Holwell S E, Cooper P A, Grosios K, Lippert J W, Pettit G R, Shnyder S D, Bibby M C
Cancer Research Unit, University of Bradford, UK.
Anticancer Res. 2002 Mar-Apr;22(2A):707-11.
In view of the clinical potential of a number of natural products, Combretastatin A-1 phosphate was developed as a water-soluble derivative of combretastatin A-1. This study examined the anti-tumour activity of this compound against an experimental colon tumour (MAC29) in mice. A comparison was made with the clinically active combretastatin A-4 phosphate. The new compound was well-tolerated up to a dose of 250 mg/kg and was more effective at producing tumour growth delays than the A-4 analogue. Significant growth delays were seen at a dose of 50 mg/kg whereas the A-4 phosphate produced no measurable growth delay until a dose of 150 mg/kg was administered. Histological examination of treated tumours indicated that combretastatin A-1 phosphate caused very severe haemorrhagic necrosis in the tumour tissue and analysis of the sections indicated that almost 94 percent of the tumour was dead within 24 hours of treatment. The mechanism of action of combretastatin A-1 phosphate appears to be similar to the A-4 phosphate in that tumour vascular shutdown occurs within 4 hours of treatment. In summary combretastatin A-1 phosphate, the water-soluble analogue of combretastatin A-1, is more potent against a well-vascularised murine colon tumour than its predecessor, combretastatin A-4 phosphate. These data suggest this compound may have potential for clinical development.
鉴于多种天然产物的临床潜力，癌抑素A - 1磷酸酯作为癌抑素A - 1的水溶性衍生物被研发出来。本研究检测了该化合物对小鼠实验性结肠肿瘤（MAC29）的抗肿瘤活性。并与具有临床活性的癌抑素A - 4磷酸酯进行了比较。新化合物在高达250mg/kg的剂量下耐受性良好，并且在延缓肿瘤生长方面比A - 4类似物更有效。在50mg/kg的剂量下可见显著的生长延迟，而癌抑素A - 4磷酸酯直到给予150mg/kg的剂量才产生可测量的生长延迟。对治疗后的肿瘤进行组织学检查表明，癌抑素A - 1磷酸酯在肿瘤组织中引起了非常严重的出血性坏死，对切片的分析表明，在治疗后24小时内几乎94%的肿瘤细胞死亡。癌抑素A - 1磷酸酯的作用机制似乎与癌抑素A - 4磷酸酯相似，即在治疗后4小时内肿瘤血管关闭。总之，癌抑素A - 1的水溶性类似物癌抑素A - 1磷酸酯，对血管丰富的小鼠结肠肿瘤比其前身癌抑素A - 4磷酸酯更有效。这些数据表明该化合物可能具有临床开发潜力。
