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

Home , Ornithine decarboxylase

[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).

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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 4-10Â° 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 -Â¡yCM-jCMCOOM Q-AWNQHIPPURIC ACÃ“ 10% buffered formalin, and sections were stained with nematoxylin ) Ã‘Hg 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 GLUGURONIDÃ• were solubilized in an appropriate solvent (Table 1), diluted with dis PÃ–-CM2CHCOOH tilled water to the final indicated solvent percentage, and administered NH2 NH2 (^XN>^OOH

K YNURÂ£:MNÂ£ KYNURENIC ACÃ“ in a volume of 0.10 ml as described previously (22). For histological \\ TC-CHÂ£CHCOOH , study, 3 or 6 mice were killed at 3, 5, 7, 10, 12, 24, 48, 120, and 168 Ã‘HCOCHj hr after instillation of tryptophan metabolites. ACÂ£TYLKYNURÂ£MNÂ£ COOM B-HYDROXr- Tissue Preparation and Enzyme Assays. Mice were killed at pre f^r G-CHgCMCOOH NH^SÃS00" X*NTHURÂ£NIG ACiD LNHg NMCOCM JUtHALD/C ACID determined times by cervical dislocation. Whole bladders from 3 mice >nÂ»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-Â«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 _OÃ•T! 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 activities Five hr prior to being killed, groups (3 mice each) were treated with the indicated chemicals at the designated doses applied by urethral catheter. Following death, bladder isolation and homogenization, ODC and SAMD activities, and protein concentrations were measured. Enzyme activity 5 hr after treatment (pmol CO2/ 30 min/mg protein) Experi Dose ment Chemical (/imol) Groups ODC Groups SAMD L-Tryptophan 1.0 29 Â± 8* 45 Â± Vehicle control (0.9% NaCI 35 Â± 8 30 Â± solution) 58 Â±20"144 Xanthurenic acid .0.0.0.0.0.0.01.01.01.00.46768685119656191Â±863 DL-Kynurenine Â±29"138 Â±1160 Anthranilic acid Â±20"W7 Â±1082 Quinaldic acid Â±23*95 Â±1663 3-Hydroxy-DL-kynurenine Â±1690 Â±1355 Quinolinic acid Â±1377 Â±655 3-Hydroxyanthranilic acid Â±1674 Â±842 Kynurenic acid Â±1471 Â±489 Nicotinic acid Â±1056 Â±12C87 Picolinic acid Â±11310 Â±10e62 ANFT (positive control) Â±26"77 Â±846 Vehicle control (10% dimethyl Â±1056664364336652Â±12 sulfoxide)

8-Methyl ether of xanthurenic 1.0 61 Â±23 57 Â± 5 acid Â±1860 Â±460 acid3-Hydroxy-DL-kynurenineVehicle3-Hydroxyanthranilic Â±2461 Â±1947 Â±1861 Â±785 control"4 Â±2177 Â±2161

L-KynurenineDL-KynurenineD-KynurenineVehicle Â±8"56 Â±1177 Â±T32 Â±1758 Â±732 Â±1062 control (0.2% di Â± 54446544570 Â± 9 methyl sulfoxide)3.01.01.01.01.01.04446544575 â€¢MeanÂ±S.E. for duplicate assay. 6 p < 0.01. C0.05 >p>0.01. " A few drops of 7.16 N NH,OH diluted with 2x10" M phosphate buffer (pH 7.4).

