A mouse model of early-stage peritoneal metastasis: optimal RT-PCR-based method for detection of peritoneal micrometastases.

The presence of peritoneal micrometastasis in the abdomen is a poor prognostic factor in advanced gastric cancer. However, there is no standardized method for detection of peritoneal micrometastases. The aim of this study was to establish an animal model mimicking early phase peritoneal dissemination of advanced gastric cancer and then to use this model to compare the sensitivity and specificity of reverse transcription-polymerase chain reaction (RT-PCR) with peritoneal lavage fluid, randomly collected omentum with or without milky spots stained with activated carbon particles for detection of disseminated cancer cells. MKN-45-EGFP gastric cancer cells (1 x 10(3), 5 x 10(3) and 1 x 10(4)) were injected intraperitoneally into 4-week-old female BALBc nu/nu mice on day 0. Mice were sacrificed at 7 or 14 days postinjection. Peritoneal seeding was assessed by fluorescence stereomicroscopy. The sensitivities of RT-PCR with peritoneal lavage fluid, omentum with or without milky spots, were compared. Peritoneal seeding was confirmed in 8 of 10 mice injected with 1 x 10(4) MKN-45-EGFP cells by fluorescence stereomicroscopy. On days 7 and 14, the rate of the detection of CEA mRNA was 0, 50.0, and 87.5% in the omentum, omentum with milky spots and peritoneal lavage fluid, respectively. On days 7 and 14, the average level of CEA mRNA was 0, 51113+/-28225, and 3556+/-2842 in the omentum, omentum with milky spots and peritoneal lavage fluid, respectively. Molecular diagnosis using peritoneal lavage fluid is more sensitive than that using the omentum.

Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): phase I study.

Lipoplatin, a new liposomal cisplatin formulation, is formed from cisplatin and liposomes composed of dipalmitoyl phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC-3), cholesterol and methoxy-polyethylene glycol-distearoyl phosphatidylethanolamine (mPEG2000-DSPE). Following intravenous infusion, the nanoparticles (110 nm) are distributed into tissues and concentrate preferentially at tumor sites supposedly via extravasation through the leaky tumor vasculature. This study was designed to investigate the pharmacokinetics and the toxicity of this new liposomal cisplatin in patients with pretreated advanced malignant tumors. The drug was infused for 8 h every 14 days at escalating doses. Twenty-seven patients were included and 3-5 patients were selected for each dosage level; levels started at 25 mg/m2 and were increased by 25 to 125 mg/m2. Three patients were also treated at higher dose levels, one each at 200, 250 and 300 mg/m2. Blood was taken at certain time intervals in order to estimate total platinum plasma levels. At level 5 (125 mg/m2), grades 1 and 2 GI tract and hematological toxicities were detected. No nephrotoxicity was observed. Seven additional patients were added at the 4th level (100 mg/m2) for further pharmacokinetic evaluation. Measurement of platinum levels in the plasma of patients as a function of time showed that a maximum platinum level is attained at 6-8 h. The half-life of Lipoplatin was 60-117 h depending on the dose. Urine excretion reached about 40% of the infused dose in 3 days. The data demonstrate that Lipoplatin up to a dose of 125 mg/m2 every 14 days has no nephrotoxicity and it lacks the serious side effects of cisplatin.