5 research outputs found
HatĂ©kony tumorellenes kĂ©szĂtmĂ©nyek előállĂtása target Ă©s drug molekulák kombináciĂłjával = Synthesis of effective antitumoricidal compounds with the combination of target and drug molecules
Az irányĂtott tumorterápiában alkalmazhatĂł Ăşj vegyĂĽleteket terveztĂĽnk Ă©s állĂtottunk elĹ‘. GnRH-III dimer származĂ©kok nagyobb tumorellenes hatást Ă©s kisebb endokrin aktivitást mutattak, mint a monomer. Enzim stabilitásuk szintĂ©n fokozĂłdott. In vivo tumorellenes hatásukat HT-29 vastagbĂ©l tumort hordozĂł egereken tesztelve 50%-os gátlást Ă©rtĂĽnk el. GnRH-I illetve GnRH-II Ă©s GnRH-III hormone peptideket tartalmazĂł vegyes dimereket is előállĂtottunk. T47-D emlĹ‘tumor sejteken 80% fölötti gátlást tapasztaltunk egy GnRH-I Ă©s GnRH-III peptidet tartalmazĂł dimer esetĂ©n. A dimerek szabadalmaztatása folyamatban van. A GnRH-III hormont hatĂłanyagok szállĂtására is felhasználtuk. Antraciklineket kapcsoltunk hozzá Ă©szter-, hidrazon- oxim Ă©s amidkötĂ©ssel. Az utobbi kivĂ©telĂ©vel valamennyi konjugátum jelentĹ‘s in vitro tumorellenes hatást mutatott. A daunorubicin-GnRH-III oximkötĂ©sű konjugátumot választottuk ki in vivo kĂsĂ©rletekhez C26 egĂ©r vastagbĂ©ltumort hordozĂł egereken. Ha a kezelĂ©st a 4. Ă©s 7. napon vĂ©geztĂĽk a tumorbeĂĽltetĂ©st követĹ‘en, 40-50%-os tumornövekedĂ©s gátlást kaptunk (15 mg/kg Dau hatĂłanyag tartalom mellett). Ugyanakkor a konjugátum kivĂ©dte a drog toxikus hatását, Ă©s tĂşlĂ©lĂ©snövekedĂ©st is eredmĂ©nyezett a szabad droghoz kĂ©pest. Ez az elsĹ‘ olyan eredmĂ©ny, ahol oximkötĂ©ssel konjugált daunorubicin származĂ©kkal tumorellenes hatást Ă©rtek el. Tuftsin-szerű hordozĂłmolekulák alkalmazásával kemotaxison alapulĂł hatĂłanyag cĂ©lbajuttatást tudtunk megvalĂłsĂtani. | New derivatives for targeted cancer therapy were developed. Dimers derived from GnRH-III had higher antitumor effect on cancer cells and lower activity on LH secretion than the monomer. Enhanced enzymatic stability of the dimers was also determined. The in vivo antitumor effect of the dimers was studied on HT-29 colon tumor bearing mice and 50% tumor growth inhibition was detected. Asymmetric dimer derivatives derived from GnRH-I or GnRH-II and GnRH-III were prepared. The combination of GnRH-I and GnRH-III resulted in a superagonist compound having 80% in vitro antiproliferative effect on T47-D human breast cancer cells. GnRH-III was also used as targeting moiety for anticancer drug delivery. Anthracyclines were attached to it via ester, hydrazone, oxime or amide bond. Except amide bond containing derivatives all compounds with other type of linkage have significant antitumor activity. Oxime bond-linked Daunorubicin?GnRH-III conjugate was selected for in vivo studies on C26 murine colon carcinoma bearing mice. The results showed that the application of the conjugate prevent the toxic side effect of the free drug. The highest tumor growth inhibition (40-50%) was observed when the treatments were performed on days 4 and 7 after tumor transplantation using 15 mg Dau content in conjugate/kg body weight. This is the first study indicating significant antitumor effect of a Dau-conjugate with oxime linkage. Chemotactic drug targeting with tuftsin like carriers was also used