538 2. ANALOGS OF ENZYME REACTION COMPONENTS 



not clear (Madinaveitia, 1946). Toxoflavin is a poisonous substance from 

 Pseudomonas cocovenenans and responsible for some fatal food poisonings in 

 Java. It quite potently inhibits the growth of E. coli, S. aureus, B. subtilis, 

 and Shigella, as well as being toxic to experimental animals (Latuasan and 

 Berends, 1961). The mechanism is unknown but it was postulated that tox- 

 oflavin is an effective electron-acceptor and removes electrons from the 

 transport chains to form hydrogen peroxide, possibly competing with the 

 natural flavin coenzymes (or accepting electrons from them). Relatively 

 little has been done on the induction of riboflavin deficiency in animals. 

 Isoriboflavin almost stops the growth of young rats at 2 mg/day and ribo- 

 flavin is able to reverse this (Emerson and Tishler, 1944), and galactoflavin 

 appears to produce very similar effects (Emerson et al., 1945). The 6-chloro 

 and 7-chloro analogs of riboflavin (Lambooy, 1955) and the dinitrophena- 

 zine analog (Woolley, 1944 b) produce mild deficiency states in rats and 

 mice. Effects have usually been determined by growth rates, and typical 

 symptoms of riboflavin deficiency have seldom been noted, mainly because 

 it requires a fairly long time to deplete the tissues of enzyme-bound co- 

 enzymes. 



Some interesting and suggestive reports on the carcinostatic activity of 

 certain analogs have appeared. The 6,7-dichloro-9-(r-D-sorbityl)isoalloxa- 

 zine analog causes regression of mouse lymphosarcoma, the ribityl compound 

 has slight activity, and the other sugar alcohol derivatives are inactive 

 (Holly et al., 1950). Replacement of the ribityl group with nonsugar residues 

 gives riboflavin antagonists which inhibit L. casei and produce deficiency 

 states in rats. The 9-hydroxyethyl analog of riboflavin (U-2113) weakly 

 suppresses mouse adenocarcinoma (Shapiro et al., 1956), and the 9-aceto- 

 xyethyl analog (11-2112) behaves similarly (Lane et al., 1958). However, 

 U-2112 given to patients with various types of cancer (0.25-6 g/day for 

 5-84 days, with total doses 1.25-226 g) exhibits no beneficial action and 

 no evidence of riboflavin deficiency is seen; this was attributed to the rapid 

 hydrolysis of this substance in man. The 9-hemisuccinoxyethyl analog (U- 

 6538) does not inhibit L. casei but depresses growth in rats at 10 mg/kg/ 

 day, which is reversible with riboflavin (Lane et al., 1959). It is quite ef- 

 fective against lymphosarcoma in rats and at 5 mg/kg/day leads to a 66% 

 inhibition of tumor growth without depressing the over-all growth rate. 

 Two of four patients receiving the compound showed changes suggestive 

 of riboflavin deficiency but no evidence of carcinostasis was observed, per- 

 haps due to the terminal nature of the disease and the metabolism of the 

 analog. Galactoflavin is known to cause tumor regression in rodents. It is 

 tolerated by patients at a dose of 1 g every 8 hr for 2-5 months, and de- 

 ficiency symptoms do not occur unless the diet is low in riboflavin (Lane 

 and Brindley, 1964). Presumably reports on its carcinostatic activity will 

 be published. 



