engleski

Antitumor activity of novel N-sulfonylcytosine derivatives on the growth of anaplastic mammary carcinoma in vivo

Background: we have designed and synthesized N-sulfonylpyrimidine derivatives as a new type of sulfonylcycloureas (1). These types of compounds showed potent inhibitory activity on the growth of human tumor cell lines in vitro, at concentrations of 10-8-10-5 M (25-75%). In comparison with 5-fluorouracil some of N-sulfonylpyrimidine derivatives showed 10 times stronger activity in induction of apoptosis in treated tumor cells (2). The inhibitory effect of the investigated derivatives on normal human cell lines was lower in comparison to antitumor effects. The aim of the present study was to investigate in vivo antitumor activity of novel N-sulfonylpyrimidine derivatives. Material and methods: In this study we used a transplantable mouse mammary carcinoma (TMMCa). Tumour cells (106) were injected into the thigh of the right hind leg of CBA mice. Tumor bearing mice were treated with new compounds or with 5-fluorouracil (positive control) on different time interval after tumor cells transplantation. The end point was tumor growth time (TGT). TGT is the time needed for tumor volume to grow five times over the treated volume measured by caliper and calculated by the formula AxBxCx /6. All new compounds were synthesized in "R. Bošković" Institute. Antitumor activity was examined for: 1-(p-toluenesulfonyl) cytosine (4H), 1-(p-toluenesulfonyl) cytosine hydrochloride (4HxHCl) and zinc(II) complex with 1-(p-toluenesulfonyl) cytosine (4K). The therapeutic doses used in this antitumour therapeutic protocol, for examined derivatives, were determined on the basis of toxicological studies of LD50 for these agents. Results: All new tested compounds (4H, 4HxHCl, 4K) had shown good antitumour activity against TMMCa in vivo. Antitumour effect depends on drug doses, number of drug injections and the time interval between tumour transplantation and drug application. The single dose injection of 4HxHCl showed better antitumour effect than multiple dose injection, while 4H showed good efficacy given as a single or multiple dose injection. The compound 4K had antitumour effect similar to 4HxHCl. Minor toxic effect was seen only on blood lymphocyte count without any other toxicological signs. Conclusions: All tested new agents showed good antitumour effect, which depends on drug doses and time interval between tumour transplantation and drug application. 1. Ruđer Bošković Institute (B. Žinić et all.), EP 0 877 022 B1, 16.04.2003. 2. Lj. Glavaš-Obrovac et all. Anticancer Res. 21:1979, 2001.

Antitumor activity; mice; anaplasti mammary carcinoma; N-sulphonylcytosine derivatives

nije evidentirano