Inhibition of plasmacytoma development in BALB/c mice by indomethacin.

Indomethacin given continuously in the drinking water (20 micrograms/ml) to BALB/cAn pi mice during the latent period of pristane-induced plasmacytoma development dramatically reduced the plasmacytoma incidence from 34.9 to 2.2%. Additionally, indomethacin given from day 0 to 120 or begun as late as 60 d after a single injection of 1.0 ml pristane was also highly effective in reducing the development of plasmacytomas. Indomethacin treatment did not prevent the formation of a peritoneal inflammatory exudate or peritoneal oil granulomatous tissue, although it had a mild inhibitory effect on the intensity of the cellular inflammation, particularly after extensive treatment of greater than 100 d. Indomethacin treatment reduced the incidence of arthritis by 50%. A major effect of indomethacin treatment was a reduction in the appearance of microscopic plasmacytomas that appear in the oil granuloma before plasmacytomas can be detected by routine sampling of the peritoneal exudate. Between days 116 and 181, 16 of 20 mice given 0.5 ml pristane were found to have foci of plasmacytoma cells, while only 2 of 20 indomethacin-treated mice had foci-containing plasmacytoma cells. The number of mice with microscopic foci in the pristane-treated group greatly exceeded the expected incidence of plasmacytomas (22%) at this dose of pristane. The growth of primary plasmacytomas in transplant that is dependent on the pristane-conditioned peritoneal environment was not inhibited by indomethacin treatment. The role of indomethacin in inhibiting plasmacytoma development was not established; two possibilities are that it inhibits production of mutagenic and tissue destructive oxidants by inflammatory cells, and it inhibits prostaglandin synthesis and intracellular production of oxidant biproducts.

Intracavitary chemotherapy.

Pharmacokinetic modeling has suggested, and clinical investigations have confirmed, that intracavitary drug administration can result in a much greater drug exposure for the cavity into which the agent is instilled compared to the plasma. Both the safety and the efficacy of several agents administered individually or in combination have now been demonstrated. Several malignancies, in particular ovarian carcinoma and malignant mesothelioma, which remain confined to body cavities for much of their natural history, might be most rationally treated by the intracavitary treatment approach. Early clinical trials have demonstrated significant activity of intracavitary chemotherapy in both of these malignancies. Optimal drugs and dosages as well as appropriate scheduling for the various tumors involving body cavities remain to be defined. Whether or not combination intracavitary chemotherapy will significantly improve survival of patients with malignant disease confined to body cavities must await carefully controlled clinical trials comparing this treatment approach to standard systemically administered chemotherapy.

Immunocytochemical detection of P-glycoprotein in the management of malignant effusions.

P-glycoprotein (P-gp), a cell membrane protein, has been found in multidrug-resistant cancer cells. A total of 104 smears from patients with breast-cancer-associated pleural effusions and ovarian-cancer-related peritoneal effusions were studied for P-gp with the antibody C-219 and the avidin-biotin-immunoperoxidase method. Samples were taken before and 3 and 7 days after intracavitary bleomycin therapy and reaccumulation of effusion was assessed at 30 days. Smears that were P-gp-negative by the 7th day were associated with a good 30-day response to bleomycin in the majority of cases, while P-gp-positive smears were associated with a significant reaccumulation of fluid at 30 days. P-gp status is a valuable prognostic indicator of response to intracavitary bleomycin treatment in effusions from breast or ovarian cancer.

Cationic emulsions improves the delivery of oligonucleotides to leukemic P388/ADR cells in ascite.

The aim of this study was to investigate the in vivo ability of O/W cationic emulsions to deliver oligonucleotides (ON) in leukemic P388/ADR cells in ascite, after intraperitoneal (IP) administration in mice. Cationic emulsions were prepared by microfluidization as previously described by Teixeira et al. [Pharm. Res 16 (1999) 30]. The formulations consisted mainly of medium chain triglycerides, phosphatidylcholine (PC), poloxamer, and either a monocationic lipid stearylamine (PC/SA-emulsion) or a polycationic lipid RPRC(18) (PC/RPRC(18)-emulsion). A model ON (33P-pdT(16)) was associated with cationic emulsions by single addition at the end of the manufacturing process. Seven days after P388/ADR inoculation IP to mice, ON free or associated with PC/SA or PC/RPRC(18) emulsions was injected IP at a dose of 0.5 mg/kg. At different interval times, ascite including cells, blood and the main organs were collected and the radioactivity counted by liquid scintillation. The overall results showed significantly high amounts of ON in the leukemic cell pellet, 24 h after administration of ON associated to either PC/SA (AUC(0-24 h)=13634, %injected dose/min) or PC/RPRC(18) (AUC(0-24 h)=22592, % injected dose/min), contrary to the free ON solution (AUC(0-24 h)=3095, %injected dose/min), which displayed only reduced capture by cancer cells. In conclusion, complexation of ON with cationic emulsions had a beneficial effect in increasing tumor cells uptake in vivo (up to sevenfold for PC/RPRC(18)-emulsion) after IP administration. This could open interesting prospects for the treatment of ovarian cancers.

