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Induction of Ornithine Decarboxylase Activity in Mouse Urinary Bladder by L-Tryptophan and Some of Its Metabolites1

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Induction of Ornithine Decarboxylase Activity in Mouse Urinary Bladder by L-Tryptophan and Some of Its Metabolites1 [CANCER RESEARCH 42, 3587-3591, September 1982] 0008-5472/82/0042-0000$02.00 Induction of Ornithine Decarboxylase Activity in Mouse Urinary Bladder by L-Tryptophan and Some of Its Metabolites1 Masahiro Matsushima,2 Sadamu Takano,3 Erdogan Erturk. and George T. Bryan4 Division of Clinical Oncology, Department of Human Oncology, Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792 ABSTRACT between elevated urinary tryptophan metabolite levels and bladder cancer in humans was proposed (3, 4, 32, 40). Recent The responses of female noninbred mouse urinary bladder data (11, 12, 16, 21, 34) suggest that tryptophan or its urinary ornithine decarboxylase (EC 4.1.1.17) (ODC) and S-adenosyl- metabolites may be cocarcinogens or promoters of bladder u-methionine decarboxylase (EC 4.1.1.50) (SAMD) activities to neoplasia. We first proposed (4-6, 9, 40) that bladder carci L-tryptophan feeding and to topical intraurethral administration nogenesis was a multifactorial process that might involve of L-tryptophan and some of its urinary metabolites were stud stages of induction and promotion analogous to those of skin ied. Mice fed a diet containing 1% L-tryptophan demonstrated tumorigenesis (1, 39). This proposal has been confirmed and significant increases in vesical ODC and SAMD activities as extended by others (11, 12, 16, 17, 21 ). early as 2 weeks after the commencement of the diet. By the Evidence that polyamines and the enzymes responsible for end of the third week, ODC and SAMD activities reached peak their biosynthesis play a significant role in carcinogenesis, values of 7- and 3-fold, respectively, significantly greater than tumor promotion, and cellular hyperplasia has been presented the control levels (p < 0.05 and p < 0.01, respectively). Then, (1, 19, 28, 35, 39). Data have been presented that ODC5 enzyme activities gradually decreased but remained at levels induction by 12-O-tetradecanoylphorbol-13-acetate in mouse significantly higher than those of the control mice until the end skin, although not sufficient (20, 27), is an important compo of the sixth week when the study was terminated. Topical nent of the mechanism of tumor promotion by 12-O-tetrade- application by urethral catheter of some urinary tryptophan canoylphorbol-13-acetate (1, 28, 38). ODC induction also was metabolites was followed by a rapid, transient induction of reported to occur in carcinogenesis of liver (30, 36), lung (13), urinary bladder ODC activity within 5 hr. Statistically significant and colon (37), as well as urinary bladder (22). Single topical differences between vehicle controls and xanthurenic acid (p i.u. administration of the vesical carcinogens FANFT and ANFT < 0.01), DL-kynurenine (p < 0.01), L-kynurenine (p < 0.01), resulted in early, exaggerated ODC activity in rodent urinary anthranilic acid ( p < 0.01 ), and quinaldic acid ( p < 0.05) were bladders (22). We report here the induction of mouse urinary observed. However, no significant differences were seen with bladder ODC and SAMD activities following systemic adminis L-tryptophan, 3-hydroxy-DL-kynurenine, the 8-methyl ether of tration of L-tryptophan and following i.u. administration of some xanthurenic acid, or D-kynurenine or with 3-hydroxyanthranilic, tryptophan metabolites. kynurenic, quinolinic, picolinic, and nicotinic acids. Bladder SAMD was not elevated significantly by most of these directly applied tryptophan metabolites. ODC inducibility by active com MATERIALS AND METHODS pounds was followed by mucosal hyperplasia within 7 days. Chemicals. The following chemicals were purchased: reagent grade These data suggest that certain L-tryptophan metabolites may dimethyl sulfoxide and L-tryptophan (Aldrich Chemical Co., Milwaukee, be involved in two-stage urinary bladder carcinogenesis in a Wis.); anthranilic acid and 3-hydroxyanthranilic acid (Sigma Chemical manner similar to that shown to occur in murine skin tumor Co., St. Louis, Mo.); ANFT (Saber Laboratories, Morton Grove, III.); systems by other chemicals. DL-[1-'4C]ornithine hydrochloride (specific activity, 52.5 mCi/mmol) and S-adenosyl-L-[carooxy/-MC]methionine (specific activity, 52.3 mCi/mmol) (New England Nuclear, Boston, Mass.). The tryptophan INTRODUCTION metabolites nicotinic acid; picolinic acid; quinaldic acid; quinolinic acid; kynurenic acid; D-, L-, and DL-kynurenine; 3-hydroxy-DL-kynurenine; The urinary bladder epithelium is susceptible to a wide the 8-methyl ether of xanthurenic acid; and xanthurenic acid were variety of chemical carcinogens (4-6, 11, 12, 31, 32). L- generously provided by Dr. R. R. Brown (University of Wisconsin Tryptophan, an