Experimental study on intraperitoneal administration of 5-fluorouracil for liver metastasis in comparison with intravenous administration

We studied the effects of 5-fluorouracil intraperitoneal administration using mouse liver metastasis model. We inoculated 50 microliters Colon26 cell suspension into the spleen and resected it 15 min after cell inoculation under general anesthesia with Ketamine. Control group (n = 7) had no treatment. The intraperitoneal (i.p.) group (n = 8) and intravenous (i.v.) group (n = 7) underwent the treatment on the 2nd and 4th day after the operation. Experimental chemotherapies consisted of 1.5 ml 5-fluorouracil solution (50 mg/kg) for i.p. group and 0.2 ml 5-fluorouracil solution (50 mg/kg) for i.v. group. On the 14th day after the cell implantation, necropsies were performed. Deposits on mouse livers were counted and the mouse livers weighted. Counting of metastatic liver deposits revealed the number of deposits in the control group was 25.6 +/- 12.9, against 2.9 +/- 1.9 and 16.0 +/- 15.6, in the i.p. and i.v. group, respectively. Significant differences in the number of liver deposits were obtained between the control group and i.p. group, and between i.p. group and i.v. group (p < 0.05). The mean liver weight (mg)/mouse body weight (g) were 76.3 +/- 24.7 in the control group, 54.3 +/- 4.7 in the i.p. group and 60.0 +/- 12.7 in the i.v. group. A significant difference was observed only between the control group and the i.p. group (p < 0.05). I.p. administration of 5-fluorouracil was superior to i.v. administration for control of the liver metastasis. Moreover, the side effect by 5-fluorouracil i.p. treatment was milder than by i.v. therapy. We confirmed the effectiveness of 5-fluorouracil intraperitoneal chemotherapy for the potential liver metastasis and liver micrometastasis. Intraperitoneal chemotherapy is also useful for peritoneal seeding. We think intraperitoneal chemotherapy is a recommendable administration route for gastrointestinal malignancies.     

Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis

CPT-11 is an effective antitumor agent for gastrointestinal malignancy, but the optimum route of administration is unclear. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. CPT-11 (40 mg/kg) was injected intraperitoneally or intravenously on days 2 and 5 after inoculation of tumor cells. Intraperitoneal administration of CPT-11 was significantly more effective than intravenous administration for control of both peritoneal seeding and liver metastasis. Intraperitoneal administration of CPT-11 may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.     

Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis

Paclitaxel is an effective antitumor agent that shows ideal pharmacological characteristics for intraperitoneal chemotherapy. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of Colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. Paclitaxel (20 mg/kg) was injected into the peritoneal seeding model intraperitoneally or intravenously on day 2 and 4 after inoculation of tumor cells. Paclitaxel (30 mg/kg) was injected into the liver metastasis model intraperitoneally and intravenously on days 4 and 8 after inoculation of tumor cells. Median survival time for intraperitoneal administration (17.50 +/- 0.86 days) was longer than that for intravenous administration (13.70 +/- 0.47 days) in the peritoneal seeding model experiment. Median survival time for intraperitoneal administration (19.78 +/- 0.74 days) was longer than that for intravenous administration (17.50 +/- 0.54 days) in the liver metastasis model experiment. Intraperitoneal administration of paclitaxel may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.     

5—氟尿嘧啶腹腔和静脉化疗药代动力学的比较研究

Pharmacokinetic comparison of 5-Fluorouracil (5-Fu) administered ip versus iv was made in rabbits. Ip administration of bolus and large volume of 5-Fu could maintain high, stable and sustained concentration in the peritoneal cavity, portal vain and liver while sparing the systemic circulation. After iv bolus administration of 5-Fu, drug concentration in the systemic circulation was very high. Although iv administration of 5-Fu could lead to high concentration in the portal vein and liver, sustainment of concentration was relatively of short duration and the 5-Fu concentration was very low in the peritoneal fluid. The authors believe that ip chemotherapy has a significant pharmacokinetic advantage over the conventional iv route in preventing and treating recurrences in the peritoneal cavity and liver metastasis after surgery for gastro-intestinal malignancies.     

Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse

Summary The pharmacokinetics of doxorubicin in nude mice have been investigated following intravenous and intraperitoneal administration of single doses of 12 mg/kg. The areas under the concentration curves of doxorubicin in kidney, heart, and striated muscle following intraperitoneal administration were approximately half the areas following intravenous injection, whereas plasma and liver showed nearly identical concentrations after a distribution phase of 2 h. Only minor differences in pharmacokinetics were found between nude and normal mice.     

Treatment of VX2 carcinoma implanted in the liver with arterial and intraperitoneal administration of oily anticancer agents

PURPOSE: Long-term survival and cure cannot be achieved in patients with unresectable, advanced abdominal cancer, because no chemotherapeutic treatment has definite antitumor activity for malignant solid tumor and its dissemination. In this study, arterial and intraperitoneal administration of oily anticancer agents, which have properties that permit targeted chemotherapy for VX2 carcinoma implanted in the liver, was attempted to achieve long-term survival. MATERIALS AND METHODS: Rabbits bearing VX2 tumors in the liver measuring 1-2 cm in diameter received an arterial injection of 0.2 ml of nitrogen mustard N-Oxide (HN2-O) dissolved in Lipiodol (7.5 mg/ml), a newly developed oily anticancer agent, for the tumor and an intraperitoneal injection of a cocktail of oily anticancer agents for the prevention of intraperitoneal dissemination. RESULTS: Twelve out of thirteen rabbits survived and VX2 cancer was not observed in these 12 rabbits. The controls received a sham operation, an intraperitoneal injection of the cocktail of oily anticancer agents alone, or an arterial injection of HN2-O/Lipiodol alone. In these control groups, 27 out of 29 rabbits died of cancer. To examine the dose form for arterial injection, 14 rabbits received an arterial injection of the simple mixture of HN2-O dissolved in physiological saline and Lipiodol, with an additional intraperitoneal injection of the cocktail. Eight of these 14 rabbits died of enlargement of the hepatic tumor and peritoneal dissemination. CONCLUSION: Long-term survival and cure was achieved in almost all rabbits bearing VX2 tumor in the liver by simultaneous arterial and intraperitoneal injection of oily anticancer agents.     

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BackgroundA phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis.Patients and methodsGastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m² and i.p. at 20 mg/m² on days 1 and 8. S-1 was administered at 80 mg/m²/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety.ResultsForty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1–23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%).ConclusionCombination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.     

Experimental studies on oral administration of nitrosourea anti-tumor agent, MCNU

Experimental studies with orally administered MCNU, a water-soluble nitrosourea, yielded the following results. MCNU produced a significant increase in life span, and 60-day survivors were observed by various schedules in L1210 leukemia. The therapeutic ratios of MCNU were almost similar to those of CCNU. With Lewis lung carcinoma and Ehrlich ascites carcinoma implanted into the stomach wall, its antitumor activity by oral administration was slightly more effective than by intravenous route. In Beagle dogs, hematologic toxicity and gastrointestinal toxicity (vomiting, diarrhea) were noted by oral administration, similar to intravenous administration, but its toxicity was mild. The maximum blood level of MCNU was noted at 30 minutes after oral administration in Beagle dogs. The half life (23.7 min) by oral administration was similar to that by intravenous route. From these results, the oral administration of MCNU deserves the consideration as a form of treatment now given other MCNU routes.     