Reactive oxygen species mediated membrane damage induced by fullerene derivatives and its possible biological implications.

Fullerenes have attracted considerable attention in recent years due to their unique chemical structure and potential applications. Hence it is of interest to study their biological effects. Using rat liver microsomes as model systems we have examined the ability of the most commonly used fullerene, C60 and its water-soluble derivative, C60(OH)18 to induce membrane damage on photosensitization. For photoexcitation, UV or tungsten lamps were used. Damage was assessed as lipid peroxidation products like conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS). protein oxidation in the form of protein carbonyls, besides loss of membrane bound enzymes. Both fullerene derivatives induced significant oxidative damage. The alterations induced were both time- and concentration-dependent. Role of different reactive oxygen species (ROS) in the damage induced was examined by various scavengers of ROS and by deuteration of the buffer. The changes induced by C60 were predominantly due to 1O2 while that by C60(OH)18 was mainly due to radical species. Biological antioxidants such as glutathione, ascorbic acid and alpha-tocopherol were capable of inhibiting membrane damage induced by both the fullerenes. However, the damage induced by C60(OH)18 was more for both lipids and proteins than that showed by C60. C60 also showed enhancement in the formation of lipid peroxidation in sarcoma 180 ascites microsomes. In conclusion, our studies indicate that fullerene/its derivative can generate ROS on photoexcitation and can induce significant lipid peroxidation/protein oxidation in membranes and these phenomena can be prevented by endogenous/natural antioxidants.

Treatment with biologic response modifiers in patients with ovarian cancer.

The therapeutic and immunomodulating potential of biological response modifiers (BRM) such as OK-432 (a streptococcal preparation) and recombinant interferon gamma (rIFN-gamma) has been evaluated in 15 patients with advanced chemotherapy resistant ovarian cancer, presenting malignant ascites and/or pleural effusions. OK-432 was injected intracavitary in 10 patients in increasing doses from 0.2 up to 7.5 mg weekly. Five women were treated intracavitary with rIFN-gamma twice a week. The initial dose was 0.1 mg/m2 which was raised up to 12 mg/m2 over 6 weeks. With OK-432 a complete response was achieved for 14.1 + 8.9 months in 4 patients, a partial response for 1.7 + 0.3 months in 3 patients. The survival time of the 4 responders was significantly longer (21.1 + 8.3 months) than the survival time of the patients with partial or no response (4.9 + 2.7,4.1 + 2.3 months, respectively). In the rIFN-gamma therapy group, we found a partial response in one and no response in 4 patients. Toxicity observed under OK-432 and rIFN-gamma was minimal in all patients, suggesting a lack of systemic effect of intracavitary-applied BRM. With both agents, augmentation of certain immune responses, especially in the peritoneal cavity and to a lesser extent in the peripheral blood, has been documented. In 5 patients treated with OK-432, we found an overall augmentation of the effusion macrophage killer activity. rIFN-gamma augmented natural killer activity in 2 of 3 patients.

Taxol effect: bizarre mitotic figures (abnormal spindle asters) in a malignant peritoneal effusion: report of a case.

Taxol (Paclitaxol) is a diterpenoid taxane derivative found in the bark and needles of the Western yew, Taxus brevifolia, indigenous to the old growth forests of the Pacific Northwest. As compared with other antineoplastic agents (vinca alkaloids and colchicine) that enhance microtubule disassembly, taxol promotes microtubule polymerization. In interphase cells, abnormal microtubular bundles or arrays are seen. In mitotic cells, abnormal spindle asters form. Such morphologic changes have been described frequently in cell culture systems and in in vitro systems using fresh tumor tissue. To our knowledge, these changes have not been described in a peritoneal effusion specimen from a patient with stage III ovarian cancer treated with taxol. In addition, the mitotic stabilization produced interpretative difficulties in evaluating the peritoneal fluid because a vast majority of the presumed malignant cells were in mitosis and, hence, not evaluable by ordinary cytologic criteria.

