PREVIOUS studies on the localization of fluorene-2,7-di-(sulfonamido-2-naphthalene)-S35 revealed that the presence of a subcutaneously transplanted tumor decreased the uptake of this radioactive compound by the liver and spleen of mice (Argus and Hewson, 1954; Argus, Hewson and Ray, 1956). This phenomenon was demonstrated in both CAF1/Jax mice bearing a squamous cell stomach carcinoma and C3H mice bearing the Barrett mammary adenocarcinoma. Autoradiograms indicated that it is a phagocytic function of the reticuloendothelial system that is impaired (Argus, Hewson and Ray, 1956). Subsequent studies to determine if other stress conditions produce this phenomenon showed that, unlike the presence of a tumor, neither X-irradiation nor cortisone affects the uptake of fluorene-2,7-di-(sulfonamido-2-naphthalene)-S35 by the liver and spleen of mice or rats (Argus, Kane and Ray, 1960;Malejka, Argus and Ray, 1961).In the present studies this localization phenomenon was investigated in hamsters and rats as influenced by the presence of two different types of transplanted tumors (a fibrosarcoma and Walker carcinosarcoma 256). The effect of metastatic tumors existing after surgical removal of the transplanted sarcoma was studied in hamsters, and the effects of liver regeneration (resulting from partial hepatectomy) and of pregnancy were observed in rats. To determine if the phenomenon occurs as a result of the increase in proliferation of liver cells (Laird andBarton, 1959, 1960) caused by the carcinogen, 2-acetylaminofluorene, before the gross appearance of tumors, the uptake of fluorene-2,7-di-(sulfonamido-2-naphthalene)-S35 by the liver and spleen of rats fed the carcinogen, 2-acetylaminofluorene, for varying periods of time was investigated. MATERIALS AND METHODSFluorene-2,7-di-(sulfonamido-2-naphthalene)-S35 having a specific activity of 13,400 disintegrations/sec. /mg. (0-36 /ac/mg.) was prepared as previously reported (Argus and Hewson, 1954). For administration, the radioactive compound was dissolved (9 mg./ml.) in 0 05N NaOH except for a study of two groups of hamsters where the injection medium was dilute sodium bicarbonate and * Present address:

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THE desirability of finding a radioactive compound that would localize in tumor tissue and which could be used in the diagnosis and therapy of internal cancer has long been recognized. Previous studies carried out in our Laboratory have shown that with certain sulfur 35-labeled derivatives of fluorene, localization in tumor tissue is favorable compared to liver, kidneys, spleen, blood and muscle. The first of these promising compounds was disodium fluorene-2,7-disulfonate-S35 (Argus, 1953). This compound was then used as the basis for the synthesis of a number of related substances which could be used for investigating the relation of chemical structure to tumor localizing properties in the hope of obtaining compounds of improved characteristics. Of those tested, sulfonated fluorene-2,7-di-(sulfonamido-2'-naphthalene)-S35 showed the best tumor localization. Two compounds without free sulfonic acid groups, fluorene-2,7-disulfonamide-S35 and fluorene-2,7-di-(sulfonamido-2'-naphthalene)-S35, did not selectively concentrate in tumor tissue (Argus and Hewson, 1954). There seemed to be some indication at 8 hours, however, that the latter compound showed a differential in the blood between tumor-bearers and non-tumor-bearers. This difference was not large but if real could be of considerable diagnostic importance since there was the possibility that the effect could be enhanced in a new compound of suitable structure.In the present study three new substances were investigated in tumor-bearing and tumor-free mice. These were fluorene-2,7-di-(sulfonamidobenzene)-S35 (I), a disulfonamido derivative of fluorene with molecular weight falling between the compounds previously tested; and two related biphenyl derivatives, biphenyl-4, 4'-di-(sulfonamidobenzene-4-carboxylic acid)-S35 (II) and biphenyl-4,4'-di-(sulfonamidobenzene-S35-4-sulfonamide) (III Biphenyl-4,4'-di-(sulfonamidobenzene-4-carboxylic acid)-S35 (II).-Biphenyl-4, 4'-disulfonyl chloride-S35, 1-7 g. (0-005 moles), was finely powdered and slowly added to a solution of p-aminobenzoic acid, 2-8 g. (0-020 moles), in 30 ml. anhydrous acetone. The mixture was stirred for 30 minutes at reflux temperature and for 10 hours at room temperature. The light gray precipitate was collected, washed with 750 ml. hot water and dried over phosphorus pentoxide. The yield was 2-6 g. (82-6 per cent of theory); the compound melted at 3200. Recrystallization by dissolving in 70 ml. of a 2: 5 mixture of water: dimethylformamide and precipitating with 30 ml. of water gave a white product melting at 3270 and having a specific activity of 16,000 disintegrations per second per mg. Analyses gave 56-15 and 56-20 per cent C, 4-96 and 5-03 per cent N, and 11-26 and 11-28 per cent S; the calculated values are 56-51 per cent C, 5-07 per cent N, and 11-61 per cent S.Biphenyl-4,4'-di-(sulfonamidobenzene-S35-4-sulfonamide) (111).-Biphenyl-4,4'-disulfonyl chloride-S35, 3 g. (0-0085 moles), dissolved in 35 ml. of anhydrous acetone was added with stirring to a solution of sulfanilamide, 7-35 g. (0-42 mole...