Fujita F, Fujita M, Inaba H, Sugimoto T, Okuyama Y, Taguchi T
Dept. of Surgery, Osaka University.
Gan To Kagaku Ryoho. 1991 Oct;18(13):2263-70.
Antitumor effect of HO-221, a derivative of benzoylphenylurea, has been previously studied against seven human cancer xenografts in nude mice established and maintained in our laboratory. In this study, the effect of combination chemotherapy was examined with six of the above seven human cancer cell lines. These consisted of four gastric cancers (H-55, H-111, H-81 and H-154), one breast cancer (H-31) and one pancreatic cancer (H-48). HO-221 was used in combination with one of the following widely used anticancer drugs; mitomycin (MMC), adriamycin (ADM), CDDP, VP-16 and 5-fluorouracil (5-FU). When the tumor growth inhibition rate (IR) by combination of two drugs (at 1/2 MTD for each drug) exceeded both of IR obtained separately with single drug at 1/2 MTD, the combination regimen was rated as showing an additive effect. When IR by combination of two drugs at the same dose level exceeded both of IR obtained separately by MTD of each single drug, the regimen was rated as showing a synergistic effect. Histological changes and side-effects were also taken into consideration for the evaluation of the drug. Combination of HO-221 and MMC produced an additive effect against H-55 and H-111, a synergistic effect against H-81. In the treatment of H-31 which was highly susceptible to these drugs, a remarkable effect was shown in both IR and cellular changes even by combination using 1/2 MTD and 1/4 MTD doses. Combination with ADM at 1/2 MTD for both produced an additive effect against H-111 and H-48. Combination at MTD produced a marked antitumor effect against H-111 and a strikingly remarkable combination effect was confirmed. Combination with CDDP produced an additive effect against H-81 and a synergistic effect against H-154. Moreover, the weight loss by this combination regimen was far less than that by single administration of CDDP at MTD. An additive effect was demonstrated by combination with VP-16. Combination with 5-FU produced minimal combination effect. HO-221 was thus found to have a high antitumor effect by combination with various anticancer agents that are at present widely used clinically. HO-221 is expected to be a promising anticancer drug in its clinical application.
苯甲酰基苯基脲衍生物HO - 221对在我们实验室建立并维持的裸鼠体内的七种人癌异种移植瘤的抗肿瘤作用此前已进行过研究。在本研究中，对上述七种人癌细胞系中的六种进行了联合化疗效果检测。这些细胞系包括四种胃癌（H - 55、H - 111、H - 81和H - 154）、一种乳腺癌（H - 31）和一种胰腺癌（H - 48）。HO - 221与以下广泛使用的抗癌药物之一联合使用：丝裂霉素（MMC）、阿霉素（ADM）、顺铂（CDDP）、依托泊苷（VP - 16）和5 - 氟尿嘧啶（5 - FU）。当两种药物联合（每种药物均为1/2最大耐受剂量）时的肿瘤生长抑制率（IR）超过每种药物单独使用1/2最大耐受剂量时的IR时，联合用药方案被评定为具有相加作用。当两种药物在相同剂量水平联合时的IR超过每种单一药物最大耐受剂量时单独获得的IR时，该方案被评定为具有协同作用。在评估药物时还考虑了组织学变化和副作用。HO - 221与MMC联合对H - 55和H - 111产生相加作用，对H - 81产生协同作用。在对这些药物高度敏感的H - 31的治疗中，即使使用1/2最大耐受剂量和1/4最大耐受剂量联合使用，在IR和细胞变化方面均显示出显著效果。两种药物均以1/2最大耐受剂量与ADM联合对H - 111和H - 48产生相加作用。以最大耐受剂量联合使用对H - 111产生显著的抗肿瘤作用，并确认了显著的联合效果。与CDDP联合对H - 81产生相加作用，对H - 154产生协同作用。此外，这种联合用药方案导致的体重减轻远低于单独使用最大耐受剂量的CDDP时的体重减轻。与VP - 16联合显示出相加作用。与5 - FU联合产生的联合效果最小。因此发现HO - 221与目前临床上广泛使用的各种抗癌药物联合使用时具有较高的抗肿瘤作用。HO - 221有望在其临床应用中成为一种有前景的抗癌药物。