Intracavitary cisplatin chemotherapy experience with six dogs.

Six dogs with a median age of 7 years (range = 5-14 years) were presented for signs referable to thoracic or abdominal effusion associated with neoplasia of the body cavities. Intracavitary cisplatin was administered at 50 mg/m2 every 4 weeks for a median of 2.5 treatments (mean = 3, range = 1-6). Three dogs with pleural mesothelioma had complete resolution of effusion for 289, 129, and greater than 306 days without evidence of tumor growth. Resolution of effusion occurred after one treatment in two dogs and after two treatments in one dog. In three dogs with carcinomatosis of unknown origin, complete responses was seen in two dogs after one treatment for 255 and greater than 807 days, respectively. Intracavitary chemotherapy with cisplatin was associated with palliation and control of malignant pleural and/or abdominal effusion in five of six dogs. Toxicity was minimal, and this method of therapy should be further explored in dogs with similar malignancies.

[Hemorrhagic ascites disclosing massive Fasciola hepatica infection]. / Ascite hémorragique révélant une infection massive à Fasciola hepatica.

Multi-organ infection with Fasciola hepatica is uncommon. We report a case of severe infection with Fasciola hepatica as a cause of liver and peritoneum injuries with hemorrhagic ascites as well as pulmonary, pericardial, splenic and portal system injuries in a 37-year old man who was a native of Green Cape. The patient was in poor general health, had a major inflammatory syndrome, and polyclonal hypergammaglobulinemia (90 g/L). The diagnosis was confirmed by positive distomatosis serology and the presence of eggs of Fasciola hepatica in the histological samples of the liver and peritoneum. After treatment with praziquantel then triclabendazole, the global outcome was favorable.

[Can septicemia and ascitic fluid infections in cirrhotic patients be treated by the oral route alone?]. / Les septicémies et les infections du liquide d'ascite du cirrhotique peuvent-elles être traitées exclusivement par voie orale?

The aim of this study was to determine the efficacy of oral antibiotics in the treatment of severe infections in cirrhosis. Twenty-two patients (17 males, 5 females) with spontaneous bacteremia (n = 7) or bacterial peritonitis (n = 15) were treated with oral pefloxacin 400 mg per 24 hr alone (n = 1) or in combination with another oral antibiotic, trimethoprimsulfamethoxazole (n = 13), amoxicillin (n = 6), cefadroxil (n = 2), or metronidazole (n = 1). In patients with spontaneous bacteremia, all organisms were found to be sensitive to oral antibiotics, and a favorable response was elicited in 6 out of 7 (86 p. cent) within 3 days (mean) of treatment. In patients with spontaneous peritonitis, ascitic fluid cultures were positive in 11 cases, and organisms were sensitive to pefloxacin in 9 out of 11 cases. A favorable response was elicited in 13 out of 15 within 2 to 8 days of treatment. Fourteen patients died (64 p. cent), 3 of infection (bacteremia n = 1, peritonitis n = 2), and 11 patients of causes unrelated to infection, mainly variceal hemorrhage, hepatorenal syndrome or hepatocellular carcinoma, although the clinical symptoms of infection were controlled. One-year survival was 57 p. cent in patients with bacteremia and 33 p. cent in those with bacterial peritonitis. Oral treatment was well tolerated in all patients. We suggest that most bacteremia and spontaneous bacterial peritonitis in cirrhotic patients can be treated with oral antibiotics. In some patients, this may be accomplished on an out patient basis.

[Phase III clinical trial of elemenum emulsion in the management of malignant pleural and peritoneal effusions].

From July 1994 to June 1995, a prospective multicenter phase III clinical trial was conducted to evaluate the efficacy of Injectio Emulsioni Elemeni in the management of malignant effusions. Four hundred and eighty-four patients, including 313 with pleural effusion and 171 with peritoneal effusion, were evaluable. The drug was administered in 0.5% emulsion, with a dosage of 200 mg/m2 for intrapleural injection once every week for 1-2 weeks and 300-400 mg/m2 for intraperitoneal injection once or twice every week for 2 weeks. The response rates were 77.6% in patients with malignant pleural effusion, 66.1% in patients with peritoneal effusion. There were no bone marrow, liver, cardiac and renal toxicities; while fever, local pain and gastro-intestinal reaction were the major adverse effects. It is concluded that Elemenum emulsion is one of the active agents in the management of malignant effusions.