3588 CANCER RESEARCH VOL. 42

between those of the L and D isomers. L-Tryptophan 3-hydroxy- DL-kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, kyn- I 30 urenic acid, and the 8-methyl ether of xanthurenic acid stimu lated neither ODC nor SAMD activities to significant levels. Nicotinic acid and picolinic acid did not induce ODC activity but significantly stimulated SAMD activity. Â£8 3-Â« Effects of Tryptophan Metabolites on Urinary Bladder Mor UJ (vj phology. Following tryptophan metabolite or vehicle treatment, Â£* IO some bladders showed mucosal hyperemia, congestion, and focal hemorrhage as early as 3 hr, but these changes were not observed consistently with any treatment. By 24 hr following i.u. treatment with xanthurenic acid, DL-kynurenine, L-kynurenine, anthranilic acid, or quinaldic acid, the urothelial cells il!100 demonstrated positional irregularity and crowding, and by 48 hr mitotic figures were frequently observed. By 7 days, mild, multifocal hyperplasia appeared as the epithelial mucosa be i-SÃ¬ Â¿Se50 came 4 to 5 cells thick. This hyperplastic effect of the tested Â§O ~ Å“ N tryptophan metabolites was parallel to their ODC inducibility. u o: O Q< u DISCUSSION

Time After Start of no 1% L-Tryptophon Diet Since the report of Dunning ef al. (14) that added dietary (weeks) tryptophan enhanced the rat bladder carcinogenicity of 2-ace- Chart 2. Effect of L-tryptophan diet on mouse urinary bladder ODC (Ai and SAMD (8) activities. Groups of mice fed 1% L-tryptophan diet ad libitum were tylaminofluorene, a number of studies have been conducted in killed for bladder enzyme activity assays at weekly intervals. O. control groups an effort to ascertain if the essential amino acid L-tryptophan fed a powdered unmedicated rodent diet. Points, mean of 4 (control groups) or or its urinary metabolites are bladder carcinogens (3-9). Sev 8 (experimental groups) duplicate determinations of enzyme activities from com bined bladder extracts prepared from 3 mice for each group determination; bars, eral of these metabolites exhibited bladder oncogenicity when S.E.; asterisks, statistically significant differences for treatment versus control tested by the intravesical pellet implantation technique (4, 9), groups at indicated weeks: â€¢,0.05> p > 0.01 ; â€¢â€¢,p< 0.01 ; * â€¢â€¢,p< 0.001. although the systemic administration of tryptophan or some of its metabolites did not induce bladder cancer (4, 21, 25, 29, weekly intervals after the start of the 1% L-tryptophan diet, 34). Recent studies (1 1, 12, 16, 21, 34) suggested that tryp increased significantly by 3 weeks and reached peak values 7- tophan or its urinary metabolites might be cocarcinogens or and 3-fold, respectively, greater than the control levels. Then, promoters of bladder neoplasia. Promoting activity of dietary the activities gradually decreased but remained at significantly DL-tryptophan for the bladder was demonstrated in rats (12) higher levels compared with the control levels through the sixth and dogs (34) following initiation by FANFT or arylamines, week. By 2 weeks, the epithelial mucosa of some mice fed L- respectively. Dietary L-tryptophan was shown to promote blad tryptophan became 4 to 5 cells thick (normally 3 cells thick) in der tumor formation in mice (21 ) and rats (1 6) following initia focal areas. This epithelial change did not appear progressive tion by FANFT. It also significantly increased the labeling and or involve more than 1 or 2 mice at each time period studied. hyperplastic indices of mouse bladder urothelium (21 ). No epithelial changes were evident in control mice. Effects of Direct Intravesical Administration of Some Tryp- tophan Metabolites on Urinary Bladder ODC and SAMD Ac 200 tivities. Following the instillation of 1 jumolof xanthurenic acid into the bladder, the ODC activity increased rapidly to a sig isI < o nificant (p < 0.01) maximum at 5 hr, 2-fold over the control UJ S. level, and quickly decreased to control levels by 24 hr (Chart 3). This kinetic pattern was similar to that obtained after treat ment with ANFT (22) except that the magnitude of ODC induc si 100 tion was much greater with ANFT treatment (Table 1). Nicotinic acid treatment did not activate ODC significantly compared 2 -E LU cj with the vehicle control at any time (Chart 3). Other tested <=>0 LlJ O metabolites (Table 1) showed the same kinetic patterns as that of xanthurenic acid or nicotinic acid. rz o. Peak ODC and SAMD activities at 5 hr following i.u. admin rr 0257 12 24 istration of L-tryptophan and some of its metabolites are pre O sented in Table 1. Xanthurenic acid, DL-kynurenine, anthranilic Hr After Administration Chart 3. Effects of a single intravesical instillation of xanthurenic acid (â€¢)and acid, and quinaldic acid showed significant inductions of ODC nicotinic acid (A) on mouse urinary bladder ODC activity. One /imol of each but not of SAMD when compared with the matched vehicle compound dissolved in 10% dimethyl sulfoxide was administered by urethral controls. L-Kynurenine activated ODC significantly whereas D- catheter at zero time, and animals were killed for enzyme activity assays at the kynurenine did not. Furthermore, the racemic compound DL- times indicated. Controls (O) were given 10% dimethyl sulfoxide only. Points, the mean of 4 to 6 duplicate determinations of enzyme activity from combined kynurenine resulted in a value of ODC activity intermediate bladder extracts prepared from 3 mice for each determination; bars, S.E.