Pilot study of intraperitoneal administration of paclitaxel and oral S-1 for patients with peritoneal metastasis due to advanced gastric cancer

Background  There is no standard treatment for peritoneal dissemination from gastric cancer. A novel combination chemotherapy has been introduced for patients with advanced gastric cancer with peritoneal metastasis. Methods  This pilot study was performed on four patients to confirm safety and efficacy. They were diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy, or with metastasis to the transverse colon. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m² or 60 mg/body was administered intraperitoneally on days 1 and 8 and S-1, at 80–120 mg/body, was administered orally for 14 days followed by 7 days’ rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated by conventional examinations, and second-look laparoscopy was performed to assess the efficacy of the treatment against the peritoneal metastases. Results  After five courses, primary tumor reductions were confirmed, and no cancer cells were detected on pathocytological investigation during second-look laparoscopy in any of the patients. Three patients underwent total gastrectomy with lymph node dissection and one underwent left upper abdominal evisceration. Final histological staging showed two stage 3 and two stage 4 patients. The intraperitoneal administration of paclitaxel and the oral administration of S-1 were well tolerated. Three patients died, at 8, 15, and 29 months, respectively, after the initial treatment, and one has been alive for 54 months without recurrence. Conclusion  This chemotherapy can be used in the treatment of patients with peritoneal metastasis of gastric cancer.     

Effect of tolmetin sodium dihydrate on adhesion formation by intraperitoneal administration of antineoplastic agents

Summary Antineoplastic agents are currently being administered through catheters placed intraperitoneally to treat cancer localized to the peritoneum. This route allows for high local concentrations of antineoplastic drug at the tumor site with low levels of the drug systemically, thereby reducing the systemic toxicity. However, there are complications with this mode of delivery, including a decrease in catheter patency and induction of adhesion formation, which leads to decreased drug dispersion and limits continuing drug administration. A model was developed in rats to mimic this method of antineoplastic drug administration that produced fibrin deposition around the catheter and adhesion formation invoving bowel, intestines and liver. All antineoplastic agents tested, including Adriamycin, methothexate, bleomycin, mitoxantrone and cisplatin, induced moderate to severe adhesion formation with varying effects on catheter patency. When an intraperitoneal bolus of tometin encapsulted in liposomes was tested with Adriamycin delivered via an osmotic minipump, a reduction in adhesion formation was observed. However, highly significant adhesion reduction was found when tolmetin was coadministered with the antitumor agents.     

Enhanced effect of intraperitoneal administration of CDDP combined with caffeine against peritoneal metastasis

The enhanced effect of CDDP combined with caffeine against P-388 leukemia was investigated. No synergistic effect was shown after one hour simultaneous treatment with CDDP and caffeine. But the growth inhibition was enhanced by the addition of caffeine after one hour treatment with CDDP. It is suggested that caffeine inhibits DNA repair by the reduction of CDDP-induced elongation of G2 + M phase. The increase in life span of mice after ip transplantation was observed by frequent ip injections of caffeine after CDDP injection. It is suggested that the effect of intraperitoneal administration of CDDP against peritoneal metastasis is enhanced by combination with caffeine.     

Intrahepatic and intravenous administration of adriamycin--a comparative pharmacokinetic study in patients with malignant liver tumours

The pharmacokinetics of adriamycin in patients with malignant tumours of the liver were studied after peripheral intravenous treatment and after regional administration of the drug either by the arterial route or by the portal vein, with or without hepatic artery ligation. The plasma concentration of adriamycin after intravenous as well as after intrahepatic administration followed a three-compartment open model. The results in the present study confirm previous reports of a large inter-individual variation of the pharmacokinetics of adriamycin. After intravenous administration the individual variations in AUC/mg/m2 and Cp,max/mg/m2 (dose normalized area under plasma concentration time curve and dose normalized maximum plasma concentration, respectively) were more than 5-fold. The area under the plasma concentration time curve (AUC) was on the average 1.5 times higher after the peripheral intravenous administration than after intrahepatic administration. The reduction of maximum plasma concentration (Cp,max) of adriamycin after intrahepatic administration was even more pronounced than the reduction in AUC (mean value Cp,max iv/Cp,max ihep = 1.7). The plasma concentration of adriamycinol did not exceed 20 ng/ml. The AUC values of adriamycinol were 20% (median value) of the AUC values of adriamycin, indicating the importance of adriamycinol in the adriamycin therapy.     