[Clinical and pharmacokinetic study of pefloxacin in spontaneous ascitic fluid infections]. / Etude clinique et pharmacocinétique de la péfloxacine dans les infections spontanées du liquide d'ascite.

Ten patients with spontaneous ascitic fluid infections received intravenously 400 mg of pefloxacin for pharmacokinetic evaluation of the drug and its diffusion into peritoneal space. The patients were then treated with oral pefloxacin (400 mg every 36 h except for icteric patients: 48 h) during 21 days. Total body clearance was decreased (0.66 +/- 0.16 ml/min/kg) and elimination half life was increased as compared to that observed in normal subject (28.2 +/- 7.6 h), the longest half-lives being observed in the cases with the most severe alteration of hepatic function. Peritoneal concentrations were higher than 1 microgram/ml (i.e. exceeding the minimal inhibitory concentrations for most of the bacterial species involved in ascitic fluid infections) from the first half-hour after infusion to at least 36 hours. 9 of the 10 cases were cured. Pefloxacin provided a well spaced rythm of administration is a suitable antibacterial drug for ascitic fluid infections in cirrhotic patients with two advantages: its effectiveness against Enterobacteriaceae and an oral administration.

Evaluation of intraperitoneal vincristine in malignant peritoneal effusion.

The efficacy and safety of intraperitoneal administration of vincristine sulphate was determined in mice bearing Ehrlich ascitic carcinoma. The tumor bearing animals were administered with 0.5 mg/kg body weight (b.wt) of freshly prepared vincristine sulphate intraperitoneally on day 6 after tumor transplantation followed by drug administration once daily 5 days a week consecutively. The observations regarding the survival, alteration in the volume of peritoneal fluid, increase in life span and pathological changes in the liver, kidney, gastrointestinal tract and bone tissues were made. The vincristine sulphate treatment reduced the malignant cell population significantly and there were no significant changes in the histological picture of liver, kidney, bone, except the intestine, where atropy of villi demonstrating nests and cords of uniform small round cells were observed. Our experimental data suggests that intraperitoneal administration of vincristine is beneficial in malignant peritoneal effusion.

[A case of peritonitis carcinomatosa due to advanced gastric cancer effectively treated by intraperitoneal injection of carboplatin].

The patient was a 72-year-old woman who had advanced carcinoma of the stomach. She presented massive ascites due to peritonitis carcinomatosa. The cytology of ascites was class V and the CEA level of ascites was elevated. Since renal function was low, we injected 300 mg of carboplatin intraperitoneally 2 times in 8 weeks. The amount of ascites was significantly diminished and the CEA level of ascites was decreased. The result suggested the effectiveness of intraperitoneal injection of carboplatin for the therapy of peritoneal metastasis of gastric cancer.

[A case of advanced gastric cancer that was resectable after asctic fluid had disappeared following administration of TS-1].

A 60-year-old man who had suffered from epigastic pain and general malaise from November 1999 was admitted to our hospital due to Borrmann type 3 gastric cancer with ascites on December 7, 1999. We considered a radical B operation impossible, and placed the patient on neoadjuvant TS-1 chemotherapy consisting of 1 M tegafur, 0.4 M gimestat, and 1 M otastat potassium. There were no side effects other than Grade 1 nausea and mild loss of appetite throughout the chemotherapy. After 8 weeks of administration, the primary lesion was reduced in size, and ascitic fluid had disappeared on abdominal computed tomography images. Therefore, a total gastrectomy with splenectomy and D2 lymph node dissection was performed on March 31, 2000. This was a radical B operation that was not possible earlier. The pathological diagnosis was tub2, SE, N1, CY0, H0, P0, M0, INF gamma, ly1, v1, PM (-), DM (-) and the antitumor efficacy of TS-1 was Grade 2 histologically. The patient remains alive and in good condition with no relapse of the gastric cancer 8 months after surgery.

[A case of pancreatic tail cancer with peritoneal carcinosis treated with gemcitabine hydrochloride].