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Although the initiation-promotion concept was developed as 50% of patients with bladder neoplasia (3). Additionally, from tumorigenicity investigations with mouse skin, recent stud patients with certain elevated urinary tryptophan metabolites ies have suggested that tumor promotion may be operative in exhibited a significant tendency towards the development of some other organs including the urinary bladder (4-6, 9, 11, heterotopic bladder recurrences following removal of initial 12, 16, 17, 21, 34). Several properties of initiation and pro low-stage, low-grade bladder neoplasia (40). Because metab motion have been characterized experimentally in the murine olism of L-tryptophan is dependent on the bioavailability of skin cancer model (1, 28, 39). Most initiating agents are vitamin B6 (pyridoxine), the metabolism of tryptophan to some mutagenic in various short-term in vitro assays, whereas pro of these promoting or cocarcinogenic metabolites can be min moting agents are not necessarily mutagenic or have only weak imized by pyridoxine administration. Of substantial interest is mutagenic activity. Promoting agents usually have the ability to the report (10) that pyridoxine was significantly better than induce hyperplasia of target tissues without initiation, but this placebo in preventing recurrence of Stage I bladder cancer in alteration does not progress toward cancer formation unless those patients not developing recurrence within a 10-month the tissues first have been treated with initiating agents. Tryp- period, although quantitative urinary tryptophan metabolism tophan and several of its metabolites were not mutagenic by was not measured in these patients. the Ames test (2). However, focal hyperplasia or cellular prolif eration following tryptophan feeding was reported in mice (21 ), ACKNOWLEDGMENTS rats (25), and dogs (33). We now have demonstrated that mouse urinary bladder ODC We thank Drs. R. K. Boutwell and A. K. Verma of the McArdle Laboratory for Cancer Research. University of Wisconsin, for assistance with method develop and SAMD activities were stimulated by feeding L-tryptophan, ment and critical discussions; D. Lueder for preparation of histology sections; the method generally selected for experimental induction of and S. Pertzborn and K. Blomstrom for aid with manuscript preparation. bladder neoplasia by this chemical (12, 16, 21, 25, 34), that direct application of several tryptophan metabolites to the REFERENCES mouse urinary bladder led to a rapid, transient induction of urinary bladder ODC activity within 5 hr, and that the metabo 1. Boutwell, R. K. Biochemical mechanism of tumor promotion. Carcinog. Compr. Surv., 2: 49-58. 1978. lites which activated ODC also induced a hyperplastic reaction 2. Bowden, J. P., Chung, K.-T., and Andrews, A. W. Mutagenic activity of of the urothelium following their topical application. Xanthu- tryptophan metabolites produced by rat intestinal microflora. J. Nati. Cancer renic acid, ou-kynurenine, L-kynurenine, anthranilic acid, and Inst., 57:921-924, 1976. 3. Brown, R. R., Price, J. M., Frieden, G. H., and Burney, S. W. Tryptophan quinaldic acid showed significant increases of bladder ODC metabolism Â¡npatients with bladder cancer: geographical differences. J. activity; all these compounds except anthranilic acid were Nati. Cancer Inst.. 43: 295-301, 1969. 4. Bryan. G. T. The role of urinary tryptophan metabolites in the etiology of active carcinogens by the bladder pellet implantation technique bladder cancer. Am. J. Clin. Nutr., 24: 841-847, 1971. (4, 9). Conversely, L-tryptophan or D-kynurenine, 3-hydroxy- 5. Bryan, G. T. 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The effect of added dietary nomenon is not simply the result of physical or chemical tryptophane on the occurrence of 2-acetylaminofluorene-induced liver and bladder cancer in rats. Cancer Res., 10: 454-459, 1950. irritation but is due to rather specific biological or biochemical 15. Erturk. E., Cohen, S. M.. and Bryan, G. T. Induction, histogenesis. and processes. isotransplantability of renal tumors induced by formic acid 2-{4-<5-nitro-2- furyl)-2-thiazolyl]hydrazide in rats. Cancer Res., 30: 2098-2106, 1970. The results of the present study provide additional evidence 16. Fukushima, S., Frieden, G. H.. Jacobs. J. B., and Cohen, S. M. Effect of L- that some L-tryptophan metabolites have properties consistent tryptophan and sodium saccharin on urinary tract carcinogenesis initiated with those of a promoter for urinary bladder carcinogenesis. by A/-[4-{5-nitro-2-furyl)-2-thiazolyl]formamide. Cancer Res., 41: 3100- Although urinary metabolites of tryptophan were not measured 3103, 1981. 17. Hicks, R. M., and Chowaniec, J. The importance of synergy between weak in this study, it was previously shown (9) that, following a single carcinogens in the induction of bladder cancer in experimental animals and dose of 25 mg of L-tryptophan to mice, increased quantities of humans. Cancer Res., 37: 2943-2949. 1977. 18. Izumi. K., Hirao, Y.. Hopp, L., and Oyasu. R. In vitro induction of ornithine several metabolites were in urine. Several of these metabolites decarboxylase in urinary bladder carcinoma cells. Cancer Res., 41: 405- are excreted in augmented quantities in the urine of as many 409. 1981.

