Dieter Werner

Catabolism of some cytotoxic purine derivatives by xanthine oxidase and peroxidase

Abstract Some cytotoxic purinyl-6-derivatives of biogenic amines and amino acids as well as the purinyl-6-derivatives of xenobiotic primary and tertiary amines can serve as substrates for xanthine oxidase. This enzymatic oxidation leads to biologically inactive 2,8-dioxy-purinyl-derivatives. The catabolism of these hydroxylated purinyl-derivatives formed by xanthine oxidase can be effected by peroxidaseJhydrogenperoxide and by catalase/alkylhydrogenperoxide. The relation between substrate specificity for xanthine oxidase and cytotoxic activity will be discussed.

Stimulierung der Proteinsynthese durch Cytotoxisches Puryl-6-tryptamin

P u r y l 6 t r y p t a m i n (I) v e r u r s a c h t in der Gewebeku l tu r in K o n z e n t r a t i o n e n yon 5 bis l0 ~g/mI Mitoses tOrungen El, 2], w~thrend hOhere K o n z e n t r a t i o n e n a l lgemeinere \ u s t 6 r u n g e n bewirken. Bei U n t e r s u c h u n g e n ~ber die DNS-, R N S u n d P r o t e i n s y n t h e s e in v i t ro d u t c h cy to tox i sche P u r i n d e r i v a t e [3-5] wurde der konzen t ra t ionsabh&ngige Einflul3 des I au f die P r o t e i n s y n t h e s e yon L ebe r schn i t t en un te r such t : bei h6he ren S u b s t a n z k o n z e n t r a t i o n e n ( c = 20 ~g/ml) wird die P r o t e i n s y n t h e s e k o n z e n t r a t i o n s a b h g n g i g g e h e m m t , bei n iedr igen K o n z e n t r a t i o n e n is t die Syn these erhSht . Der Ak t iv i e rungse f f ek t bei ~0 ~zg/ml k o n n t e s t a t i s t i s ch ges icher t werden. Ve rmu t l i ch wird d u t c h ger inge Subs t anz k o n z e n t r a t i o n e n ein Rezep to r abges~ t t ig t u n d d a m i t die Mi toses t6 rung u n d die S t imul i e rung der P r o t e i n s y n t h e s e veru r sach t . Die AbsXt t igung wei terer Rezep to ren du rch hOhere S u b s t a n z k o n z e n t r a t i o n e n ft~hrt zu einer s t a r k e n H e m m u n g der P ro t e in syn these , die sich morpholog isch in al lgeme!ner W a e h s t u m s h e m m u n g zeigt.

The pathway of catabolism of cytotoxic purinyl-6-substituted amines in vivo

Abstract 14 C-labelled purinyl-6-histamine is catabolized in vivo in the same way as in vitro . The main metabolites are 2,8-dihydroxy-purinyl-derivatives, carbon-dioxide and a product in which the imidazole ring of the purine ring system is opened. The speed of catabolism, the incorporation of produced carbon-dioxide into adenine and guanine, and the inhibition of the catabolism by allo-purinol has been measured.

Enzymatischer Abbau cytotoxischer Purinderivate

I-/Ssung behande l t und so der E m m e r i e E n g e I R e a k t i o n zugSnglich gemach t . Die M e s s u n g e n er fo lg ten bet 5 t S n m m i t d e m Spek t r a lpho tome t e r . Aus den M e s s u n g e n ergab sich, dab in der u n t e r s u e h t e n Gers te 1,2 ~MoI Ub i ch i non oder 950 ~zg/ 100 g Trs. v o r h a n d e n waren. I m Ver lauf der K e i m u n g wa r der U b i c h i n o n g e h a l t der Gers te neben ether Ver te i lung fiber K o r n u n d K e i m e einer mengenm~il3igen K n d e r u n g un te rwor fen . E ine m e r k b a r e B iosyn t he se l a n d n a c h 4 K e i m t a g e n s tar t . N a c h 7t~giger K e i m u n g b e t r u g die U b i c h i n o n k o n z e n t r a t i o n in den MXlzungsprodnk ten 2,54 ~tMol oder 20t 3 ~.g U b i e h i n o n / i 0 0 g Gers te Trs. , wovon 0 , t63 ~Mol oder t30 ~zg auf die Ke ime ent fielen. Die vor l i egenden U n t e r s u c h u n g e n w u r d e n m i t U n t e r s t i i t z u n g des B u n d e s m i n i s t e r i u m s fiir W i r t s c h a f t du rch V e r m i t t l u n g der A r b e i t s g e m e i n s c h a f t Indus t r i e l l e r F o r s c h u n g s v e r e i n i g u n g e n e.V. durchgef i ih r t , woftir an dieser SteIle bes t ens g e d a n k t set. Ffir die Bere i t s t e l lung der T e s t u b i c h i n o n e d a n k e n wir der Fa. D e u t s c h e H o f f m a n n L a R oche AG., Grenzach (Baden), u n d f~r die A n f e r t i g u n g des M a s s e n s p e k t r u m s der Fa. Scher ing AG., Berlin.

Analysis of the purinyl-6-histamine binding to ribonucleic acids.

Abstract Purinyl-6-histamine, which is selectively cytotoxic to tumour cells in tissue culture, does not inhibit the incorporation of precursors of macromolecular syntheses into acid insoluble material of ascites tumour cells in vitro , but it is bound to RNA within cells and to isolated RNA in vitro , as demonstrated by sedimentation studies, Sephadex G50 chromatography, polyacrylamide gel eclectrophoresis and Millipore filtration. The intrinsic binding constant for the binding to isolated RNA is in the order of 10 3 × M −1 (0.1 M NaCl). There is some evidence (P ≦ 0.1) that purinyl-6-histamine has a higher affinity in ascites tumour RNA and yeast sRNA than to liver RNA.