Shirasaka T, Shimamoto Y, Kato T, Fukushima M
Institute for Pathogenic Biochemistry in Medicine.
Gan To Kagaku Ryoho. 1998 Feb;25(3):371-84.
A new oral type of 5-fluorouracil (5-FU) derivative possessed of both potent antitumor activity and less gastrointestinal (GI) toxicity was investigated and developed in the form of a combination of tegafur (FT), a masked form of 5-FU, and its two peculiar biochemical modulators. One is 5-chloro-2,4-dihydroxypyridine (CDHP), a new potent inhibitor of 5-FU degradation in vivo, and another is potassium oxonate (Oxo), a characteristic inhibitor of 5-FU phosphorylation, which distributes much higher in GI tract after p.o. administration. 5-FU levels in blood of rats following administration of FT, were markedly elevated and persisted for a long-time by co-oral CDHP corresponding to over 0.4 molar ratio to FT, like the case in continuous infusion of 5-FU, which resulted in an augmentation of antitumor efficacy in Yoshida sarcoma-bearing rats, although severe GI toxicity simultaneously occurred. To reduce 5-FU-induced toxicities such as diarrhea and body weight loss and to maintain the augmented antitumor activity, 0.5 to 2 molar Oxo was orally given to rats with one molar FT plus 0.4 molar CDHP. As a result, both severe GI injury and body weight loss were markedly inhibited by coadministration of 0.5 to 1.0 molar Oxo while high antitumor efficacy (about 90% inhibition of tumor growth) was maintained. However, such almost complete antitumor effect was reduced to about 50% inhibition of tumor growth by over 2 molar Oxo combined with one molar FT plus 0.4 molar CDHP. Based on these results, a novel 5-FU derivative, named S-1, was composed of one molar FT, 0.4 molar CDHP and one molar Oxo. S-1 showed an antitumor activity over 3-fold stronger than UFT (one molar FT plus 4 molar uracil) against Yoshida sarcoma and Sato lung carcinoma in rats and human colon carcinoma (KM12C) xenografted in nude rats when its minimum toxic dose was administered. Co-oral Oxo also significantly reduced the incidence of diarrhea and stomatitis induced by administration of FT-CDHP in beagle dogs. These results suggest that high antitumor activity and less GI toxicity of S-1 was brought about by the elevation in blood and tumor tissues and by selective decrease of 5-fluoronucleotides, an active metabolite of 5-FU, in GI tract.
一种新型口服5-氟尿嘧啶（5-FU）衍生物被研发出来，它兼具强大的抗肿瘤活性和较低的胃肠道（GI）毒性，其形式为替加氟（FT，5-FU的一种掩蔽形式）与两种特殊生化调节剂的组合。一种是5-氯-2,4-二羟基吡啶（CDHP），一种新型强效体内5-FU降解抑制剂；另一种是奥索酸钾（Oxo），一种5-FU磷酸化的特异性抑制剂，口服给药后在胃肠道中的分布要高得多。口服FT后，大鼠血液中的5-FU水平通过与FT摩尔比超过0.4的口服CDHP显著升高并长时间持续，就如同持续输注5-FU的情况一样，这导致荷吉田肉瘤大鼠的抗肿瘤疗效增强，尽管同时出现了严重的胃肠道毒性。为了降低5-FU诱导的腹泻和体重减轻等毒性，并维持增强的抗肿瘤活性，给服用1摩尔FT加0.4摩尔CDHP的大鼠口服0.5至2摩尔的Oxo。结果，同时给予0.5至1.0摩尔的Oxo可显著抑制严重的胃肠道损伤和体重减轻，同时维持高抗肿瘤疗效（约90%的肿瘤生长抑制率）。然而，超过2摩尔的Oxo与1摩尔FT加0.4摩尔CDHP联合使用时，这种几乎完全的抗肿瘤作用降低至约50%的肿瘤生长抑制率。基于这些结果，一种名为S-1的新型5-FU衍生物由1摩尔FT、0.4摩尔CDHP和1摩尔Oxo组成。当给予最小毒性剂量时，S-1对大鼠吉田肉瘤、佐藤肺癌以及裸鼠移植的人结肠癌（KM12C）的抗肿瘤活性比优福定（1摩尔FT加4摩尔尿嘧啶）强3倍以上。口服Oxo还显著降低了比格犬服用FT-CDHP后诱导的腹泻和口腔炎的发生率。这些结果表明，S-1的高抗肿瘤活性和较低的胃肠道毒性是由血液和肿瘤组织中5-FU水平的升高以及胃肠道中5-FU的活性代谢物5-氟核苷酸选择性减少所致。
