Junshin Fujiyama

Cisplatin incorporated in microspheres: development and fundamental studies for its clinical application

A new drug delivery formulation, biodegradable glycolic acid-lactic acid copolymer (PGLA) microspheres incorporating cisplatin (CDDP-MS) has been developed for the treatment of peritoneal carcinomatosis. Scanning electron microscopy showed that CDDP-MS has a smooth surface and few cisplatin crystals in the hollow. An electron probe micro analyzer revealed that cisplatin was located mainly in the matrix in the state of a molecule. Release profile in vitro of CDDP from microspheres showed that the initial burst was 21.2% and the remaining CDDP was released slowly thenceforth over 14 days. Hydrolysis of CDDP-MS progresses very slowly during the 14 days, but there was no morphological change in the SEM views. The dimethylformamide content entrapped within CDDP-MS, determined by a gas chromatography, was 136 ppm at the evaporation temperature of 47 degrees C. The 50% lethal dose value of CDDP-MS, calculated by the Litchfield-Wilcoxon method, was reduced to 57% of the cisplatin solution. Therapeutic experiment on mice with peritoneal carcinomatosis showed that CDDP-MS did not enhance therapeutic effect as compared with the same dose dosage of a cisplatin aqueous solution but large quantities of cisplatin could be given in case of CDDP-MS owing to less toxicity.

Intraperitoneal injection of dextran sulfate as an anti-adherent drug for the prevention of peritoneal metastasis of cancer shows low toxicity in animals.

Intraperitoneal dextran sulfate with a mean molecular weight of 5×105 has been developed for use in an anti-adherent therapy against peritoneal carcinomatosis. The present study examined acute toxicity of i.p. injection of dextran sulfate in mice and rabbits. The 10, 50 and 90% lethal dose values are 0.213 (0.146-0.252), 0.336 (0.291-0.405) and 0.530 mg/g (0.431-0.873 mg/g: 95% confidence interval) in mice, respectively. These are markedly larger than the efficacious dose of 0.005-0.01 mg/g obtained previously. Death or symptoms of intoxication were seen within 3 days after administration of toxic doses. Rabbits received i.p. injection of dextran sulfate at 0.02 mg/g, which was close to the efficacious dose. At 2, 4, 6, 8 and 13 days after administration, blood was taken for biochemical and hematological analyses. Dextran sulfate at 0.02 mg/g induced no remarkable abnormal findings. These results suggest that the i.p. dextran sulfate is safe as an anti-adherent agent against peritoneal metastasis of cancer.

Dextran sulfate inhibits injured abdominal wall-specific tumor implantation in mice.

Tumor recurrence is often seen at sites where the peritoneum has been injured during surgery for gastrointestinal malignancies. It is thought that malignant cells released from the tumor during surgery implant in the sites of injury in the abdominal wall and cause tumor recurrence. Here we use dextran sulfate (DS) as an antagonist to cell adhesion for preventing implantation of i.p. seeded malignant cells, thus suppressing the recurrent tumor formation often observed at the site of injury in postoperative abdominal walls. DS was tested for anti-adherent activity against B-16 melanoma cells to injured abdominal wall specimens ex vivo and showed the capacity to significantly impair B-16 melanoma cell adherence compared to controls without DS. DS was also tested for the activity to prevent i.p. seeded B-16 melanoma cells from implanting in the site of injury in the abdominal wall in vivo and DS prevented B-16 melanoma cells from implanting in the sites of injury in the abdominal wall. In the test for the activity to improve survival in mice after B-16 melanoma was inoculated i.p., DS improved the survival of mice as compared to the controls without DS. We conclude that DS may be useful in preventing surgically promoting tumor implantation at sites of injury in post-operative abdominal wall treated for gastrointestinal malignancies.