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model

PURPOSE: Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue distribution of intraperitoneal versus intravenous docetaxel. METHODS: The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). RESULTS: When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 microg/ml.min) as compared to intravenous administration (0.043 microg/ml.min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 microg/ml.min) as compared to intravenous administration (4.25 microg/ml.min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall ( P=0.0079) and in the stomach and colon ( P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. CONCLUSIONS: The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans.     

Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 for peritoneal carcinomatosis in mice

hrR3 is an oncolytic herpes simplex virus 1 (HSV-1) mutant that replicates preferentially in tumors compared with normal tissues. Portal venous administration of hrR3 in mice bearing diffuse colorectal carcinoma liver metastases significantly reduces tumor burden and prolongs animal survival. In this study, we compared survival benefit and biodistribution of hrR3 following intravenous (i.v.) administration versus intraperitoneal (i.p.) administration in immunocompetent mice bearing colon carcinoma peritoneal metastases. Mice bearing peritoneal metastases received 1 x 10(8) plaque-forming units hrR3 or mock-infected media every other day for three doses and were randomized to have the viruses administered by either an i.p. or i.v. route. Biodistribution was assessed by PCR amplification of HSV-1-specific sequences from tumor and normal tissues including the small bowel, liver, spleen, kidney, lung, heart and brain. LD(50) for i.p. administration was compared with the LD(50) for i.v. administration. In subsequent experiments, animals were monitored for survival. The frequency of HSV-1 detection in peritoneal tumors was similar in mice randomized to either i.p. or i.v. administration. However, i.p. administration resulted in a more restricted systemic biodistribution, with a reduced frequency of virus detected in the kidney, lung and heart. The LD(50) associated with i.p. administration was higher than that with i.v. administration. Tumor burden was more effectively reduced with i.p. compared with i.v. administration. Median survival following i.p. administration was approximately twice that observed with i.v. administration. I.p. administration of an HSV-1 oncolytic mutant is associated with a more restricted biodistribution, less toxicity and greater efficacy against peritoneal metastases compared with i.v. administration.     

Experimental study of the prophylactic and therapeutic effects of venin on metastasis and recurrence of liver cancer

Objective To study the inhibitory effect of venin on adhesion and invasive ability of SMMC-7721 ceils and to examine the prophylactic and therapeutic effect of venin on liver cancer metastasis and recurrence after hepatectomy. Methods The blocking effect of venin on the intercellular adhesive molecule (ICAM-1) of 7721 cells was analyzed by irnmunofluorescence How cytometry. The influence of venin on the invasive ability of 7721 cells was observed by cell-migration experimentation and detachment of 7721 cells attached to fibronectin (FM), and the influence of venin on adhesion of 7721 cells to FN by the MTT method, 7721 ceils to 7721 cells, 7721 cells lo lymphocytes, and 7721 cells to endoihelial cells by a cellular adhesion test. The preventive and therapeutic eftect of venin on metastasis and recurrence of a liver cancer model was observed in nude mice alter hepatectomy. Results The expression of ICAM-1 in the venin-treated group was significantly lower than that in the untreated group. Venin could not inhibit the invasive ability of 7721 cells, and could not exfoliate the 7721 cells adhered to FN. It could inhibit the adhesion between 7721 cells and 7721 cells, and between 7721 and endothehal cells, but could not inhibit the adhesion between 7721 and lymphocytes. The nude mice treated with venin had less intrahepatic or extrahepatic metastases and recurrences after hepatectomy. Conclusion Venin can inhibit the adhesive ability of SMMC -7721 cells and can also prevent and treat the metastasis and recurrence of liver cancer in nude mice after hepalectomy.     

