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Free Amino Acids in Growing and Regressing Ascites Cell Tumors: Host Resistance and Chemical Agents*

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Free Amino Acids in Growing and Regressing Ascites Cell Tumors: Host Resistance and Chemical Agents* Free Amino Acids in Growing and Regressing Ascites Cell Tumors: Host Resistance and Chemical Agents* EUGENEROBERTS,K.KANOTANAKA,!T. TANAKA,! ANDDAISYG. SIMONSEN (Departments of Biochemistry and Cytology, Medical Research Institute, City oj Hope Medical Center, Duarte, Calif.) Previous studies have been made of the pat quent experiments with the Yoshida ascites tumor terns of free or easily extractable ninhydrin-reac- showed that glutamine can be taken up rapidly tive constituents in a variety of animal tumors and utilized by the tumor cells in vivo, but that (7, 13-17). Although each normal tissue in a par these cells possess only limited permeability to ticular species has been found to have a distribu glutamic acid (16). tion of these substances characteristic for that The present report is concerned with studies of tissue, all of the tumors examined have shown a the free or easily extractable amino acids and of similar pattern. Relatively low levels of free or the cytological characteristics of the Yoshida easily extractable glutamine have been observed sarcoma when grown in susceptible (J strain) and in the extract of the tumors. Glutamine was resistant (Wistar) strains of rats and of the effects of sarkomycin, nitromin, and crude podophyllin on the Yoshida ascites tumor and of sarkomycin on the Ehrlich tumor. MATERIALS AND METHODS The procedures for transmission of the tumor, cytological observation, and two-dimensional paper chromatography have all been described previously (14, 17). A reference diagram showing the relative positions of the detectable constitu ents on the paper chromatograms is shown in Chart 1. RESULTS AND DISCUSSION CHART 1.—Diagram showing constituents on chromato- graiHs: 1, phenylalanine; 2, tyrosine; 3, leucine and isoleucine; Free amino acids of the Yoshida sarcoma grown 4, valine; 5, ethanolamine; 6, methionine (methionine sulfone) ; in J strain or Wistar rats.—The Yoshida sarcoma 7, taurine; 8, proline; 9, a-amiiio-n-butyric acid; 10, threonine; is usually carried in J strain rats, a strain in which 11, serine; 12, cystine (cysteic acid); 13, alenine; 14, histidine; the tumor has a high degree of transplantability 15, /3-aIanine and/or glycerylphosphorylethanolamine; 16, glu (approximately 95 per cent takes). A failure of the tamine; 17, glycine; 18, glutamic acid; 19, arginine; 20, lysine; ¿1,ethanolamine phosphoric ester; 22, aspartic acid; 28, gluta- latter strain of rats to breed properly for a period thione (oxidized) ; 24, glutathione. made it necessary to transmit the tumor in Wistar rats. The tumor grows in the latter animals for not detected at any time after transplantation in several days after inoculation and then begins to the solid or ascites forms of the C1498 leukemia undergo regressive changes, finally disappearing grown in a susceptible line of mice (C57BL/ completely. The tumor persists before regressing 10-H-2b) but appeared in these tumors when they for longer periods when grown in young than in began to regress in a resistant subline (C57BL/ adult Wistar rats. However, it is possible to main 10-H-2d) which differed by one gene (13). Subse- tain the tumor indefinitely in the Wistar rats by * This investigation was supported by research grant C- serial transplantation at intervals of approximate ly 5 days.1 In this manner the Yoshida sarcoma has 2568 from the National Cancer Institute, United States Public Health Service. been maintained in animals of the Pacific Farms t Present address, Department of Zoology, Hokkaido Wistar strain (WP) for more than 60 generations. University, Japan. 1This also was observed previously for the Yoshida sarcoma Received for publication June 18, 1956. by N. Mitsuoka in unpublished observations. 970 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1956 American Association for Cancer Research. ROBERTSet cd.—FreeAmino Acids of Ascites Tumors 971 Preliminary Chromatographie examination of the WP rat. Subsequently, similar observations extracts of the cells and fluid of the Yoshida sar were made in three additional WP rats. coma grown in the WP rats revealed the presence A cytological analysis of the tumor cells in the of glutamina in some samples, while this amino two rats is shown in Table 1, and smears showing acid was not noted in any of the samples obtained the appearance of the cells at 4 and 7 days, re from J strain rats bearing the same tumor. It was, spectively, are shown in Figures 1-4. In the WP therefore, of considerable interest to follow the rat a high rate of cell division was maintained free amino acids in the cells and fluid on successive through the 6th day after transplantation (see days after transplantation of the Yoshida sarcoma Fig. 1). On the 7th day no mitotic cells were in both the WP and J strain rats and to attempt to found, and the percentage of damaged cells and TABLE1 CYTOLOGICALANALYSESOFGROWINGANDREGRESSINGTUMORSINRATS TlllEDay« PERCENTAGEDISTRIBUTIONSor CELL CATEGORY aftertransplanta NO.CELLSEXAMINED1*53124812211718850119312521185122011571240126312151197117011511178126011541123127213901227125315451456Restingtumorrelis81.780.173.738.20.081.479.280.581.586.585.081.682.584.681.080.9Mitotictumorcell»2.23.93.803.13.9403.72.41.01.91.40.20.30.1Damagedtumorcells00.22.320.0000.20.10.30.60.40.52.1.i.l5.0Nontumorcells*16.115.820.241.810015.616.915.314.710.812.516.115 TBEAT- MENT STRAIN tion456784.567891011121814Hours Xone WPf None 613.113.614.0 afterinjection(before)ÃŽ4612(before)12172436TOTAL Xitrominî 86.8 2.8 0 10.4 85.8 3.2 0.1 10.9 86.5 1.0 ¿.1 10.4 89.9 0.2 a.l 7.8 80.0 0.0 7.3 12.7 84.0 2.3 0.0 13.7 82.6 0.1 5.5 11.8 79.2 0.1 6.5 14.2 70 5 0.8 3.4 25.8 69.9 2.2 15 26.4 * These are various types of leukocytes (especially monocytes and basophils in regression) and lymphocytes. t Pacific Animal Farms, Wistar strain. ÕMethylbis(/}-chloroethyl)amine-N-oxide hydrochloride; intraperitoneal dose, 30 mg/kg. correlate the findings and cytological observations, content of leukocytes increased sharply (Fig. 2). since in the previous study with C1498 leukemia At this time a number of the tumor cells were in mice it was found that the beginning of regres found to be undergoing disintegration. At 8 days sion of the tumors grown in the resistant subline after transplantation no further tumor cells were was accompanied by the appearance of free detectable in the peritoneal fluid of the WP rat, glutamine (13). the cellular content consisting almost entirely of Yoshida sarcoma cells were transplanted from leukocytes. In the J strain rat tumor cells began a Wistar rat into a rat of the Wistar strain (240 growth immediately after inoculation, and the gm.) and one of the J strain (275 gm.). Samples of mitotic frequency was at the highest level between tumor were removed by peritoneal puncture be 4 (Fig. 3) and 7 (Fig. 4) days after transplantation. ginning with 4 days and continuing until death at The cytological features of the tumor cells during 14 days in the animal of the J strain or until regres this period resembled those observed for the 4- and sion occurred at 8 days after transplantation in 5-day cells in the WP rat. The number of mitotic Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1956 American Association for Cancer Research. 972 Cancer Research figures decreased after the 8th day. An accumula ing up to the 7th day of transplantation, and the tion of a large amount of ascitic fluid took place glutamic acid content of the fluid remained ap during this period. Toward the end of the life span proximately the same throughout the period of the J strain rat there was an increase in the per studied (Figs. 6, 8, 10, and 12). Although the centage of damaged, degenerating cells which tumor grown in WP rats was used for some of the were characterized by pyknotic masses of nuclear subsequent experiments, the results were em substance, and there was a concomitant decrease ployed only in those instances in which it was in the mitotic index. The content of leukocytes, shown that the glutamine content of the control which was minimal at 8 days, remained relatively cells and fluid was low on the day of the experi constant throughout the period of observation, ment and when the condition of the tumor was ranging between 10.8 and 16.9 per cent of the total judged to be optimal by cytological criteria. cell count. Effect of sarkomycin on the Yoshida osciles tu The patterns of free amino acids found at 4 and mor.—Sarkomycin, a weak antibiotic, has been 5 days in the cells grown in both strains of animals, found to have a marked destructive effect on cells which were not distinguishable cytologically at of the Ehrlich ascites tumor and to be somewhat this time, were similar with the exception of the less effective on the Yoshida tumor and the MTK- finding of a larger amount of glutamine in the cells sarcoma II (18, 22). Evidence has been presented grown in the WP rat (Figs. 5 and 7) than in the J which indicates that the active material is 2- strain rat (Figs. 13 and 15). Glutamine is ordinari methylene-3-oxocyclopentanecarboxylic acid (4). ly not found in this tumor in the J strain when the Preliminary results in this laboratory indicated transplantation is made from the same strain. On that sarkomycin (preparation RC-903,5F76, Bris the 6th day (Fig. 9) the amount of glutamine in tol) was rapidly effective against cells of the the tumor grown in the WP animal increased Yoshida tumor when an intraperitoneal dose of above that found on the previous 2 days, while approximately 30 mg/100 gm rat was employed.
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