essential amino acid, is extensively metabolized Clinical Cancer Center, Madison, Wis.). Chemical identity and purity of (Chart 1), resulting in urinary excretion of several metabolites, all test compounds were checked by melting point, IR and UV absorp some of which have demonstrated urinary bladder carcino tion spectrophotometry, and paper and high-performance liquid chro- genic activities in experimental systems (4-6, 9). A relationship matography (3). Animals and Treatment. Female noninbred Swiss albino mice 1 Supported in part by Grants CA 11946, CA 14520, and CA 14524 through (Sprague-Dawley, Madison, Wis.), 12 to 14 weeks old, received pel the National Bladder Cancer Project and by CA 20432 from the National Cancer leted diet (Wayne Lab Blox; Allied Mills, Inc., Chicago, III.) and water Institute, NIH. Preliminary reports of this work were made (23, 24). ad libitum and were killed between 1 and 3 p.m. in order to avoid 2 Present address: Department of Urology, Toho University School of Medi circadian rhythm variations. cine, Tokyo 143, Japan. 3 Recipient of a Rotary Foundation Educational Award for International Un For the 6-week feeding trial with L-tryptophan, the following protocol derstanding. Present address: Second Department of Surgery, Kumamoto Uni was used. L-Tryptophan (50 g; 1% w/w) was mixed mechanically with versity Medical School. Kumamoto 860, Japan. ' To whom requests for reprints should be addressed, at Department of Human 5 The abbreviations used are: ODC, ornithine decarboxylase (EC 4.1.1.17); Oncology, Wisconsin Clinical Cancer Center. University of Wisconsin Center for i.u., intraurethral; FANFT, N-{4-(5-nitro-2-furyl)-2-thiazolyl]formamide; ANFT, 2- Health Sciences, K4/528 CSC, 600 Highland Avenue, Madison, Wis. 53792. amino-4-(5-nitro-2-furyl)thiazole; SAMD, S-adenosyl-L-methionine decarboxyl Received June 29, 1981; accepted June 7, 1982. ase (EC 4.1.1.50). SEPTEMBER 1982 3587 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1982 American Association for Cancer Research. M. Matsushima et al. 40 g of anhydrous dextrose and 4910 g of ground diet and was stored killed. Food consumption was determined at weekly intervals. Eight in a refrigerator at 4-10° until used (15). This diet was fed to 180 mice groups (3 mice/group) of L-tryptophan-treated mice were killed at for 0 to 6 weeks. Forty control mice were fed unmedicated ground diet weekly intervals; 4 groups (3 mice/group) of control animals were for 0 to 6 weeks. Mice were weighed at the start of the study and when killed at the start of the study and at the end of the third and sixth weeks. For histological study, 6 mice fed the L-tryptophan-containing jTC-f-HGHgCOOM diet and 3 mice fed unmedicated ground diet were killed at weekly ^NM2 intervals. Urinary bladders were appropriately inflated with and fixed in -¡yCM-jCMCOOM Q-AWNQHIPPURIC ACÓ 10% buffered formalin, and sections were stained with nematoxylin ) ÑHg O ^rc-o-GeHgOe TPYPTOPHAN and eosin as described previously (15, 37). >NH-> ANTHRAftUC Chemicals applied by i.u. instillations directly into the vesical lumen ACID GLUGURONIDÕ were solubilized in an appropriate solvent (Table 1), diluted with dis PÖ-CM2CHCOOH tilled water to the final indicated solvent percentage, and administered NH2 NH2 (^XN>^OOH K YNUR£:MN£ KYNURENIC ACÓ in a volume of 0.10 ml as described previously (22). For histological \\ TC-CH£CHCOOH , study, 3 or 6 mice were killed at 3, 5, 7, 10, 12, 24, 48, 120, and 168 ÑHCOCHj hr after instillation of tryptophan metabolites. AC£TYLKYNUR£MN£ COOM B-HYDROXr- Tissue Preparation and Enzyme Assays. Mice were killed at pre f^r G-CHgCMCOOH NH^SíS00" X*NTHUR£NIG ACiD LNHg NMCOCM JUtHALD/C ACID determined times by cervical dislocation. Whole bladders from 3 mice >n»oxr- ^ifVfi-CHaCHCooH were pooled, homogenized, and centrifuged, and ODC and SAMD k^-NHg NM2 activities and protein content of the soluble bladder extracts were \j-«fr> XANTHURENIC ACJD determined by methods described previously (22). KrNUR 8-METHYL CTHER (^irccCOOH la^Nt NHj RESULTS OW3 Effects of L-Tryptophan Feeding on Urinary Bladder ODC OUINOLINIC _OÕT! I N-HETHYL-2- ACID NtCOTINIC CM, CH, PYRlDONE-S- and SAMD Activities. No significant differences in diet con >*C/O *â„¢.c,nri. CMfBOJfAMfOe ^/cor/A-aw/uf sumption and growth rates were found between experimental Chart 1. Metabolic scheme of the conversion of L-tryptophan to niacin, illus and control groups. The daily dose of L-tryptophan in the trating structures of metabolites studied. Compounds underlined exhibited sig nificant murine bladder carcinogenicity by the intravesical pellet implantation experimental group was about 50 mg/mouse. Urinary bladder technique (4). ODC (Chart 2A) and SAMD (Chart 28) activities, measured at Table 1 Effects of L-tryptophan or several of its urinary metabolites administered by urethral catheter on mouse urinary bladder ODC and SAMD
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