Experimental Study of the Prophylactic and Therapeutic Effects of Venin on Metastasis and Recurrence of Liver Cancer

OBJECTIVE To study the inhibitory effect of venin on adhesion and invasive ability of SMMC-7721 cells and to examine the prophylactic and therapeutic effect of venin on liver cancer metastasis and recurrence after hepatectomy.METHODS The blocking effect of venin on the intercellular adhesive molecule (ICAM-1) of 7721 cells was analyzed by immunofluorescence flow cytometry. The influence of venin on the invasive ability of 7721 cells was observed by cell-migration experimentation and detachment of 7721 cells attached to fibronectin (FN), and the influence of venin on adhesion of 7721 cells to FN by the MTT method, 7721 cells to 7721 cells, 7721 cells to lymphocytes, and 7721 cells to endothelial cells by a cellular adhesion test. The preventive and therapeutic effect of venin onmetastasis and recurrence of a liver cancer model was observed in nudemice after hepatectomy. RESULTS The expression of ICAM-1 in the venin-treated group was significantly lower than that in the untreated group. Venin could not inhibit the invasive ability of 7721 cells, and could not exfoliate the 7721 cells adhered to FN. It could inhibit the adhesion between 7721 cells and 7721 cells, and between 7721 and endothelial cells, but could not inhibit the adhesion between 7721 and lymphocytes. The nude mice treated with venin had less intrahepatic or extrahepatic metastases and recurrences after hepatectomy. CONCLUSION Venin can inhibit the adhesive ability of SMMC-7721 cells and can also prevent and treat the metastasis and recurrence of liver cancer in nude mice after hepatectomy.     

Experimental study of cancer metastasis

Chemotherapeutic assays, using nitrosoureas, performed on tumor bearing rats have shown a regression of local tumor, accompanied with an amplification of pulmonary metastases, demonstrating that the treatment of metastasis differs from the treatment of a local tumor. Cells organizing a tumor are heterogeneous for their drug resistance, and for a series of properties including their ability to form metastasis. Metastatic cells have to leave the tumoral tissue, to traverse biological barriers, to resist to immune system, to implant and growth in the target tissue. An experimental model has been used to characterize metastatic cells. Metastatic potential has been defined as the ability to invade lungs. Highly metastatic cloned cell lines, such as subline 6, were strongly stimulated to proliferate by EGF, expressed fibronectin, actively degraded the extracellular matrix, rapidly attached to endothelial vascular cells, and resisted to natural killer lymphocytes. Inversely, weakly metastatic lines, such as subline 8, were preferentially stimulated by FGF and EDGF, poorly expressed fibronectin, did not degrade extracellular matrix, slowly attached to vascular cells, and were killed by NK lymphocytes. Studies on a large series of clones showed a diversity between them, and that no one property was determinant. Modulation of these characters by growth factors, hormones and immune state of the host is discussed, and leads to conclude that the expression of metastatic potential of a tumor depends on genetically defined characters and also on influences excerted by the host.     

Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy

A new strategy currently under evaluation in patients with peritoneal carcinomatosis from gastrointestinal and gynecologic cancers is perioperative intraperitoneal chemotherapy. Although results to date show benefit to carefully selected groups of patients, continued local-regional failure is seen in many treated patients. Continued clinical and laboratory research efforts to improve local-regional effects are desired. The chemotherapeutic agents that have been used in the past or are currently being tested were reviewed. Their pharmacologic properties and clinical features were collected from the medical literature and are reviewed in the text. An organized presentation of available data concerning the drugs available for perioperative intraperitoneal chemotherapy for peritoneal surface malignancy was made. From this review, new possibilities for improved doses, schedules, and drug combinations for perioperative intraperitoneal chemotherapy may become important in future clinical studies. Continued optimal utilization of intraperitoneal chemotherapy treatments in the operating room with hyperthermia or normothermic treatment in the early postoperative period is desirable. Innovative treatment strategies can improve the outcome of patients with peritoneal surface malignancy.