Kumazawa Eiji, Ochi Yusuke
New Product Research Laboratories III, Tokyo R&D Center, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan.
Cancer Sci. 2004 Feb;95(2):168-75. doi: 10.1111/j.1349-7006.2004.tb03199.x.
DE-310 is a novel macromolecular conjugate composed of DX-8951f, a camptothecin analog, and a carboxymethyldextran polyalcohol carrier, which are covalently linked via a peptidyl spacer. In a murine Meth A (fibrosarcoma) solid tumor model, once daily x 5 treatments (qd x 5) with DX-8951f at the maximum tolerated dose (MTD) were required to shrink the tumor, and DX-8951f (qd x 5) at 1/4 MTD was required to inhibit tumor growth. A single treatment (qd x 1) with DE-310 at the MTD or 1/4 MTD shrank the tumor, with no body weight loss occurring at 1/4 MTD. Even at 1/16 MTD, DE-310 inhibited tumor growth. In a long-term assay, Meth A solid tumors disappeared in mice treated with DE-310 (qd x 1) at the MTD and 1/2 MTD, and all 6 mice remained tumor-free on the 60th day after administration. Repeated injection (4 times) on schedules of every 3 days, 7 days or 14 days demonstrated that multiple treatment with DE-310 produced greater tumor growth delay than a single treatment with DE-310. Against 5 human tumor (colon and lung cancer) xenografts in mice, DE-310 (qd x 1) was as effective as DX-8951f administered once every 4 days, 4 times. The life-prolonging activity of DE-310 was assessed in lung (3LL, Lewis lung carcinoma) and liver (M5076, histiocytoma) metastasis models. Against 3LL, DE-310 (qd x 1) at the MTD to 1/3 MTD significantly prolonged survival, with an increase in life span (ILS) of 4.8- to 1.6-fold, respectively, over that in untreated control mice. Also, DE-310 (qd x 1) significantly prolonged survival in the liver metastasis model of M5076. These results demonstrate that DE-310 is a promising agent for the treatment of cancer.
DE - 310是一种新型大分子偶联物，由喜树碱类似物DX - 8951f和羧甲基葡聚糖多元醇载体组成，二者通过肽基间隔物共价连接。在小鼠Meth A（纤维肉瘤）实体瘤模型中，以最大耐受剂量（MTD）每日一次共5次给药（qd x 5）的DX - 8951f才能使肿瘤缩小，而1/4 MTD的DX - 8951f（qd x 5）则可抑制肿瘤生长。以MTD或1/4 MTD单次给药（qd x 1）的DE - 310可使肿瘤缩小，且1/4 MTD时未出现体重减轻。即使在1/16 MTD时，DE - 310仍能抑制肿瘤生长。在一项长期试验中，用MTD和1/2 MTD的DE - 310（qd x 1）治疗的小鼠，其Meth A实体瘤消失，给药后第60天所有6只小鼠均无肿瘤。每3天、7天或14天重复注射（4次）表明，DE - 310多次给药比单次给药产生更大的肿瘤生长延迟。对于小鼠体内的5种人类肿瘤（结肠癌和肺癌）异种移植瘤，DE - 310（qd x 1）与每4天给药1次、共4次的DX - 8951f效果相同。在肺（3LL，Lewis肺癌）和肝（M5076，组织细胞瘤）转移模型中评估了DE - 310的延长生命活性。对于3LL，MTD至1/3 MTD的DE - 310（qd x 1）显著延长了生存期，与未治疗的对照小鼠相比，寿命延长（ILS）分别为4.8至1.6倍。此外，DE - 310（qd x 1）在M5076肝转移模型中也显著延长了生存期。这些结果表明，DE - 310是一种有前景的癌症治疗药物。