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19. JÃ¤nne,J.. Poso, H., and Raina, A. Polyamines in rapid growth and cancer. Effect of DL-tryptophan on tumorigenesis in the urinary bladder and liver of Biochim. Biophys. Acta, 473. 241-293, 1978. rats treated with N-nitrosodibutylamine. Gann, 62: 163-169, 1971. 20. Marks, F., FÃ¼rstenberger. G., and Kownatzki, E. Prostaglandin E-mediated 30. Olson, J. W., and Russell, D. H. Prolonged induction of hepatic ornithine mitogenic stimulation of mouse epidermis in vivo by divalent cation ionophore decarboxylase and its relation to cyclic adenosine 3':5'-monophosphate- A 23187 and by tumor promoter 12-O-tetradecanoylphorbol-13-acetate. dependent protein kinase activation after a single administration of diethyl- Cancer Res., 41: 696-702, 1981. nitrosamine. Cancer Res., 39: 3074-3079, 1979. 21. Matsushima. M. The role of L-tryptophan's promoting factor on tumorigen- 31. Oyasu, R.. and Hopp, M. L. The etiology of cancer of the bladder. Surg. esis in the urinary bladder. 2. Urinary bladder carcinogenicity of FANFT Gynecol. Obstet., Â»38.97-108, 1974. (initiating factor) and L-tryptophan (promoting factor) in mice. Jpn. J. Urol.. 32. Price, J. M. Etiology of bladder cancer. In: E. Maltry. Jr. (ed.). Benign and 68: 731-736, 1977. Malignant Tumors of the Urinary Bladder, pp. 189-261. Flushing, N. Y.: 22. Matsushima, M., and Bryan, G. T. Early induction of mouse urinary bladder Medical Examination Publishing Co., Inc., 1971. ornithine decarboxylase activity by rodent vesical carcinogens. Cancer Res., 33. Radomski, J. L., Glass. E. M.. and Deichmann. W. B. Transitional cell 40: 1897-1901, 1980. hyperplasia in the bladders of dogs fed OL-tryptophan. Cancer Res., 37: 23. Matsushima, M., Takano, S., and Bryan, G. T. Induction of ornithine decar 1690-1694, 1971. boxylase (ODC) activity in mouse urinary bladder (UB) by tryptophan (TRP) 34. Radomski, J. L., Radomski, T.. and MacDonald, W. E. Cocarcinogenic metabolites. Fed. Proc., 39. 1902, 1980. interaction between o,L-tryptophan and 4-aminobiphenyl or 2-naphthylamine 24. Matsushima, M., Takano, S.. and Bryan, G. T. Induction of mouse urinary in dogs. J. Nati. Cancer Inst.. 58: 1831-1834, 1977. bladder ornithine decarboxylase (ODC) activity by tryptophan metabolites. 