Fujimoto K, Oka T, Morimoto M
Cancer Res. 1987 Mar 15;47(6):1516-22.
A novel antitumor antibiotic, 2a,3,4,5,6,6a,7,11b-octahydro-11-methoxy-12-methyl-3,6-imino-1H-2-oxa-11 c- azanaphth(1,2,3-cd)azulene-5-carboxylic acid monocitrate (quinocarmycin citrate; KW2152) was selected for investigation in a number of experimental tumor systems because of its efficacy against P388 leukemia. In the initial studies with P388 leukemia (i.p.-i.p.), KW2152 gave an increase in life span of greater than 80%. The activity was schedule dependent and daily administration was the most effective. KW2152 caused marginal activity against L1210 leukemia, B16 melanoma, and M5076 sarcoma. The effect on cultured cells suggested that KW2152 was not cross-resistant to Adriamycin (ADM) but was cross-resistant to mitomycin C (MMC); however, KW2152 caused prolongation of life span against mice bearing P388/ADM or P388/MMC. In tests against human tumors xenografted s.c. in nude mice, KW2152 significantly inhibited the growth of MX-1 mammary carcinoma with all tumors cured at i.v. doses of 4.4 mg/kg/day and p.o. doses of 26.2 mg/kg/day given daily for 7 days. KW2152 also inhibited distinct human gastric carcinomas, St-4 and St-15 tumors, and colon carcinoma Co-3 by daily administration for 7 days. Against St-4, KW2152 gave a treated versus control percentage of 27, compared to 52 for cis-diamminedichloroplatinum. Against Co-3, KW2152 was at least as effective as MMC, ADM, cis-diamminedichloroplatinum, and bleomycin, giving a treated versus control percentage of 18 at a dose of 8.6 mg/kg/day given daily for 7 days. KW2152 showed growth inhibitory activity against cultured murine tumors and human cells. The order of in vitro efficacy of KW2152 against murine tumors, P388 leukemia greater than L1210 leukemia, B16 melanoma, correlated with the order of the sensitivity on the i.p.-i.p. systems of these tumors. The 50% inhibitory concentrations against P388 leukemia cells were 5.3 X 10(-6) and 1.1 X 10(-7) M after 1 and 72 h exposure, respectively. KW2152 caused significant inhibition of RNA synthesis after a short time exposure. In P388 leukemia cells exposed for 1 h with KW2152, the 50% inhibitory concentration for RNA synthesis was 10(-5) M, 30-fold less than that for DNA synthesis. White blood cell depression or platelet depression was not significant after administration of the i.v. 10% lethal dose given daily for 7 days. Because of its good activity against human mammary tumor MX-1 and some effectiveness against other gastric and colon carcinomas and its water solubility, a novel antitumor antibiotic, KW2152, is being developed as a Phase I anticancer agent.
一种新型抗肿瘤抗生素，2a，3，4，5，6，6a，7，11b - 八氢 - 11 - 甲氧基 - 12 - 甲基 - 3，6 - 亚氨基 - 1H - 2 - 氧杂 - 11c - 氮杂萘并(1,2,3 - cd)薁 - 5 - 羧酸单柠檬酸盐（喹诺卡霉素柠檬酸盐；KW2152）因其对P388白血病的疗效而被选用于多个实验肿瘤系统的研究。在对P388白血病的初始研究（腹腔注射 - 腹腔注射）中，KW2152使寿命延长超过80%。其活性具有给药方案依赖性，每日给药最为有效。KW2152对L1210白血病、B16黑色素瘤和M5076肉瘤的活性较弱。对培养细胞的作用表明，KW2152与阿霉素（ADM）不存在交叉耐药性，但与丝裂霉素C（MMC）存在交叉耐药性；然而，KW2152可延长携带P388/ADM或P388/MMC小鼠的寿命。在对裸鼠皮下移植的人肿瘤进行的试验中，KW2152显著抑制MX - 1乳腺癌的生长，静脉注射剂量为4.4 mg/kg/天，口服剂量为26.2 mg/kg/天，每日给药7天可使所有肿瘤治愈。KW2152通过每日给药7天也可抑制特定的人胃癌、St - 4和St - 15肿瘤以及结肠癌Co - 3。对于St - 4，KW2152的治疗组与对照组百分比为27，而顺二氯二氨铂为52。对于Co - 3，KW2152至少与MMC、ADM、顺二氯二氨铂和博来霉素一样有效，每日给药7天，剂量为8.6 mg/kg/天时，治疗组与对照组百分比为18。KW2152对培养的鼠肿瘤和人细胞显示出生长抑制活性。KW2152对鼠肿瘤的体外疗效顺序为P388白血病大于L1210白血病、B16黑色素瘤，这与这些肿瘤在腹腔注射 - 腹腔注射系统中的敏感性顺序相关。分别在暴露1小时和72小时后，对P388白血病细胞的50%抑制浓度为5.3×10(-6)和1.1×10(-7) M。KW2152在短时间暴露后可显著抑制RNA合成。在P388白血病细胞中用KW2152暴露1小时后，RNA合成的50%抑制浓度为10(-5) M，比DNA合成的抑制浓度低30倍。每日静脉注射10%致死剂量，连续7天给药后，白细胞减少或血小板减少不明显。由于其对人乳腺肿瘤MX - 1具有良好活性，对其他胃癌和结肠癌也有一定疗效且具有水溶性，一种新型抗肿瘤抗生素KW2152正在作为I期抗癌药物进行研发。