This paper reports a case of pancreatic tail cancer with peritoneal carcinosis that showed a good response to gemcitabine hydrochloride. A 52-year-old man, who had undergone a gastrojejunostomy for pancreatic tail cancer with peritoneal carcinosis, was referred to our hospital for anticancer therapy. Laboratory data on admission disclosed hypoalbuminemia and a high level of serum CA19-9 (156 IU/ml). These findings indicated that the patient was in a cancer cachexic condition. Gemcitabine hydrochloride treatment (1,000 mg/m2/week x 3/4 weeks) was started. Ascites disappeared after 2 courses of treatment, and the tumor was reduced (62% of the reduction rate) after 5 courses of treatment. Furthermore, the serum CA19-9 level and serum albumin value returned to normal, and performance status was improved to grade 1. The patient has been well for 15 months after the diagnosis of pancreatic tail cancer with peritoneal carcinosis. Gemcitabine hydrochloride may have not only reduced the tumor volume and improved cancer cachexic condition, but also prolonged the survival time in this case.

[A case of peritonitis carcinomatosa of pulmonary adenocarcinoma in which gefitinib was effective].

We report a case in which gefitinib was effective in reducing the amount of ascites. A 61-year-old man with peritonitis carcinomatosa due to metastasis from pulmonary adenocarcinoma was admitted to our hospital. Various chemotherapies were not effective for controlling his ascites. Therefore, we orally delivered gefitinib at a dose of 250 mg/day. Three days after administration, a reduction in the amount of ascites was noticed. Subjective symptoms including general fatigue and difficulty breathing were dramatically improved as was QOL. We conclude that this case was a good candidate for treatment using gefitinib.

[A case of inoperable scirrhous gastric cancer that responded remarkably to a combination of TS-1+paclitaxel and showed complete loss of ascites].

Complete loss of malignant ascites by combination chemotherapy of TS-1+paclitaxel was experienced. The case was a 56-year-old woman who was diagnosed with inoperable scirrhous gastric cancer with malignant ascites. The administered regimen of chemotherapy was TS-1 100 mg/day (80 mg/m2) for 2 weeks. Paclitaxel 60 mg/day (50 mg/m2) on day 1 and 8 of TS-1 intake, followed by 2-weeks rest. Partial response was confirmed by gastrography and gastrofiberscope after 3 courses were performed. Furthermore, computed tomography (CT) showed complete loss of malignant ascites. Adverse reactions were grade 3 leukopenia and grade 2 nausea, vomiting and diarrhea. This result indicates the possibility of combination chemotherapy of TS-1+paclitaxel becoming an effective option in treating inoperable scirrhous gastric cancer.

[Pharmacokinetic study of intraperitoneal cisplatin chemotherapy for gastric cancer as an adjuvant setting].

The pharmacokinetic studies of intraperitoneal cisplatin (CDDP) for gastric cancer were discussed elsewhere, but those studies were investigated in patients with ascites. The purpose of this study is to compare the difference in pharmacokinetics between patients with malignant ascites and those curatively resected without ascites. One hundred mg of CDDP and 300 ml of saline were administered intraperitoneally for 9 curatively resected patients by catheter just after operation, and the same doses of CDDP were administered for 3 advanced or recurrent patients with ascites just after removal of whole fluid. Blood samples were corrected at 6 points after administration. Results were as follows: The 0-t area under the curve (AUC) and the Cmax of both total and free CDDP in the patients without ascites was higher than in the patients with ascites. The 0-infinity AUC and MRT of the ascites patients were higher than in the patients without ascites. These data suggest that intraperitoneal CDDP chemotherapy for gastric cancer as an adjuvant setting is more effective than chemotherapy for advanced malignant ascites patients.

[Development of 5-fluorouracil incorporated in microspheres for peritoneal carcinomatosis--animal experiments].

A new dosage formulation (5-FU-MS), composed of 5-fluorouracil (5-FU) incorporated in polyglactin microspheres, was studied by animal experiments, which revealed the following results. Intraperitoneal 5-FU-MS delivered greater concentrations of 5-FU for longer periods selectively to the intraperitoneal tissues, whereas it delivered a lower concentration to the blood plasma, than 5-FU solution did in rats. In mice, the 50% lethal dose value of intraperitoneal 5-FU-MS was 535 mg/kg. The toxicity of 5-FU-MS was less than 1/2 that of intraperitoneal 5-FU solution, of which the 50% lethal dose value was 242 mg/kg. Intraperitoneal 5-FU-MS at 200 mg of 5-FU/kg improved the survival curve of mice with peritoneal carcinomatosis better than the identical dose of 5-FU solution.