35. Russell. D. H., and Durie. B. G. M. Prog. Cancer Res. Ther., 8: 1-178, In: Third International Symposium on Tryptophan Metabolism; Biochemistry, 1978. Pathology and Regulation. ISTRY-80 Kyoto, Japan, August 4 to 7. p. 108, 36 Scalabrino, G., Poso. H.. HÃ¶lttÃ¤.E..Hannonen, P., Kallio. A., and JÃ¤nne,J. 1980. Synthesis and accumulation of polyamines in rat liver during chemical 25. Miyakawa, M., and Yoshida, O. DNA synthesis of the urinary bladder carcinogenesis. Int. J. Cancer, 27: 239-245, 1978. epithelium in rats with long-term feeding of ot-tryptophan-added and pyri- 37. Takano, S., Matsushima, M.. Ertiirk. E.. and Bryan. G. T. Early induction of doxine-deficient diet. Gann, 64: 411-413, 1973. rat colonie epithelial ornithine and S-adenosyl-L-methionine decarboxylase 26. Morris, C. R., and Bryan, G. T. Absorption of C'4-labeled tryptophan, its activities by N-methyl-N'-nitro-W-nitrosoguanidine or bile salts. Cancer Res., metabolites, glycine, and glucose by the urinary bladder of the mouse. 41: 624-628, 1981. Invest. Urol., 3. 577-585. 1966. 38. Verma. A. K., Shapas, B. G., Rice, H. M.. and Boutwell, R. K. Correlation of 27. Mufson, R. A.. Fischer. S. M., Verma, A. K., Gleason, G. L., Slaga. T. J.. and the inhibition by retinoids of tumor promoter-induced mouse epidermal Boutwell, R. K. Effects of 12-O-tetradecanoylphorbol-13-acetate and mez- ornithine decarboxylase activity and of skin tumor promotion. Cancer Res., erein on epidermal ornithine decarboxylase activity, isoproterenol-stimulated 39: 419-425, 1979. levels of cyclic adenosine 3':5'-monophosphate, and induction of mouse 39. Weinstein, I. B., and Troll. W. National Cancer Institute Workshop on Tumor skin tumors in vivo. Cancer Res., 39: 4791 -4795, 1979. Promotion and Cofactors in Carcinogenesis (Meeting Report). Cancer Res., 28. O'Brien, T. G. The induction of ornithine decarboxylase as an early, possibly 37: 3461 -3463. 1977. obligatory, event in mouse skin carcinogenesis. Cancer Res., 36: 2644- 40. Yoshida, O., Brown, R. R., and Bryan, G. T. Relationship between tryptophan 2653, 1976. metabolism and heterotopic recurrences of human urinary bladder tumors. 29. Okajima, E., Hiramatsu. T., Motomiya, Y., Iriya, K., ljuin, M., and Ito, N. Cancer (Phila.), 25: 773-780, 1970.

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Masahiro Matsushima, Sadamu Takano, Erdogan Ertürk, et al.

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