Rail et a2. (26) first described the localization and per sistence of a yellow fluorescence in bone (32) and in a number of different animal tumors following tetracydlin& administration. The localization of fluorescence in a variety of human tumors has been confirmed (21, 25, 33) and has been used as a clinical cytologic test for gastric carcinoma (4, 12, 15) and as an aid at the operating table (20, 31). Since tetracycline drugs themselves have been shown to be without therapeutic efficacy in a large spectrum of experimental tumors (11), it has been suggested that the drug could be coupled to other agents, resulting in their migration to and concentration in tumors. McLeay €1al. (21) have suggested the use of a boron-coupled 6 This work was supported in part by grants from the United States Public Health Service, Miles-Ames Laboratories, and the Gastrointestinal Fund of the Peter Bent Brigham Hospital. t Research Fellow, Harvard Medical School and Universidad Central de Venezuela, Caracas, Venezuela. 1 Referred to hereafter as TTC. Received for publication July 2, 1964. tetracycline which could be bombarded in situ with a neutron beam. There is considerable difference of opinion regarding the site of localization, within the tumor, of the fluorophor. Fluorescence has been localized by various investigators in inflammatory tissue (9), in the macrophages (33), and in the mitochondria of normal liver and kidney cells (6). The present studies were undertaken to determine the selectivity of TTC concentration in tumor tissue and the relationship between fluorescence and TTC concentration as measured by tritiated TTC,2 which differs from the parent molecule only by the substitution of tritium for hydrogen in the 7-position. The experimental conditions under which maximal tumor fluorescence and maximal TTC concentration might be attained were also investi gated. Histologic studies were performed to determine the site of localization of the TTC within the tumor. 2This 7-tritiotetracyclinewasgenerouslycontributedby Dr. Donald Buyske of Lederle Division, American Cyanamid, Pearl River, N. Y. 1845 Factors Affecting the Site and Degree of Localization of Tetracycline in Sarcoma 37 Tumors* Luis MACHADO, ISIDORO ZAIDMAN,t JOSEPH F. GERSTEIN, FRANZ LICHTENBERG, AND SEYMOUR J. GRAY (The Medical Clinic, Peter Bent Brigham Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts) SUMMARY A study has been made of the localization of tetracycline (TTC) in transplantable tumors of the mouse (S-37) by utilizing the radioactivity and fluorescence of tritiated TTC as measures of concentration. Evidence is presented that the drug is sequestered within the tumor; that the avidity of the tumor for TTC increases with increasing age of the tumor; and that the actual site of affinity is the necrotic or prenecrotic area of the tumor, as detected by gross and histologic investigations. Fluorescence of the tumor appears definitely related to tumor age. No tumors less than 10 days old fluoresced, whereas 100 per cent of tumors 13 days or more old were fluorescent. When tritiated TTC was injected into mice bearing 9-day-old S-37 tumors, the concentration of TTC in the necrotic areas was demonstrated within 2 days after in jection. The TTC concentration in the nonfluorescent viable areas fell precipitously within 2 to 6 days, whereas the TTC concentration in the necrotic fluorescent areas decreased much more gradually, demonstrating that TTC is retained more avidly by the necrotic zones. Histologic studies indicate that the S-37 tumor cell does not display fluorescence until it begins to show cytologic evidence of necrosis. The typical zones which fluo resced under ultraviolet light manifested obvious necrosis, but had not undergone the most advanced changes of fragmentation and loss of structure. An attempt is made to hypothesize the mechanism of localization by relating the well-known propensity of the tetracydlines for binding with a variety of biologic ma terials to the phenomena occurring during the necrosis of tissues. on April 3, 2016. © 1964 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from