Kimihiko Osaki

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.

Role of milky spots as selective implantation sites for malignant cells in peritoneal dissemination in mice

We investigated the significance of milky spots for malignant cells in peritoneal dissemination using three mouse carcinomatous peritonitis models. P388 leukemia and Colon 26 cancer cells were labeled with bromodeoxyuridine (BrdU) and mice were inoculated intraperitoneally. After 24 h the greater omentum and the mesenterium were removed and stained immunohistochemically with anti-BrdU antibody. The labeled cells were found to have preferentially infiltrated into the milky spots in these specimens. Next, using B16 PC melanoma cells, which can be easily distinguished from the other cells by the intrinsic black melanin, the distribution of the melanoma cells was observed macro- and microscopically following intraperitoneal inoculation. The melanoma cells were similarly found to have selectively infiltrated into the milky spots in the omentum and mesenterium after 1 day. Moreover, the melanoma cells were growing and forming distinct metastic lesions within the milky spots 1 week later.

Endoscopic local injection of a new drug-delivery format of peplomycin for superficial esophageal cancer: A pilot study

BACKGROUND A new drug-delivery format comprising activated carbon particles adsorbing peplomycin (PEP-CH) was developed for the treatment of superficial esophageal cancer. METHODS The drug distribution was measured in rats that received subcutaneous injections of PEP-CH or peplomycin aqueous solution. In 6 patients with superficial esophageal cancer, peplomycin as PEP-CH, 5-10 mg once a week for 4-10 weeks (total, 40-100 mg/patient) was injected endoscopically into primary lesions. RESULTS Rats given PEP-CH had significantly higher peplomycin levels in the regional lymph nodes and the injection site than rats given aqueous solution. Five patients have survived to the present or died without cancer after 27-72 months. The remaining patient has survived without cancer for 8 months after a second course of PEP-CH against recurrence. CONCLUSIONS PEP-CH therapy seems to have a good therapeutic effect on superficial esophageal cancer, although the present clinical study may have been biased by patient selection.

Therapeutic effects of the angiogenesis inhibitor TNP-470 against carcinomatous peritonitis in mice.

The therapeutic effects of the new anti-angiogenesis factor TNP-470 were examined against carcinomatous peritonitis in mice. In the first experiment using carcinomatous peritonitis caused by i.p. inoculation of 10(6) M5076 tumor cells, TNP-470 solution was injected i.p. in a bolus of 50 mg/kg body weight into two groups of 10 mice either 1 or 8 days after the i.p. inoculation. The administration of TNP-470 on day 1 extended the survival time of the mice compared with 10 control mice receiving no treatment, whereas TNP-470 given on day 8 did not affect the survival time. In the next experiment on the M5076 tumor, TNP-470 solutions at 100 or 300 mg/kg were injected i.p. in a bolus into two groups of 20 mice 1 day after the inoculation 10(6) tumor cells, respectively. The administration of TNP-470 at 100 mg/kg also had an inhibitory effect. However, TNP-470 at 300 mg/kg caused toxic death in half of the mice. Next, we examined the effects of TNP-470 on another type of carcinomatous peritonitis model, which was caused by i.p. inoculation of 10(6) B16 melanoma cells. In this experiment, TNP-470 solutions in a bolus of 150 mg/kg were injected i.p. into six groups of 10 mice each on day 1 only (group 1), on days 1 and 4 (group 2), on days 1, 4 and 7 (group 3), on day 8 only (group 4), on days 8 and 11 (group 5), or on days 8, 11 and 14 (group 6), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective delivery of a greater amount of methotrexate to regional lymph nodes using a new dosage formulation, methotrexate adsorbed on activated carbon particles, in rats.

A new dosage formulation (MTX-CH) comprising methotrexate (MTX) adsorbed onto a suspension of activated carbon particles was developed for the treatment of lymph node metastases. In vitro studies showed that activated carbon particles adsorbed a great amount of MTX. Subcutaneous injection of MTX-CH into the left hind foot pad of rats distributed a greater amount of MTX selectively to the regional lymph nodes (the left popliteal node and the para-aortic nodes) for a longer period of time than similar administration of MTX aqueous solution with a smaller amount of MTX distributed to the rest of the whole body.

CISPLATIN MICROCRYSTALS SUSPENDED IN OIL : PATHOLOGICAL STUDY OF ACUTE TOXICITY IN MICE

The pathological changes brought about by the i.p. administration of a new dosage format, clsplatin micro-crystals suspended in oil (CDDP-Oil), was examined in mice. CDDP-Oil decreased the absolute weight and the relative weight (organ weight/body weight) of the kidney, liver and spleen in the mice receiving the dosage form. However, the severity of the reduction of the organ weight in the CDDP-Oil administration groups was not different from that in the cisplatin aqueous solution (CDDP-Sol) administration groups. Histologically, severe degeneration and atrophy were recognized in the kidney, large intestine, small intestine, thymus, spleen, bone marrow and lymph nodes in the CDDP-Oil administration groups as well as CDDP-Sol administration groups. However, there were no additional changes in the macroscopic and microscopic findings in the CDDP-Oil groups. From these results, we concluded that this dosage form did not change the toxicity of cisplatin in terms of pathological effects.

Cisplatin microcrystals suspended in oil--toxicity in mice.

A new dosage format, cisplatin microcrystals suspended in oil (CDDP-oil), was developed for the treatment of peritoneal carcinomatoses. We studied the acute toxicity of CDDP-oil injected intraperitoneally in mice. The 50% lethal dose was 30.3 mg/kg (27.1–33.7 mg/kg at the 95% confidence level), which was 1.79 times that of a cisplatin aqueous solution (CDDP-sol) of 16.9 mg/kg (16.1–17.8 mg/kg at the 95% confidence level). There were no significant differences in the duration of the toxic effects and the toxic symptoms between these two dosage forms. However, the severity of weight loss in the group given CDDP-oil was less than the group given CDDP-sol.

Pathological study for the acute toxicity of peplomycin adsorbed on activated carbon particles on subcutaneous adminstration in mice.

A new dosage formulation (PEP-CH) composed of activated carbon particles adsorbing peplomycin, was examined for its macroscopic and microscopic pathological effects of subcutaneous adminstration in mice. Both formulations of PEP-CH and peplomycin aqueous solution (PEP-SOL) decreased the organ weights and the relative organ weights (organ weight/body weight) of the kidney and the spleen. These two formulations caused histological damages of the renal tubules and atrophy in the spleen and the thymus. Macroscopic and microscopic examination found no pathological changes in the lung exept for the slight congestion. There were no differences between these two formulations in the autopsy findings.