The novel highly lipophilic topoisomerase I inhibitor DB67 is effective in the treatment of liver metastases of murine CT-26 colon carcinoma

Abstract

Colorectal carcinoma occurs in 1 of 20 individuals in most developed countries. The relapse after resection with metastatic liver disease is a major cause of death. 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (DB67) has been incorporated into liposomes allowing for intravenous (i.v.) administration. A preclinical efficacy study of liposomal DB67 was performed using the colon carcinoma CT-26 cell line. The therapeutic dose for DB67 and liposomal DB67 was found to be 7 mg/kg per day using the qdx5/1 schedule. The results are compared with those obtained with irinotecan. The treatment with liposomal DB67 administered intravenously was more effective in reducing the weight and volume of primary spleen tumors and the weight and extent of liver metastases than free DB67 or liposomal DB67 administered intraperitoneally, but less effective than irinotecan. When the primary tumor was resected, treatment with liposomal DB67 administered intravenously was more effective in reducing the weight and extent of liver metastases than DB67 or liposomal DB67 administered intraperitoneally, and irinotecan. DB67 showed a higher accumulation in spleen and liver after its i.v. administration in liposomal form compared with its free or liposomal form administered intraperitoneally. DB67 and liposomal DB67 are more effective than irinotecan in the treatment of liver metastases after resection of the primary tumor.

Figure 1

Toxicity of DB67 and liposomal DB67. Hsd:ICR mice were injected intraperitoneally on a schedule of daily injection for 5 days (qdx5/1). (A) DB67: 10 mg/kg (●), 40 mg/kg (■), control (not treated) (□). (B) Liposomal DB67: 10 mg/kg (●), 40 mg/kg (■), or control (not treated) (□). The data are represented as mean weights ±SD with five mice per group. Arrows indicate the day of treatment.

Figure 2

Toxicity of liposomal DB67. Hsd:ICR mice were injected intravenously on a schedule of daily injection for 5 days (qdx5/1) with 10 mg/kg liposomal DB67 (●) and control (not treated) (■). The data are represented as mean weights ±SD with five mice per group. Arrows indicate the day of treatment.