NaCI 14C]folate was added to the growth media of malignant solution, and the amount of protein remaining in the flask was determined by the method of Lowry ef a/. (18) with 1 This investigation was supported by the USPHS Grant CA 17332 and the bovine serum albumin as the standard. Julius and Dorothy Fried Research Foundation, Department of Chemistry Contribution 3926. 3 The abbreviations used are: Pt-6-CHO, pterin-6-carboxaldehyde; Pt-6- 1 To whom requests for reprints should be addressed at the Department CHjOH, 6-hydroxymethylpterin; PCS, fetal calf serum; HPLC, high-pressure of Chemistry, University of California, Los Angeles, Calif. 90024. liquid chromatography; Pt-6-COOH, pterm-6-carboxylic acid; TLC, thin-layer Received December 27, 1977; accepted April 24, 1978. chromatography. 2378 CANCER RESEARCH VOL. 38 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1978 American Association for Cancer Research. 6-Hydroxymethylpterin, a Folate Catabolite Analysis of Media. In all cases, growth media were Table 1 centrifugea in an unrefrigerated International Model V cen TLC of Pt-6-CHO and Pf-6-CHjOH trifuge at 2500 rpm for 3 min to remove floating cells. R,CompoundR-6-CHO Isopropyl alcohol was then added to the supernatant to a final concentration of 70% (v/v). This solution was stirred at 4°for at least 2 hr before the precipitated proteins were System1°0.32 System20.17 System30.43 System40.62 removed by centrifugaron. The isopropyl alcohol was then Pt-6-CHzOHSolvent 0.43Solvent 0.32Solvent 0.42Solvent 0.32 removed by 3 successive extractions with 6 volumes of " Solvent systems: 1, 3% NH4CI; 2, 5% citrate (adjusted to pH 9 toluene. The remaining aqueous phase was either filtered with concentrated NH4OH); 3, CH^Ishisopropyl alcohol:NH4OH:H2O through a Millipore filter and directly chromatographed by (7:1:1:1); 4, ethyl acetate :n-propyl alcohohHjO (4:1:2), upper HPLC or lyophilized and then redissolved in a small volume phase. of 0.1 N NH,OH as specified later in each case. HPLC was performed on a 25-cm x 4.6-mm Partisil 10- POPOP, 120 g naphthalene per liter of 1,4-dioxane). Count SCX column (Whatman, Inc., Clifton, N. J.) with an Altex ing was performed with a Beckman LS-250 or LS-100 Model 100 pump equipped with an Altex Model 904-42 sam scintillation counter. Gas chromatography-mass spectrom- ple injector (Altex Scientific, Inc., Berkeley, Calif.). Isocratic etry was performed with a Hewlett-Packard 5981A instru elution of the column was performed with 5 mM H3PO4 at a ment equipped with a 2-ft x 2-mm column of 3% OV-101 on flow rate of 3 ml/min. Under these conditions, Pt-6-COOH, 100 to 200 mesh Gas-chrom Q (Applied Science Labs, Inc., Pt-6-CHO, and Pt-6-CH2OH were separated as reported Inglewood, Calif.). Helium was used as the carrier gas (20 elsewhere.4 The eluant was detected with a Farrand A4 ml/min), and the eluting temperature was 200°. fluorometer equipped with a 7-60 excitation filter (band Chemicals. [2-'4C]Folate (specific activity, 58.2 mCi/ center at 360 nm) and a 3-72 emission filter with a cutoff at mmol) was purchased from Amersham/Searle Corp. (Ar 450 nm (Farrand Optical Co., Inc., Valhalla, N. Y.). Concen lington Heights, III.), and [3',5',9-3H]folic acid (specific trations of various pterins in the growth media were deter activity, 24 Ci/mmol) was purchased from Schwarz/Mann mined from calibration curves obtained by plotting peak (Orangeburg, N. Y.). [2-14C]Pt-6-CHO was prepared from [2- area values versus concentrations. All of the standards 14C]folate by the method of Thijssen (24) and used without used in constructing the calibration curves were incubated further purification. This preparation was found to be con in McCoy's Modified Medium 5A containing 15% FCS for 36 taminated by small amounts of [2-14C]Pt-6-COOH and [2- hr at 37°before being subjected to the extraction procedure 14C]Pt-6-CH2OH probably originating by dismutation reac and the Chromatographie separation. Incubation of the tion of the aldehyde. Pt-6-COOH and buttermilk xanthine standards for longer time periods did not have further effect oxidase were purchased from Sigma Chemical Co. (St. on recoveries or retention times. Louis, Mo.) and used without further purification. Pt-6- Miscellaneous Methods. When media supplemented CH2OH was synthesized from Pt-6-CHO also by the method with folate were analyzed, all of the operations were carried of Thijssen (24), modifed as follows. Pt-6-CHO was sus out in semidarkness.
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